September 2013
Volume 54, Issue 9
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Clinical Trials  |   September 2013
Hypotensive Effect of Latanoprost/Timolol Versus Travoprost/Timolol Fixed Combinations in NTG Patients: A Randomized, Multicenter, Crossover Clinical Trial
Author Affiliations & Notes
  • Takuhei Shoji
    Department of Ophthalmology, Saitama Medical University, Iruma, Saitama, Japan
    Department of Ophthalmology, Yukisada Hospital, Kawagoe, Saitama, Japan
  • Hiroki Sato
    Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan
  • Atsushi Mizukawa
    Department of Ophthalmology, Yukisada Hospital, Kawagoe, Saitama, Japan
  • Naoto Hirota
    Higashicho Eye Clinic, Tokorozawa, Saitama, Japan
  • Toshio Enoki
    Enoki Eye Clinic, Sayama, Saitama, Japan
  • Teruo Kojima
    Department of Ophthalmology, Yukisada Hospital, Kawagoe, Saitama, Japan
    Enoki Eye Clinic, Sayama, Saitama, Japan
  • Takayuki Kanda
    Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan
  • Masaru Takeuchi
    Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan
Investigative Ophthalmology & Visual Science September 2013, Vol.54, 6242-6247. doi:10.1167/iovs.13-11942
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      Takuhei Shoji, Hiroki Sato, Atsushi Mizukawa, Naoto Hirota, Toshio Enoki, Teruo Kojima, Takayuki Kanda, Masaru Takeuchi; Hypotensive Effect of Latanoprost/Timolol Versus Travoprost/Timolol Fixed Combinations in NTG Patients: A Randomized, Multicenter, Crossover Clinical Trial. Invest. Ophthalmol. Vis. Sci. 2013;54(9):6242-6247. doi: 10.1167/iovs.13-11942.

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Abstract

Purpose.: To compare the ocular hypotensive effect of travoprost plus timolol (TTFC) and latanoprost plus timolol fixed combinations (LTFC) in patients with normal-tension glaucoma (NTG).

Methods.: A two-sequence 12-week, multicenter, prospective, randomized, single-blinded, crossover clinical trial examined 59 NTG patients. If both eyes were eligible, only one eye (chosen at random) was used for analytical purposes. After a 12-week run-in period with dorzolamide plus timolol fixed combination (DTFC), patients were randomized into one of the two crossover sequences of treatment for 12 weeks with TTFC or LTFC and were subsequently crossed over to the alternative treatment for a further 12 weeks. The primary endpoint was reduction in IOP after 12 weeks of each treatment sequence. The effect of treatment on IOP was assessed using a linear mixed model.

Results.: The mean baseline IOP was 14.8 ± 3.3 mm Hg (95% confidence interval [CI], 14.1–15.3 mm Hg) for treatment with DTFC. The TTFC treatment period showed consistently lower mean IOP compared with LTFC treatment period at all measurement time points. Mean reduction in IOP at 12 weeks was significantly greater in the TTFC group than in the LTFC group (−2.4 ± 2.3 mm Hg vs. −1.1 ± 2.3 mm Hg; P = 0.021). No interaction between the drug and treatment sequence was detected. The effects of intraocular lens implantation and measurement time were also not significant. The tolerability profiles of both treatments were similar.

Conclusions.: The additional reduction in IOP was greater with TTFC than with LTFC, and their tolerability profiles were similar. ( http://www.umin.ac.jp/ctr/ number, UMIN 000005974.)

Introduction
Glaucoma is one of the main causes of blindness and irreversible deterioration of vision worldwide. 1 It affects approximately 70 million people and is the leading cause of irreversible blindness in approximately 10% of those affected. Approximately half of all patients with glaucoma live in East Asia. 2 The only treatment that can effectively prevent the development and progression of glaucoma is reduction of IOP. 3,4  
Normal-tension glaucoma (NTG) accounts for 92% of POAG in Japanese patients. 5 Normal-tension glaucoma is often used to describe patients with open-angle glaucoma when their untreated IOP is maintained within a statistically normal range. Multicenter clinical trials have confirmed the importance of reducing IOP in patients with POAG and NTG, 3,6 and lowering IOP reduces the risk of visual field progression from 13% to 19% per 1 mm Hg of IOP lowering. 7  
Monotherapy is frequently insufficient for reaching the preset target IOP. 8 When two drugs are required to control IOP, there are a number of potential advantages to using a fixed combination, including no risk of drug washout, 9 reduced exposure to preservatives, and ultimately better patient compliance and quality of life. 10 To our knowledge, few studies are available 11 that compare these fixed combinations in Asian patients, particularly those with NTG. Travoprost plus timolol (TTFC) and latanoprost plus timolol fixed combinations (LTFC) are prostaglandin/timolol fixed combinations medication currently available in Japan. Thus, the purpose of the present study was to compare the ocular hypotensive effect of LTFC and TTFC in glaucoma patients not fully controlled with monotherapy. 
Methods
The Ethics Committee of the National Defense Medical College approved this prospective, multicenter, randomized, crossover clinical trial, which was conducted in accordance with the tenets of the Declaration of Helsinki. This study is registered with the University Hospital Medical Information Network (UMIN) clinical trials registry, number UMIN 000005974. This study was conducted at four Japanese centers. Patients were included only if they were 20 years old or more, fulfilled the eligibility requirements detailed below, and signed an informed consent at the screening visit. 
Inclusion Criteria
To be eligible for the study, patients had to have been previously diagnosed with NTG that fulfilled the criteria as follows: (1) IOP consistently lower than 21 mm Hg, (2) characteristic glaucomatous optic nerve head damage such as notch and neuroretinal rim thinning, and glaucomatous loss of visual field in accordance with the criteria of Anderson and Patella, 12 (3) absence of a neurologic disorder that could affect the optic nerve and open iridocorneal angle, (4) normal chamber angle structure on gonioscopic examination, and (5) repeatable and progressive glaucomatous visual results using the Humphrey Field Analyzer (HFA; Carl Zeiss Meditec, Dublin, CA) and the standard 30-2 program of Swedish interactive threshold algorithm (SITA). 
Exclusion Criteria
Exclusion criteria were as follows: (1) visual acuity worse than 20/40, (2) having poor reliability on visual field analysis (>20% fixation loss and >15% false-positive or false-negative answers), (3) having high myopia or hyperopia (>6.0 diopters), (4) any other ophthalmic disease, including media opacity, diabetic retinopathy, or other diseases capable of causing visual field loss or optic nerve deterioration, (5) other diseases affecting the visual fields such as neuro-ophthalmologic diseases, uveitis, retinal or choroidal diseases and trauma, and (6) a history of intraocular surgery or laser treatment except for uncomplicated cataract surgery. Systemic exclusion criteria were as follows: (1) contraindications to treatment with β-blockers, (2) severe or uncontrolled cardiovascular, renal, or pulmonary disease that would preclude safe administration of a topical β-adrenergic antagonist, (3) prior myocardial infarction or stroke, (4) concomitant topical ocular medications that can interfere with study medications, (5) hypersensitivity to benzalkonium chloride (BAK) or to any other component of the trial drug solutions according to the investigator's judgment, and (6) participation in any other clinical trial within 6 months before this pretrial visit. 
Study Plan
Normal-tension glaucoma patients, who had been treated with monotherapy but continued to have a progressive visual field according to the investigator's judgment, and who required further IOP reduction, were enrolled in the study. Patients were checked for eligibility and scheduled for a run-in period of 12 weeks with dorzolamide plus timolol fixed combination (DTFC; CosoptRophthalmic solution; Santen Pharmaceutical, Japan, Tokyo) at the prescreening visit. It is ethically difficult to set the full washout period; patients treated with DTFC twice a day at 8 AM and 8 PM for more than 12 weeks were regarded as having the prostaglandin washout period. At the baseline visit, they were randomized at a ratio of 1:1 to one of the two crossover sequences to 12-week treatment with travoprost plus timolol (TTFC; Duotrav combination ophthalmic solution; Alcon Japan, Tokyo, Japan) or latanoprost plus timolol fixed combinations (LTFC; Xalacom combination eye drops; Pfizer Japan, Tokyo, Japan) (period 1) and were subsequently crossed over to the alternative treatment for 12 additional weeks (period 2) at a centrally located facility. We used a permuted block randomization procedure in which each block contained four assignments stratified by study site. Both groups were treated at 8 PM. There was no washout between the two treatments. Assessment of baseline data was performed before randomization, and assessment of IOP and tolerability was performed at baseline and then at 4, 12, 16 (4 weeks in period 2), and 24 weeks (12 weeks in period 2) after randomization. The investigator could choose to make a nonscheduled safety visit between the scheduled visits. At the baseline visit, patients' ophthalmic and systemic history and gonioscopy results were recorded, and standard automated achromatic perimetry was performed. A complete ophthalmologic examination including visual acuity and refraction as well as lid and slit-lamp examination was performed at baseline and every 12 weeks. Intraocular pressure was also measured by the same masked investigator using the same calibrated Goldmann tonometer from 10 AM to 11 PM or from 3 PM to 4 PM. If both eyes were eligible, only one eye (chosen at random) was used for analytical purposes. 
Study Endpoints
The primary endpoint was reduction of IOP after the 12-week treatment with LTFC or TTFC, and the secondary endpoint was the occurrence of adverse events related to ocular treatment between LTFC and TTFC. 
Assessment of Clinical Tolerability
Best-corrected visual acuity (BCVA) (decimal chart), biomicroscopy, and ophthalmoscopy were recorded at the pretrial visit and at each follow-up visit. Any adverse event was recorded. 
Statistical Analyses
Sample-size calculation was based on the primary endpoint of the study, IOP at 12 weeks. We estimated that 52 patients would be required for a 2-tailed α = 0.05 and a power of 80% to detect a mean difference of 1.4 mm Hg in IOP between TTFC and LTFC at 12 weeks. This assumed a standard deviation (SD) of 2.5 mm Hg. 13 Data are presented as mean and SD or median with interquartile range for continuous variables and as frequency with percentage for categorical variables. Baseline characteristics were summarized by treatment sequences and compared using an unpaired t test or the Wilcoxon rank sum test for continuous variables and χ2 test for categorical variables. The effect of treatment on IOP was assessed using a linear mixed model. Period and sequence were included in the model as fixed effects. Patients within a sequence were included in the model as a random effect. The model was adjusted for the presence or absence of IOL implantation and time of measurement (AM/PM). Tests for the conversion and period effects were also performed. 
For the IOP recordings, the mean value of two measurements at each time point (or the median of three readings if the first two were not within 2 mm Hg) was used in the calculations. 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. For all analyses, a two-sided P value of <0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.3 (SAS Institute, Inc., Cary, NC). 
Results
Patients
Figure 1 shows the procedure for selecting participants for this study. Eighty-two eyes of 82 patients were enrolled, 60 eyes were randomized and 59 eyes were included in the analysis. One participant treated with LTFC was lost to follow-up after randomization without performing any follow-up visits and was excluded from the IOP and tolerability analyses. Three patients were lost to follow-up after switching the second medication (one patient was LTFC treated and two patients were TTFC treated) and before the last follow-up visit. Within the intent-to-treat analysis, these three missing data, resulting from subject dropout, were imputed by carrying the last observation forward. Demographic variables and baseline characteristics were well balanced between the groups (Table 1). 
Figure 1
 
Flowchart of participant progress in this study.
Figure 1
 
Flowchart of participant progress in this study.
Table 1.
 
Baseline Characteristics
Table 1.
 
Baseline Characteristics
LTFC→TTFC Group, 29 Patients TTFC→LTFC Group, 30 Patients P Value
Male, eyes (%) 12 (41.4) 14 (46.6) 0.680*
Age, y 65.0 ± 12.1 67.5 ± 11.7 0.429†
MD value, dB −2.3 (−7.5, −0.8) −2.4 (−9.9, −1.1) 0.635‡
IOL, eyes (%) 19 (65.5) 22 (75.9) 0.387*
Measurement at night, eyes (%) 19 (65.5) 22 (75.9) 0.387*
IOP
The histograms shown in Figure 2 describe distribution of relative IOP reductions from baseline observed in each group after 12 weeks of treatment. The mean IOP at 4 weeks and 12 weeks was similar in each group and period. The mean IOP at all time point measurements was reduced compared with at baseline. Furthermore, TTFC treatment period had a consistently lower mean IOP compared with LTFC treatment period. Table 2 reports the mean IOP at baseline and after 12 weeks of treatment with either TTFC or LTFC. After 12 weeks of treatment, the reduction of the mean IOP from baseline was significantly greater in the TTFC treatment period ( −2.4 ± 2.3 mm Hg [95% confidence interval (CI), −2.8 to −1.9 mm Hg]) than in the LTFC treatment period (−1.1 ± 2.3 mm Hg [95% CI, −1.5 to −0.7 mm Hg]; P = 0.021). Tests for the carryover effect (P = 0.734) and period effect (P = 0.979) were not significant. The effects of IOL implantation (P = 0.122) and measurement time (P = 0.285) were also not significant. 
Figure 2
 
Mean change in IOP at each time of measurement.
Figure 2
 
Mean change in IOP at each time of measurement.
Table 2.
 
Comparison of Mean IOP mm Hg (95% CI)
Table 2.
 
Comparison of Mean IOP mm Hg (95% CI)
DTFC, Baseline LTFC TTFC
IOP, mm Hg 14.8 ± 3.3 13.8 ± 3.9 12.4 ± 2.90
ΔIOP from baseline, mm Hg 1.1 ± 1.3 −2.4 ± 1.3
P value* 0.143 <0.001
ΔIOP between LTFC and TTFC, mm Hg 1.4 ± 2.4
P value† 0.021
Adverse Events
No serious adverse events were identified during this study. Mild punctuate keratitis occurred in three patients (5.2%) receiving LTFC and in one patient receiving TTFC. Burning eye sensation occurred in three patients (3.4%) receiving LTFC, whereas in the TTFC-treatment period, one patient reported conjunctival hyperemia, one patient reported burning eye sensation, and one patient reported foreign body sensation. The incidence of adverse events was similar during both treatments. No changes in hypertrichosis from baseline were reported during either treatment (Table 3). 
Table 3.
 
Ocular Treatment-Related Adverse Events
Table 3.
 
Ocular Treatment-Related Adverse Events
Adverse Event, n (%) Latanoprost Plus Timolol Travoprost Plus Timolol P Value
Conjunctival hyperemia 0 1 (1.7) 1.000
Burning eye sensation 3 (5.1) 1 (1.7) 0.618
Foreign body sensation 0 1 (1.7) 1.000
Mild SPK 3 (5.1) 1 (1.7) 0.618
Hypertrichosis 1 (1.7) 1 (1.7) 1.000
Skin pigmentation 1 (1.7) 3 (5.1) 0.618
Discussion
The present randomized, multicenter study found that there was a statistically significant greater reduction of mean IOP after 12 weeks of treatment with TTFC compared with the LTFC treatment period in NTG patients previously treated with DTFC. To our knowledge, this is the first randomized study to compare TTFC, LTFC, and DTFC treatments in patients with NTG. The prevalence of NTG is higher among Asians, particularly Japanese and Chinese, than among blacks, whites, and Latinos. 14 East Asians account for approximately half of all glaucoma patients, and the management of glaucoma in East Asia has become a pressing issue. 15 However, randomized studies for the Asian population, especially NTG patients are still rare, although many comparative studies have been reported in Western countries. 16,17 Studies of TTFC were also limited in contrast to many studies of LTFC. 17 Moreover, the present randomized study used blinding, sample-size assessment, and intention-to-treat analysis, and received no financial support. These are additional strengths of this study because Cheng et al. recently indicated that many trials lacked these factors. 18  
In the present study, we found that treatment with TTFC was significantly superior to LTFC in lowering IOP. Despite the relatively low baseline IOPs (mean, 14.8 ± 3.3 mm Hg) with DTFC, both LTFC and TTFC were able to further reduce IOP after 12 weeks of treatment (−2.4 ± 2.3 mm Hg [95% CI, −2.8 to −1.9 mm Hg] and −1.1 ± 2.3 mm Hg [95% CI, −1.5 to −0.7 mm Hg]), respectively. Latanoprost plus timolol fixed combinations seemed to be more effective for NTG patients than DTFC in lowering mean IOP, which is comparable to recent meta-analysis. 18 Past clinical studies showed that TTFC is superior to LTFC or DTFC in lowering IOP. 1921 In contrast, other studies reported the opposite. 22,23 The reason for this discrepancy is unclear but might be explained by the design of future studies. In the present study, we conducted a crossover study because the effects of the antiglaucoma medications are reversible. Although the difference in lowering IOP was relatively small, the drug response in individual variability was widely spread. Because a crossover design can adjust for individual variability, it is more likely to detect a statistically significant difference compared with a parallel-group design. Another explanation is that only Japanese patients were included in this study. We are aware of only a limited number of antiglaucoma medication studies on Asian patients. 11 Ikeda et al. 24 reported that nonresponders to latanoprost are more frequently Japanese, particularly in low-baseline patients with IOP. Thus, these nonresponders may be the cause of the differences between these studies. 
The mean differences reported here in IOP between treatments with TTFC and LTFC or DTFC were 1.4 mm Hg and 2.4 mm Hg. Randomized trials show that lowering IOP with medical therapy slowed progression of optic disc and visual field damage in NTG or LTG. 4,6 The Early Manifest Glaucoma Trial (EMGT) shows that for every 1 mm Hg increase in pressure, there is a 12% to 13% increased likelihood of progression over 5 years even when the baseline IOP is <20 mm Hg. 7 Thus, we believe the present results are important for clinical practice. Moreover, there was no significant difference between the two treatment groups in the frequency of adverse events (P > 0.05). According to the past meta-analysis of randomized clinical trials, it has been described that conjunctival hyperemia occurs more frequently with travoprost than with latanoprost. 25 Recently, Aihara et al. reported that treatment with benzalkonium chloride (BAK)-free travoprost after BAK-preserved latanoprost decreased hyperemia in Japanese patients. 26 Travoprost plus timolol available in Japan was formulated in an ion-buffered system (sofZia; Alcon Laboratories, Fort Worth, TX) with borate, zinc, and sorbitol instead of BAK, which may explain the low number of patients with conjunctival hyperemia. The tolerability profiles for both fixed combinations were good, consistent with the results of others. 7,19,22  
One limitation of the present study is its relatively short duration (12 weeks) and the measurement of IOP at only two measurements at each time point (or the median of three readings if the first two were not within 2 mm Hg) at each visit. Although the difference in measurement time (AM or PM) was not significant in mixed-model analysis, others reported that travoprost was significantly more effective for reducing 24-hour IOP than latanoprost in other types of glaucoma (exfoliative glaucoma) patients. 21,27 Moreover, whereas past clinical randomized studies suggested that both LTFC and TTFC provided greater IOP reduction at evening dosing than at morning dosing, 28,29 the effect of time of dosing is not fully understood in NTG patients. In this study, all patients were administered both medications in the evening. Regarding DTFC dosing, the patients were told to instill the drugs at 8AM and 8PM. Recently, Kim et al. 30 reported that DTFC showed significant efficacy at 8 hours compared with trough time in Korean NTG patients. Thus, we expected that DTFC was effective in lowering IOP at the measuring time point. Further studies should evaluate long-term efficacy and tolerability more frequently. Also, though a washout design is valuable because it helps to temporally and physiologically isolate the experimental intervention, study designs involving medication-free intervals, including the washout phase at the beginning of trials, have become difficult for ethical reasons. The purpose of this study was to compare the hypotensive effect between two prostaglandin/timolol fixed combinations medications. The run-in period treated with DTFC was regarded as the prostaglandin-washout period. The lack of washout between treatment periods may be considered another limitation of this study. Nevertheless, the hypotensive effect was evaluated 12 weeks after randomization and 12 weeks after crossing over when any previous treatment was likely to be completely washed out. Another limitation is that the study population, which consisted entirely of Japanese patients, could have potentially restricted the external validity of our study. However, we believe that our stringent eligibility criteria, diagnostic methods, and the very few instances of incomplete data support its internal validity. 
In conclusion, this study suggests that compared with LTFC, TTFC reduced IOP to a greater extent and was similar in tolerability profile. Despite some limitations, this study is informative for the management of NTG and might be helpful in the future in subsequent investigations of hypotensive medications. 
Acknowledgments
The authors alone are responsible for the content and writing of the paper. 
Disclosure: T. Shoji, None; H. Sato, None; A. Mizukawa, None; N. Hirota, None; T. Enoki, None; T. Kojima, None; T. Kanda, None; M. Takeuchi, None 
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Figure 1
 
Flowchart of participant progress in this study.
Figure 1
 
Flowchart of participant progress in this study.
Figure 2
 
Mean change in IOP at each time of measurement.
Figure 2
 
Mean change in IOP at each time of measurement.
Table 1.
 
Baseline Characteristics
Table 1.
 
Baseline Characteristics
LTFC→TTFC Group, 29 Patients TTFC→LTFC Group, 30 Patients P Value
Male, eyes (%) 12 (41.4) 14 (46.6) 0.680*
Age, y 65.0 ± 12.1 67.5 ± 11.7 0.429†
MD value, dB −2.3 (−7.5, −0.8) −2.4 (−9.9, −1.1) 0.635‡
IOL, eyes (%) 19 (65.5) 22 (75.9) 0.387*
Measurement at night, eyes (%) 19 (65.5) 22 (75.9) 0.387*
Table 2.
 
Comparison of Mean IOP mm Hg (95% CI)
Table 2.
 
Comparison of Mean IOP mm Hg (95% CI)
DTFC, Baseline LTFC TTFC
IOP, mm Hg 14.8 ± 3.3 13.8 ± 3.9 12.4 ± 2.90
ΔIOP from baseline, mm Hg 1.1 ± 1.3 −2.4 ± 1.3
P value* 0.143 <0.001
ΔIOP between LTFC and TTFC, mm Hg 1.4 ± 2.4
P value† 0.021
Table 3.
 
Ocular Treatment-Related Adverse Events
Table 3.
 
Ocular Treatment-Related Adverse Events
Adverse Event, n (%) Latanoprost Plus Timolol Travoprost Plus Timolol P Value
Conjunctival hyperemia 0 1 (1.7) 1.000
Burning eye sensation 3 (5.1) 1 (1.7) 0.618
Foreign body sensation 0 1 (1.7) 1.000
Mild SPK 3 (5.1) 1 (1.7) 0.618
Hypertrichosis 1 (1.7) 1 (1.7) 1.000
Skin pigmentation 1 (1.7) 3 (5.1) 0.618
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