Randomized Multicenter Clinical Trial Comparing 0.1% Brimonidine/0.5% Timolol Versus 1% Dorzolamide/0.5% Timolol as Adjuncts to Prostaglandin Analogues: Aibeta Crossover Study.

INTRODUCTION: This multicenter, randomized, comparative, and investigator-masked crossover clinical trial sought to compare the efficacy and tolerability of fixed combinations of 0.1% brimonidine/0.5% timolol (BTFC) versus 1% dorzolamide/0.5% timolol (DTFC) as adjunctive therapies to prostaglandin analogues. METHODS: A total of 110 patients with open-angle glaucoma or ocular hypertension previously treated with prostaglandin analogue monotherapy were randomized to receive either BTFC or DTFC as adjunctive therapy for 8 weeks. These patients were then crossed over to the alternative treatment arm for another 8 weeks. The reduction in intraocular pressure (IOP) (primary outcome), occurrence of adverse events, ocular discomfort after instillation, and patient preference (secondary outcomes) were recorded through patient interviews. RESULTS: BTFC instillation for 8 weeks reduced IOP by 3.55 mmHg, demonstrating non-inferiority to DTFC instillation (3.60 mmHg; P < 0.0001, mixed-effects model). Although adverse events were rare with both combinations, patients reported greater discomfort with DTFC than with BTFC (P < 0.0001). More patients preferred BTFC (P < 0.0001) over DTFC, as BTFC caused minimal or no eye irritation. CONCLUSION: As BTFC offered better tolerability than DTFC with comparable reduction in IOP, we recommend it as an alternative for patients who experience ocular discomfort with DTFC-prostaglandin analogue combination therapy. TRIAL REGISTRATION NUMBER: jRCTs051190125.

Patients with glaucoma who require further reduction in intraocular pressure while undergoing monotherapy with prostaglandin analogue ophthalmic solution have been prescribed two enhanced treatment options: 0.1% brimonidine/0.5% timolol fixed combination ophthalmic solution (BTFC) and 1% dorzolamide/0.5% timolol fixed combination ophthalmic solution (DTFC). The Aibeta Crossover Study Group in Japan compared the efficacy and tolerability of fixed combinations of BTFC versus DTFC when an additional fixed combination ophthalmic solution was prescribed in patients with open-angle glaucoma or ocular hypertension who had been treated with prostaglandin analogue monotherapy. We recruited 110 patients previously treated with prostaglandin analogue monotherapy at 20 clinical centers in Japan, then randomly assigned them to two alternative treatment groups: the BTFC to DTFC group or the DTFC to BTFC group, as an adjunctive therapy to prostaglandin analogues for total of 16 weeks. We compared the reduction in intraocular pressure, occurrence of side effects, eye discomfort after instillation, and patient preference between BTFC versus DTFC instillations. The intraocular pressure reduction of BTFC instillation was comparable to that of DTFC instillation, showing non-inferiority to DTFC (3.55 mmHg vs. 3.60 mmHg; P < 0.0001, mixed-effects model). Both eye drops caused few side effects; however, patients felt greater eye discomfort with DTFC than with BTFC (P < 0.0001). Because of less eye irritation, more patients preferred BTFC (P < 0.0001) over DTFC. We can recommend using BTFC for patients who feel eye discomfort with DTFC­prostaglandin analogue combination therapy.

Phase 2b, Randomized, 3-Month, Dose-Finding Study of Sepetaprost in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: The ANGEL Study.

Purpose: This phase 2b, randomized, observer-masked, placebo- and active-controlled, parallel-group, multinational (USA and Japan), multicenter study (NCT03216902) assessed the optimal dose of sepetaprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension. Methods: After washout, patients ≥18 years (USA) or ≥20 years of age (Japan) received once-daily sepetaprost for 3 months [0.0005% (n = 43); 0.001% (n = 43); 0.002% (n = 44); and 0.003% (n = 45)], latanoprost 0.005% (n = 44) or placebo until week 6, followed by sepetaprost 0.003% until month 3 (n = 22). Safety assessments included adverse event (AE) occurrence. Results: Baseline mean diurnal intraocular pressure (IOP) was 24.3 mmHg for latanoprost and ranged between 24.1 and 24.5 mmHg for the sepetaprost groups. Sepetaprost 0.002% had the lowest IOP at each month 3 time point (9:00 AM; 1:00 PM; 5:00 PM) of all sepetaprost concentrations (mean ± standard error: 17.6 ± 0.5; 17.4 ± 0.4; 16.7 ± 0.4 mmHg); similar values were observed with latanoprost (18.1 ± 0.6; 17.3 ± 0.5; 17.2 ± 0.5 mmHg). A positive dose-response relationship was observed with the 3 lower sepetaprost doses; sepetaprost 0.002% had numerically greater IOP-lowering effects than sepetaprost 0.003%. All sepetaprost doses had statistically significantly greater IOP reductions from baseline versus placebo at week 6 (P < 0.0001). This IOP-lowering effect was consistent between Japan- and USA-based patients. Most AEs were mild and occurred numerically less frequently with sepetaprost 0.002% (34.1%) versus latanoprost (50.0%). The most frequently reported AE was conjunctival hyperemia. Conclusion: In this study, sepetaprost 0.002% was the optimal concentration, showing comparable IOP-lowering efficacy and safety with latanoprost 0.005%. Most AEs were mild; occurrence was numerically lower with sepetaprost 0.002% than latanoprost 0.005%.

Interim Results of Post-Marketing Observational Study of Omidenepag Isopropyl for Glaucoma and Ocular Hypertension in Japan.

INTRODUCTION: This post-marketing observational interim analysis evaluated the 12-month effectiveness and safety of omidenepag isopropyl (OMDI) ophthalmic solution in daily clinical settings. METHODS: This was a multicenter, large-scale, non-interventional, prospective, observational study conducted in Japan. The target enrollment was 3900 patients, and the overall observation period was 12 months. Patients with glaucoma and ocular hypertension (OH) with no previous history of OMDI use were enrolled. The key endpoints were change in intraocular pressure (IOP) from baseline and the incidence of adverse reactions (ADRs). RESULTS: A total of 1862 patients were evaluated in this 12-month interim analysis. Most patients were diagnosed with normal-tension glaucoma (NTG, 62.0%). The treatment patterns with OMDI were naïve monotherapy (48.4%), switching monotherapy (18.4%), and concomitant therapy (31.1%). The overall incidence of ADRs was 24.3%, which was similar between the monotherapy and concomitant therapy groups. Common ADRs were conjunctival hyperemia, refractive disorder, and myopia. Macular edema was observed in four patients. No ADRs categorized as prostaglandin-associated periorbitopathy were observed. There was a significant reduction in mean IOP at 12 months, with a change of - 1.9 ± 2.9 mmHg from baseline (reduction - 10.4 ± 16.5%). The mean IOP change from baseline was - 2.7 ± 2.6 mmHg in the naïve monotherapy group, - 1.1 ± 2.6 mmHg in the switching monotherapy group, and - 1.6 ± 3.1 mmHg in the concomitant therapy group (all P < 0.05). The mean IOP decreased by - 2.5 ± 3.2 mmHg, - 1.5 ± 2.4 mmHg, and - 2.3 ± 4.5 mmHg in the primary open-angle glaucoma (POAG), NTG, and OH groups, respectively. The treatment persistence with OMDI was 82.4%. CONCLUSION: This study demonstrated the safety and efficacy of OMDI for glaucoma and OH as monotherapy and concomitant therapy in daily clinical settings. In this interim analysis, OMDI showed a favorable benefit-risk profile, and can be first-line therapy for glaucoma.

Twelve-month efficacy and safety of glaucoma filtration device for surgery in patients with normal-tension glaucoma.

PURPOSE: To assess the efficacy and safety of filtration surgery using the EX-PRESS glaucoma filtration device in patients with normal-tension glaucoma (NTG). STUDY DESIGN: Prospective, single-arm, multicenter interventional case series. METHODS: Eyes with NTG underwent EX-PRESS implantation with or without cataract surgery. The efficacy and safety were assessed at 1 day; 1 and 2 weeks; and 1, 3, 6, and 12 months after surgery. The main outcome measure was reduction in intraocular pressure (IOP) from baseline at 3, 6, and 12 months after surgery. Safety assessments included adverse event incidence, postoperative inflammation, and corneal endothelial cell density. RESULTS: Thirty-two Japanese patients (37 eyes) with NTG were enrolled. The mean IOP decreased from 14.8 ± 2.3 mmHg at baseline to 10.0 ± 3.1 mmHg at 12 months after surgery (mean reduction 4.9 ± 4.2 mmHg [31.1%]; P < .0001). IOP-lowering medication use decreased from a mean of 3.3 medications per eye before surgery to 0.1 medications per eye at 12 months after surgery. IOP reductions > 20% were achieved by 61.5% of the eyes at 12 months. Adverse events were typical for filtration procedures, and none was deemed device-related. Postoperative inflammation was mild and self-limiting. The mean corneal endothelial cell density had decreased by 3.3% at 12 months after surgery. CONCLUSION: The EX-PRESS glaucoma filtration device is safe and effective for filtration surgery in patients with NTG, providing mean IOP reduction consistent with recommendations based on the Collaborative NTG Study.

Frequencies of 4 Distinct Patterns of Glaucomatous Disc Appearance and Their Clinical Associations in Japanese Population-based Studies.

PURPOSE: To study the frequencies and factors associated with 4 disc patterns in primary open-angle glaucoma (POAG) identified in population-based studies: focal glaucomatous (FG type), generalized enlargement of cup (GE type), myopic glaucomatous (MG type), and senile sclerotic glaucomatous (SS type) patterns. SUBJECTS: In total, 270 disc photographs of acceptable quality were extracted from the records of 270 definitive POAG cases diagnosed according to the International Society of Geographical and Epidemiological Ophthalmology Criteria in 2 Japanese population-based glaucoma surveys. One randomly chosen eye from the bilateral POAG cases was included. RESULTS: Using a method of κ coefficient of reproducibility of classification of 0.80 according to a preliminary study, 143 discs were classified as FG, GE, MG, or SS types with respective frequencies of 57% (95% confidence interval [CI], 48-66), 33% (95% CI, 25-42), 7% (95% CI, 3-13), and 3% (95% CI, 0-7), and 127 discs as the miscellaneous type. Multinomial logistic regression analysis showed that the MG type was associated (P=0.052, 0.025, 0.019, and 0.018) with younger age, lower body mass index (BMI), and greater disc area and ovality, and the GE type was associated (P<0.001, 0.036, and 0.056) with greater disc area, corneal radius, and hyperopic refraction than the FG type. CONCLUSIONS: The FG type occurs most frequently in Japanese POAG followed by the GE type. The MG and SS types occurred much less often than previously reported in Japanese. Associations with age, BMI, disc area and ovality, refraction, and corneal radius differed among the FG, GE, and MG types.

Correction to: Multicenter, Randomized, Controlled Study Comparing Tafluprost/Timolol Fixed Combination with Latanoprost/Timolol Fixed Combination in Primary Open-Angle Glaucoma and Ocular Hypertension.

In the original publication, the range to derive the P values is incorrectly represented in Table 2 and Table 3. The corrected tables are provided below.

Multicenter, Randomized, Controlled Study Comparing Tafluprost/Timolol Fixed Combination with Latanoprost/Timolol Fixed Combination in Primary Open-Angle Glaucoma and Ocular Hypertension.

INTRODUCTION: This was the first exploratory randomized controlled study to compare the efficacy and safety of a preserved tafluprost/timolol fixed combination (TAF/TIM) with a preserved latanoprost/timolol fixed combination (LAT/TIM). METHODS: This prospective, randomized, open-label study was conducted in Japanese patients with primary open-angle glaucoma, including normal-tension glaucoma or ocular hypertension. Following a 4-week LAT/TIM run-in period, eligible patients entered a 12-week treatment period, during which they received either LAT/TIM or TAF/TIM. The efficacy endpoint was the change in intraocular pressure (IOP) from baseline to week 12 and the safety endpoints included the changes from baseline to week 12 in superficial punctate keratopathy (SPK) score, tear breakup time (TBUT), and hyperemia score, as well as adverse events (AEs). At week 6, ocular symptoms were evaluated using a questionnaire. RESULTS: In total, 131 patients provided informed consent. Of these, 115 completed the run-in period and were assigned to receive TAF/TIM (n = 60) or LAT/TIM (n = 55). At week 12, there were no significant differences between the TAF/TIM and LAT/TIM groups in the change from baseline in trough IOP and IOP at 4-6 h after instillation. There were no significant differences between the two groups in the change from baseline to week 12 in SPK score, TBUT, and hyperemia score. However, only in the TAF/TIM group, the total SPK score and the inferior cornea SPK score were significantly lower at week 12 compared with baseline. Eye irritation and eye pain were significantly decreased in the TAF/TIM group compared with the LAT/TIM group. Two treatment-related AEs were reported in the TAF/TIM group (3.3%) and none in the LAT/TIM group, while no serious AEs were reported in either group. CONCLUSION: TAF/TIM is as effective as LAT/TIM in terms of IOP-reducing effect, with fewer ocular symptoms. TAF/TIM was associated with a significant improvement in SPK scores. TRIAL REGISTRATION: UMIN Clinical Trials Registry Identifier, UMIN000023862. FUNDING: Santen Pharmaceutical Co., Ltd., Osaka, Japan.

The clinical effectiveness of tafluprost on Japanese normal-tension glaucoma patients.

PURPOSE: This study evaluates the effect of tafluprost on visual field progression in normal-tension glaucoma (NTG) in a Japanese population under daily clinical practice settings. PATIENTS AND METHODS: This is a post-marketing, multicenter, non-interventional, observational study. Patients with NTG who initiated tafluprost treatment were registered and prospectively observed for 2-3 years to investigate its effectiveness on visual field progression and intraocular pressure (IOP) and safety in Japan. Visual field progression was evaluated using mean deviation (MD) slopes in a visual field analysis set that comprised patients with reliable Humphrey visual fields taken at 5 or more time points throughout the 2-3 years. RESULTS: Of the 1,454 patients registered from 160 medical institutions, 1,353 were set for safety analysis and 416 were set for visual field analysis. Due to insufficient effectiveness or safety reasons 194 patients discontinued tafluprost, and 388 patients discontinued tafluprost due to being lost to follow-up or another reason. The MD slopes were -0.09±0.85 dB/year in the entire visual field analysis set, -0.02±0.80 dB/year in naïve monotherapy patients, -0.07±0.68 dB/year in switching monotherapy patients, and -0.32±1.04 dB/year in concomitant therapy patients. In naïve monotherapy, a significant difference in MD slopes was observed between patients with an IOP reduction of 10% or higher (0.11±0.73 dB/year) vs patients with an IOP reduction of <10% (-0.22±0.87 dB/year). Significant differences were also observed in the subset analyses when the patients were divided by both MD and IOP at baseline, and presence of vitreoretinal concomitant disease. The adverse reactions were observed in 9.53% patients without any serious adverse reactions. CONCLUSION: An at least 10% IOP reduction with tafluprost monotherapy in 56.7% of the treatment-naïve NTG eyes was sufficient to significantly reduce the MD rate of progression.

Efficacy of predetermined therapeutic measures against bleb-related infection in the Collaborative Bleb-related Infection Incidence and Treatment Study.

PURPOSE: To report the efficacy of the predetermined treatment protocol of the Collaborative Bleb-related Infection Incidence and Treatment Study (CBIITS) for bleb-related infection (BRI) patients. METHODS: A prospective, observational cohort study was conducted at 34 clinical centres in Japan. Nineteen eyes from 19 patients that developed BRI were treated using the CBIITS protocol at 34 clinical centres. The visual acuity (VA) and intraocular pressure (IOP) were monitored for 6 and 12 months after treatment with the predetermined protocol. RESULTS: The logMAR was 0.623 ± 0.748 (mean ± standard deviation) before the infection developed. It was 1.054 ± 1.156 and 0.950 ± 1.168 at 6 months and 12 months post-infection, respectively. However, in subgroup analyses, there was no significant decrease in post-infection logMAR in stages I and II. In contrast, decimal VA was decreased ≥2 lines in all four cases in stage III. The IOP did not change after infection. It was 10.2 ± 5.0 mmHg (range, 3-22 mmHg) before the infection developed, and 12.9 ± 5.2 mmHg (5-24 mmHg) and 10.7 ± 4.7 mmHg (3-18 mmHg) at 6 months and 12 months after infection, respectively. CONCLUSION: Because of the small number of BRI patients, the superiority of the treatment was not definitively determined. However, VA was almost maintained in stages I and II, and the IOP did not change after infection. Although further study is necessary, the treatment protocol shown in the study might be a valuable treatment regime.

Evaluating the Quality of Life of Glaucoma Patients Using the State-Trait Anxiety Inventory.

PURPOSE: To evaluate anxiety felt by glaucoma patients. PATIENTS AND METHODS: In total, 472 glaucoma patients responded to a questionnaire on anxiety, subjective symptoms, and vision-related quality of life (VR-QOL) associated with glaucoma. Anxiety was evaluated using the State-Trait Anxiety Inventory (STAI), state anxiety (STAI-State) subscale along with our novel questionnaire, assessing visual function and subjective symptoms, specialized for glaucoma. VR-QOL was evaluated using 5 subitems from the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). Adherence to ophthalmic antiglaucoma agents was confirmed. As indexes of visual function, corrected visual acuity (measured by eye chart), mean deviation (MD) score (measured with static perimetry), and 4 thresholds at the center of vision were determined. Stages were classified according to the Aulhorn Classification. From the STAI-State scores, the prevalence of anxiety in glaucoma patients was evaluated. We analyzed the correlation between the STAI-State and VFQ-25, anxiety, subjective symptoms, adherence, and visual function indexes. RESULTS: In total, 78% of glaucoma patients experienced at least an intermediate level of anxiety. The STAI-State correlated significantly with anxiety and subjective symptoms as measured by our novel questionnaire, particularly for questions "current anxiety about loss of vision" and "current anxiety in life" (r=0.468 and 0.500; both P<0.0001). However, STAI-State correlated weakly with VFQ-25, and not at all with visual function indexes and adherence. CONCLUSIONS: Many glaucoma patients feel anxiety. The STAI-State is correlated with the VR-QOL and anxiety in glaucoma patients, making it useful for understanding the anxiety present in glaucoma patients.

Prospective Observational Post-Marketing Study of Tafluprost for Glaucoma and Ocular Hypertension: Effectiveness and Treatment Persistence.

INTRODUCTION: The aim of this study was to investigate the long-term intraocular pressure (IOP)-lowering effect and safety of tafluprost, a prostaglandin analogue, in actual clinical practice and to determine persistency of tafluprost as an indicator of its benefit-risk balance. METHODS: This was a large-scale, post-marketing, multicenter, non-interventional, open-label, long-term study. Patients with glaucoma or ocular hypertension who initiated tafluprost treatment were registered and prospectively observed over a 2-year period in the real-world setting in Japan. Long-term IOP and safety data were collected. RESULTS: Of the 4502 patients registered from 553 medical institutions, 4265 patients were analyzed. The majority of patients had normal-tension glaucoma (44.4%) and primary open-angle glaucoma (37.8%), and patients with ocular hypertension constituted 7.0%. Treatment patterns with tafluprost during the study period were as follows: naïve monotherapy (48.1%), switching monotherapy (18.4%), and concomitant therapy (33.5%). In all patients analyzed, mean IOP was significantly reduced from 18.6 ± 5.9 mmHg (month 0) to 15 mmHg or below throughout the 2-year observation period after initiation of tafluprost. Significant IOP-lowering effects were shown in various treatment patterns and disease types. Adverse reactions were observed in 795 patients (18.64%). Major adverse reactions included eyelid pigmentation, ocular hyperemia, eyelash changes, eyelid hypertrichosis, and iris hyperpigmentation. Kaplan-Meier curves showed that 84.6% and 76.1% of patients were persistent on tafluprost for 1 and 2 years, respectively, when discontinuation due to insufficient efficacy or adverse events was defined as a treatment failure event. Furthermore, among treatment-naïve patients (n = 2304), the persistency rates on tafluprost monotherapy were 77.0% for 1 year and 67.0% for 2 years. CONCLUSION: Tafluprost showed significant long-term IOP-lowering effects regardless of treatment patterns or diagnosis, with minimum safety concerns in the actual clinical practice. The observed treatment persistence suggests that tafluprost can be used long term owing to its benefit-risk profile. FUNDING: Santen Pharmaceutical Co., Ltd., Osaka, Japan.

Change in visual acuity and associated risk factors after trabeculectomy with adjunctive mitomycin C.

PURPOSE: To report the 5-year incidence of visual impairment after mitomycin C-augmented trabeculectomy (MMC trabeculectomy) and the risk factors for visual impairment. METHODS: This is a multicentre prospective observational cohort study. Among glaucoma patients registered in the Collaborative Bleb-related Infection Incidence and Treatment Study performed in Japan, the patients with eyes meeting the following qualifications were included: eyes with primary open-angle glaucoma; eyes with primary angle-closure glaucoma; eyes with exfoliative glaucoma; eyes with ≥3/60 in blindness analysis; and eyes with ≥20/60 in low-vision analysis and visual acuity loss analysis. The patients were followed at 6-month intervals for 5 years. The entry data and follow-up data were analysed to determine the incidence of blindness (<3/60), low vision (≥3/60 and <20/60) and visual acuity loss (≥0.2 logMAR) during the follow-up period. Risk factors for visual impairment were also analysed. RESULTS: A total of 694 eyes of 694 or 559 eyes of 559 glaucoma patients were subjected to the blindness analysis or the low-vision and visual acuity loss analysis, respectively. Visual acuity significantly deteriorated (p < 0.0001): 12.2% (95%CI: 9.8-14.7%) of the patients became blind; 12.1% (95%CI: 9.4-14.9%) were judged to have low vision at the final examination; 28.3% (95%CI: 24.5-32.0%) were judged to have visual acuity loss. Glaucoma subtypes, poor preoperative visual function and postoperative complications are the main risk factors for visual impairment. CONCLUSIONS: Visual acuity was significantly reduced after MMC trabeculectomy in 5 years, and we identified several risk factors associated with this complication.

One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertension.

PURPOSE: To investigate the intra-ocular pressure (IOP)-lowering effects and safety of 0.4% ripasudil (K-115), a Rho kinase inhibitor, twice daily for 52 weeks, in patients with open-angle glaucoma or ocular hypertension (OHT). METHODS: In this multicentre, prospective, open-label study, 388 patients with primary open-angle glaucoma, OHT or exfoliation glaucoma were enrolled and 354 of them were subdivided into four cohorts (monotherapy, 173; additive therapy to prostaglandin analogs, 62; ß-blockers, 60; or fixed combination drugs, 59). The IOP reduction at trough and peak from baseline and adverse events was investigated. RESULTS: Ripasudil showed IOP-lowering effects over 52 weeks in all the analyses of monotherapy, additive therapy and both subgroups (baseline IOP ≥21 mmHg and <21 mmHg) of monotherapy. The mean IOP reductions at trough and peak at week 52 were -2.6 and -3.7 mmHg for monotherapy, and -1.4 and -2.4, -2.2 and -3.0, and -1.7 and -1.7 mmHg, respectively, for additive therapy described above. The most frequently observed adverse events were conjunctival hyperaemia (n = 264, 74.6%), blepharitis (n = 73, 20.6%) and allergic conjunctivitis (n = 61, 17.2%). Most of the conjunctival hyperaemia findings were mild (97.0%), transient and resolved spontaneously (78.0%). Although 51 patients discontinued from the study due to blepharitis and/or allergic conjunctivitis (blepharitis, 28; allergic conjunctivitis, 17; both, 6), all the events resolved with or without treatment after the discontinuation of ripasudil administration. CONCLUSION: Fifty-two week administration of 0.4% ripasudil revealed IOP-lowering effects and an acceptable safety profile when administered as monotherapy or as additive therapy, in patients with open-angle glaucoma or OHT.

Evaluation of Quality of Life in Japanese Glaucoma Patients and its Relationship With Visual Function.

PURPOSE: We assessed vision-related quality of life (VR-QOL) in glaucoma patients and examined the relationship between VR-QOL and indices of visual function and subjective symptoms. PATIENTS AND METHODS: Four hundred seventy-two glaucoma patients completed a questionnaire concerning VR-QOL and subjective symptoms of glaucoma. VR-QOL was based on 5 subscales selected from the National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25), whereas subjective symptoms were examined using original questions that we prepared. The following were selected as visual function indices: corrected visual acuity measured with a distance visual acuity chart, mean deviation scores measured with a static perimeter, and 4 threshold levels in the innermost center of a visual field (4 pericentral test points). Disease staging was conducted according to the Aulhorn classification system. Correlations of visual function with VR-QOL were evaluated using the Spearman test. RESULTS: Correlations were observed in almost all subscales of the NEI VFQ-25, including correlations with corrected vision, disease stage, mean deviation score, and minimum threshold values of the 4-point pericentral test on the temporal side (P<0.0001). Visual function indices affecting driving differed between daytime and night driving (P<0.0001). NEI VFQ-25 subscales were correlated with subjective symptoms felt by the patients while driving (P<0.0001). CONCLUSIONS: Minimum threshold values of the 4 pericentral test points on the temporal side are useful for the assessment of VR-QOL. Minimum threshold values of the 4 pericentral test points on the temporal side are useful for assessing visual field abnormalities that are associated with decreased VR-QOL.

Changes in filtering bleb morphology after bleb-related infection.

PURPOSE: To verify, by use of data collected by the Japan Glaucoma Society Survey of Bleb-related Infection (JGSSBI), that bleb morphology changes within 12 months of the development of bleb-related infection. METHODS: JGSSBI data from 57 eyes of 57 patients with primary open-angle glaucoma and normal tension glaucoma who developed a bleb-related infection were analyzed. Morphological features of the blebs were graded by use of a predetermined grading system. Multiple logistic regression analysis was conducted to identify factors relating to bleb morphology which were associated with poor outcome. RESULTS: Bleb sizes, including both circumferential and tangential lengths, were significantly smaller for stage IIIa/IIIb infections than for stage I/II bleb infections (P = 0.009 and P = 0.026 for the circumferential and tangential lengths, respectively; Fisher's direct probability test). The bleb wall also became significantly thicker during stage IIIa/IIIb infections (P = 0.003). After infection, intraocular pressure (IOP) increased significantly for all cases but was no different in the three subgroups (i.e. stage I, stage II, and stage IIIa/IIIb bleb infections). Multiple logistic regression analysis revealed that a stage III infection was significantly associated with a poor outcome for the bleb. CONCLUSIONS: This study revealed that the filtering bleb became smaller, both tangentially and circumferentially, and thicker, after stage III infections than after stage I or II infections.

Additive Intraocular Pressure-Lowering Effects of the Rho Kinase Inhibitor Ripasudil (K-115) Combined With Timolol or Latanoprost: A Report of 2 Randomized Clinical Trials.

IMPORTANCE: Ripasudil hydrochloride hydrate (K-115), a novel rho kinase inhibitor, provides statistically significant intraocular pressure (IOP)-lowering effects and has a tolerable safety profile. However, no studies have evaluated ripasudil combined with ß-blockers and prostaglandin analogues. OBJECTIVE: To evaluate the additive IOP-lowering effects and the safety of ripasudil, 0.4%, combined with timolol, 0.5%, or latanoprost, 0.005%, in patients with primary open-angle glaucoma or ocular hypertension. DESIGN, SETTING, AND PARTICIPANTS: We conducted 2, multicenter, randomized, double-masked, parallel group comparison studies of ripasudil-timolol and ripasudil-latanoprost in 29 and 36 Japanese clinical centers, respectively. Analyses were performed on an intention-treat-treat basis. After appropriate run-in periods with timolol or latanoprost, 208 and 205 patients whose IOP levels were 18 mm Hg or higher were enrolled in the ripasudil-timolol and ripasudil-latanoprost groups, respectively. Enrollment began December 1, 2011, and follow-up was completed on September 7, 2012, in the ripasudil-timolol study. Enrollment began December 1, 2011, and follow-up was completed on September 27, 2012, in the ripasudil-latanoprost study. INTERVENTIONS: Patients were subdivided into 2 groups in each study and were treated with ripasudil or placebo twice daily for 8 weeks. MAIN OUTCOMES AND MEASURES: The IOP reductions in the ripasudil and placebo groups were analyzed with a repeated-measures analysis of variance model at weeks 4, 6, and 8, at trough (before instillation [9 am]) and peak (2 hours after instillation [11 am]) levels. RESULTS: In the ripasudil-timolol study, the mean IOP reductions from baseline in the ripasudil and placebo groups were -2.4 and -1.5 mm Hg at 9 am for a difference of 0.9 mm Hg (95% CI, 0.4-1.3 mm Hg; P < .001) and -2.9 and -1.3 mm Hg at 11 am for a difference of 1.6 mm Hg (95% CI, 1.1-2.1 mm Hg; P < .001), respectively. In the ripasudil-latanoprost study, those IOP reductions were -2.2 and -1.8 mm Hg at 9 am for a difference of 0.4 mm Hg (95% CI, -0.0 to 0.9 mm Hg; P = .06) and -3.2 and -1.8 mm Hg at 11 am for a difference of 1.4 mm Hg (95% CI, 0.9-1.9 mm Hg; P < .001), respectively. The most frequently reported adverse event was conjunctival hyperemia, which was mild and in most cases resolved without treatment before the next instillation. CONCLUSIONS AND RELEVANCE: These clinical trials found additive IOP-lowering effects of ripasudil from placebo at trough and peak levels in combination with timolol and at peak level in combination with latanoprost. However, a definitive difference in the addition of placebo to latanoprost was not identified in the trough level. TRIAL REGISTRATION: clinicaltrials.jp Identifiers: JAPIC111700 and JAPIC111701.

Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over 24 hours in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover study.

PURPOSE: To investigate the intra-ocular pressure (IOP)-lowering effects of a selective Rho kinase inhibitor, ripasudil (K-115), over 24 hr in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). METHODS: In this multicenter, prospective, randomized, open-label, 3-period, Latin-square crossover clinical study, 28 patients with POAG or OHT whose IOP level was 21 mmHg or higher were subdivided into three groups. Each patient was treated with placebo and ripasudil in concentrations of 0.2 and 0.4%, at 9:00 and 21:00 on day 1 through a total of 3 periods separated by washout periods. IOP was measured at 9:00, 10:00, 11:00, 13:00, 16:00, 19:00, 21:00, 22:00 and 23:00 on day 1, and 1:00, 4:00, 7:00 and 9:00 on day 2 in sitting position using Goldmann applanation tonometer. Main outcome measure was the IOP reduction of placebo and ripasudil from baseline. RESULTS: The mean IOP reduction was -5.2 mmHg for 0.2%, -6.4 mmHg for 0.4% and -2.0 mmHg for placebo at 2 hr after the first instillation. Also, the corresponding values were -6.8 mmHg for 0.2%, -7.3 mmHg for 0.4% and -4.1 mmHg for placebo at 2 hr after the second instillation. Statistically significant IOP reduction, compared with placebo, was found for both 0.2 and 0.4% from 1 through 7 hr after each instillation. In safety, conjunctival hyperaemia was observed in 22 patients (79%) for 0.2%, 27 patients (96%) for 0.4% and three patients (11%) for placebo. CONCLUSION: Ripasudil is a promising new topical medication to lower IOP for at least 7 hr after instillations in patients with POAG or OHT.

Fornix-based Trabeculectomy With Mitomycin C Using the Horizontal Conjunctival Suture Technique.

PURPOSE: The aim of this study was to determine the safety, efficacy, and bleb morphology of fornix-based trabeculectomy with mitomycin C using the horizontal suture technique. MATERIALS AND METHODS: A retrospective noncomparative case series of 79 eyes of 69 patients, who underwent fornix-based trabeculectomy with mitomycin C, was studied. Conjunctival closure of all eyes was with the horizontal suture technique using 10-0 nylon suture to prevent bleb leakage and improve bleb morphology posttrabeculectomy. The main outcome measures were the bleb morphology, outcome of surgery, and complications posttrabeculectomy. RESULTS: At a mean follow-up period of 25.5±9.3 months, 65 eyes (82.3%) had diffuse blebs with horizontal extent between 2 and 4 clock hours. Low-lying bleb was found in 35 eyes (44.3%), whereas 39 eyes (49.4%) had moderately elevated bleb. Fifty-one eyes (64.6%) had complete success, 18 eyes (22.8%) had qualified success, whereas 10 eyes (12.6%) were classified as treatment failures. Overall, 87.4% of the patients had a successful outcome. Corneal encroachment/overhanging blebs were found in 3 eyes (3.8%). Bleb leakage was found in 7 eyes (8.8%). There was overfiltration in 2 eyes (2.5%) with shallow anterior chamber. CONCLUSIONS: The horizontal suture technique is an easily applied, less time-consuming technique that gives excellent bleb morphology with few complications in the long term.

Blindness following bleb-related infection in open angle glaucoma.

PURPOSE: To estimate the risk of blindness following bleb-related infection after trabeculectomy with mitomycin C in open angle glaucoma, utilizing data obtained from two prospective multicenter studies. METHODS: The incidence of bleb-related infection in open angle glaucoma after the first or second glaucoma surgery was calculated using a Kaplan-Meier analysis and data from the Collaborative Bleb-related Infection Incidence and Treatment Study (CBIITS). The rate of blindness following bleb-related infection was calculated using data from the Japan Glaucoma Society Survey of Bleb-related Infection (JGSSBI). Finally, the rate of blindness following bleb-related infection after filtering surgery was estimated based on the above two data sets. Blindness was defined as an eye with a visual acuity of 0.04 or less. RESULTS: The incidences of development of bleb-related infection at 5 years were 2.6 ± 0.7 % (calculated cumulative incidence ± standard error) for all infections and 0.9 ± 0.4 % for endophthalmitis in all cases in the CBIITS data. The rates of blindness in the JGSSBI data were 14 % for the total cases with bleb-related infection and 30 % for the endophthalmitis subgroup. The rate of blindness developing within 5 years following trabeculectomy was estimated to be approximately 0.24-0.36 %. CONCLUSIONS: The rate of blindness following bleb-related infection within 5 years after trabeculectomy is considerable and thus careful consideration must be given to the indication for trabeculectomy and the selection of surgical techniques.

Prospective observational post-marketing study of tafluprost for glaucoma and ocular hypertension: short-term efficacy and safety.

INTRODUCTION: This study investigated the intraocular pressure (IOP)-lowering effects and safety of tafluprost ophthalmic solution 0.0015% in actual clinical practice. METHODS: We started a mandatory prospective 2-year observational study, which collected IOP, conjunctival hyperemia score, corneal staining score, and adverse event data from glaucoma and ocular hypertension (OH) patients not previously treated with tafluprost at 2, 12, and 24 months. This report analyzes the 2-month findings. RESULTS: Of the 4,180 patients from 553 medical institutions in Japan, most patients had primary open-angle glaucoma (POAG, 38.1%) or normal-tension glaucoma (NTG, 44.2%). After 2 months of tafluprost administration, IOP was significantly reduced by 4.3 ± 5.2 mmHg in POAG, 2.4 ± 2.5 mmHg in NTG, 3.6 ± 5.3 mmHg in primary angle-closure glaucoma, 5.6 ± 7.1 mmHg in other types of glaucoma, and 5.3 ± 4.8 mmHg in OH. IOP was significantly reduced by 4.3 ± 4.0 mmHg in the naïve monotherapy group, 1.9 ± 3.5 mmHg in switching from prior treatment, and 3.7 ± 4.1 mmHg in the add-on therapy group. Among patients switched, the prostaglandin analog (PGA) latanoprost was the previous predominant drug (57.4%), followed by travoprost (13.8%). Significant IOP reductions were observed by 1.5 ± 3.4 mmHg in switching from latanoprost and 1.3 ± 3.7 mmHg in switching from travoprost. The conjunctival hyperemia score peaked at 1 month in the naïve monotherapy and add-on therapy groups, whereas it was significantly decreased in patients switched from another PGA. The corneal staining score showed no particular changes. Incidence of adverse drug reaction (ADR) was 7.70 % (322/4,180 patients), and all major ADRs involved the eyes or skin around the eyes. CONCLUSION: Tafluprost showed significant IOP-lowering effects without any safety concerns in patients with various types of glaucoma and OH in daily clinical practice and tafluprost is highly effective in any therapeutic patterns.