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Figure 1.
Study Participants in Each Study
Study Participants in Each Study

Adverse event refers to any untoward medical occurrence without regard to use of given medications.

Figure 2.
Intraocular Pressure (IOP) Reduction From Baseline of Ripasudil and Placebo in Each Study
Intraocular Pressure (IOP) Reduction From Baseline of Ripasudil and Placebo in Each Study

Reduction of IOP at time-matched points with ripasudil and placebo at each week. Error bars indicate 95% CI.
aP < .05.
bP < .01.

Table 1.  
Patient Demographics of the Full Analysis Set in Each Studya
Patient Demographics of the Full Analysis Set in Each Studya
Table 2.  
Adverse Events and Adverse Drug Reactions in Each Studya
Adverse Events and Adverse Drug Reactions in Each Studya
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American Academy of Ophthalmology Preferred Practice Patterns Committee Glaucoma Panel. Preferred Practice Patterns: Primary Open-Angle Glaucoma. San Francisco, CA: American Academy of Ophthalmology; 2010.
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Honjo  M, Tanihara  H, Inatani  M,  et al.  Effects of rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility. Invest Ophthalmol Vis Sci. 2001;42(1):137-144.
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Isobe  T, Mizuno  K, Kaneko  Y, Ohta  M, Koide  T, Tanabe  S.  Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits. Curr Eye Res. 2014;39(8):813-822.
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Kameda  T, Inoue  T, Inatani  M,  et al.  The effect of rho-associated protein kinase inhibitor on monkey Schlemm’s canal endothelial cells. Invest Ophthalmol Vis Sci. 2012;53(6):3092-3103.
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Koga  T, Koga  T, Awai  M, Tsutsui  J, Yue  BY, Tanihara  H.  Rho-associated protein kinase inhibitor, Y-27632, induces alterations in adhesion, contraction and motility in cultured human trabecular meshwork cells. Exp Eye Res. 2006;82(3):362-370.
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Tanihara  H, Inoue  T, Yamamoto  T, Kuwayama  Y, Abe  H, Araie  M; K-115 Clinical Study Group.  Phase 1 clinical trials of a selective rho kinase inhibitor, K-115 [published correction appears in JAMA Ophthalmol. 2014;132(6):787]. JAMA Ophthalmol. 2013;131(10):1288-1295.
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Tanihara  H, Inoue  T, Yamamoto  T, Kuwayama  Y, Abe  H, Araie  M; K-115 Clinical Study Group.  Phase 2 randomized clinical study of a rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol. 2013;156(4):731-736.
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Tanna  AP, Rademaker  AW, Stewart  WC, Feldman  RM.  Meta-analysis of the efficacy and safety of α2-adrenergic agonists, β-adrenergic antagonists, and topical carbonic anhydrase inhibitors with prostaglandin analogs. Arch Ophthalmol. 2010;128(7):825-833.
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Kitazawa  Y, Araie  M; Research Group on MK-0507A.  Double-masked, phase III comparative study of the combination ophthalmic solution of the 1% dorzolamide hydrochloride/0.5% timolol maleate (MK-0507A) in patients with glaucoma and ocular hypertension [in Japanese]. Nihon Ganka Gakkai Zasshi. 2011;115(6):495-507.
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Original Investigation
Clinical Trial
July 2015

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

Author Affiliations
  • 1Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
  • 2Department of Ophthalmology, Gifu University Graduate School of Medicine, Gifu, Japan
  • 3Fukushima Eye Clinic, Osaka, Japan
  • 4Department of Orthoptics and Visual Sciences, Niigata University of Health and Welfare, Niigata, Japan
  • 5Kowa Company Ltd, Nagoya, Japan
  • 6The Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo, Japan
JAMA Ophthalmol. 2015;133(7):755-761. doi:10.1001/jamaophthalmol.2015.0525
Abstract

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 β-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

Introduction

Even though filtering surgery is more effective than medical therapy in lowering intraocular pressure (IOP),1 medical therapy is regarded as the most common initial intervention for the treatment of glaucoma if not contraindicated, and prostaglandin analogues and β-blockers are regarded as representative first-line drugs because of their potent IOP-lowering effects.2 Prostaglandin analogues and β-blockers lower IOP by increasing aqueous humor uveoscleral outflow and decreasing aqueous humor production, respectively.2 However, even with their use, the IOP of many patients is not adequately controlled because of adverse effects and/or nonresponse. Indeed, as indicated in the Ocular Hypertension Treatment Study,3 a number of patients required 2 or more medications to reach their target IOPs. Because of this, development of new antiglaucoma drugs with novel IOP-lowering mechanisms is strongly needed.

Some investigators have reported that rho kinase inhibitors lower IOP by modulating the actin cytoskeleton and altering the conventional outflow of aqueous humor, which is different from the currently used IOP-lowering drugs.48 Our previous phase 1 and phase 2 clinical trials found that monotherapy with ripasudil hydrochloride hydrate (K-115), a novel rho kinase inhibitor, provides significant IOP-lowering effects and has a tolerable safety profile in patients with primary open-angle glaucoma (POAG) and ocular hypertension (OHT).9,10 However, additive effects and safety of this novel IOP-lowering drug have not been examined, especially in combination with representative first-line drugs for the treatment of glaucoma. In this article, we report the additive IOP-lowering effects of ripasudil, 0.4%, in combination with timolol, 0.5%, or latanoprost, 0.005%.

Methods

We conducted 56-day, multicenter, randomized, placebo-controlled, double-masked, parallel group comparison studies at 29 Japanese clinical centers in the ripasudil-timolol study and at 36 Japanese clinical centers in the ripasudil-latanoprost study. Each study was designed and conducted in accordance with the principles of the Declaration of Helsinki. Institutional review board approval was obtained from the institutional review boards of each center in each study. In both studies, candidates received complete information regarding the study protocol, and written informed consent was obtained from each participant before entry to the studies. The trial protocols can be found in the Supplement.

Inclusion criteria were as follows: men or women with POAG or OHT, age of 20 years or older, IOP after run-in periods (treated with timolol, 0.5%, twice daily or latanoprost, 0.005%, once daily for ≥4 weeks) of 18 mm Hg or higher, IOP difference within 3 mm Hg in at least 1 eye at 2 eligibility visits (9 am) 2 to 14 days apart, and treated IOP of less than 35 mm Hg in both eyes. Patients with narrow angles defined as grade 2 or less by the Shaffer classification by gonioscopy or who had undergone ocular surgery (other than cataract surgery >1 year ago, retinal laser treatment or Nd:YAG laser posterior capsulotomy >90 days ago, and eyelid surgery >120 days ago) in either eye were excluded from the study. Patients with severe visual field defects or a corrected visual acuity of worse than 20/70 in either eye also were excluded. During the study, patients were prohibited from receiving other IOP-lowering agents, receiving any ophthalmic agents (excluding artificial tears) or corticosteroids, wearing contact lenses, and changing dosages of any concomitant systemic medications that may affect IOP.

In the ripasudil-timolol and ripasudil-latanoprost studies, the run-in period (with instillation of timolol or latanoprost alone) was 4 weeks or more. The IOPs for eligibility were measured (9 am) at 2 separate visits (another run-in period, 2-14 days apart), and the IOPs (obtained at 9 and 11 am) for the second visit (week 0) were used as the baseline. In both studies, patients who fulfilled these criteria were assigned randomly to 2 groups and were treated with ripasudil, 0.4%, or placebo (in addition to timolol, 0.5%, or latanoprost, 0.005%, therapy), according to the permuted blocks method, which treated clinical sites as strata. The block size was 4, and the allocation ratio of the 2 groups was 1:1; site investigators were not informed about the block size throughout the study period. Vehicle was used as the placebo, and the bottles for the ripasudil and placebo groups were indistinguishable. After randomization, 1 drop of study drug was instilled into each eye twice daily at 9 am and 9 pm for 8 weeks. The IOP reduction and the incidence of adverse events by ripasudil or placebo from baseline were investigated. The IOP was measured with Goldmann tonometry every 2 weeks before instillation (9 am) and 2 hours after instillation (11 am).

To evaluate the safety of ripasudil, ophthalmologic findings and physiologic parameters were examined, and adverse events were collected during the studies. The palpebral and bulbar conjunctiva, cornea, anterior chamber, iris, and lens were examined with slitlamp microscopy during the studies. Other ocular examinations, including visual acuity, ocular fundus examination, and visual field, were conducted. Duration of conjunctival hyperemia was evaluated as transient (appeared after twice-daily instillation of ripasudil or placebo and spontaneously resolved within <12 hours) or not transient.

One eye per patient (the one with greater IOP at baseline) was included in the efficacy analysis of these studies. If the IOPs were the same, the right eye was chosen as the study eye. The primary efficacy analysis set was defined as the full analysis set. The changes in IOP at weeks 4, 6, and 8 from baseline (week 0) at time-matched points (9 and 11 am) were calculated as the primary efficacy end points. The repeated-measures analysis of variance model, including terms for group and visit points (weeks 4, 6, and 8), was applied to the change in IOP data as the primary analysis for each time point (9 and 11 am), then the least squares means of 2 groups were compared. Multiplicity of 2 time points was adjusted by defining significance as only when the results of the primary analysis for 2 time points were significant. Secondary end points were the change in IOP at weeks 2, 4, 6, and 8 from baseline (week 0) at time-matched points (9 and 11 am). Secondary efficacy analyses were as follows: the same model as the primary analysis with the visit points of weeks 2, 4, 6, and 8 and 2-sample t test for the value before instillation and 2 hours after instillation at weeks 2, 4, 6, and 8. In the ripasudil-latanoprost study, the repeated-measures analysis of covariance model, including terms for group and visit points (weeks 4, 6, and 8) and baseline IOP, was applied to the change in IOP data before instillation (9 am) for additional analysis. Adverse events, adverse drug reactions, ophthalmologic findings except IOP, blood pressure, pulse rate, and hematologic and biochemical tests were used for safety assessments.

Sample size estimation was calculated based on the results of the phase 2 study.10 The repeated-measures analysis of variance model, including terms for group (placebo and ripasudil in concentrations of 0.1%, 0.2%, and 0.4%), visit points (week 4, 6, and 8), time points (9 and 11 am), and interaction between group and time point, was applied to the change in IOP data from baseline. The differences of the least squares means between the 0.4% ripasudil and placebo groups for 2 time points (9 and 11 am) were estimated to be −1.20 and −2.17 mm Hg, respectively. The between- and within-subject variances were estimated to be 2.01 and 2.26 mm Hg, respectively. In the ripasudil-timolol and ripasudil-latanoprost studies, the mean difference estimates between the 2 groups were −1 and −2 mm Hg for 2 time points (9 and 11 am), respectively, and both between- and within-subject variances were conservatively set to 3. From these estimation results, 85 individuals per group were required to achieve the 90% power of the primary analysis for both studies. The sample sizes were determined to be 100 individuals per group, taking dropouts into account for both studies.

All statistical analyses were performed with SAS statistical software, version 9.2 (SAS Institute Inc), at Kowa Company Ltd. The level of significance was .05 (2-sided). All patients, physicians, and technicians were masked to treatment assignment during the study period.

Results

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. In these phase 3 clinical studies, patients with POAG or OHT were enrolled. Patients who fulfilled the eligibility criteria were subdivided randomly into a ripasudil, 0.4%, group and a placebo group. 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. All the patients, including patients who discontinued the study after randomization, were subjected to the analyses on efficacy and safety with the full analysis set (Figure 1). Masking was maintained throughout the study period.

The baseline characteristics of the included population and their eye complications are given in Table 1. The mean (SD) baseline IOP at 9 am for the full analysis set population was 19.8 (1.8) mm Hg and 19.8 (1.9) mm Hg, respectively, in the ripasudil-timolol and ripasudil-latanoprost studies.

Reductions in IOP at trough and peak levels from baseline in each week are shown in Figure 2. 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 before instillation (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 2 hours after instillation (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, the mean IOP reductions from baseline in the ripasudil and placebo groups 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. These IOP differences between the ripasudil and placebo groups were statistically significant in the ripasudil-timolol study; however, confidence that there were differences in the ripasudil-latanoprost study was not identified.

In the ripasudil-latanoprost study, disproportionate baseline IOPs between the 2 groups did not affect (P = .96) the estimation of drug efficacy (−0.4 mm Hg) by the repeated-measures analysis of covariance model with each baseline IOP as a covariate. In the secondary efficacy end point, which adds the time points at week 2 to the primary efficacy end point, the mean IOP reductions were −2.1 mm Hg from baseline and −1.7 mm Hg before instillation, and these IOP differences between the ripasudil and placebo groups revealed a further IOP reduction of 0.4 mm Hg (95% CI, 0.0-0.8 mm Hg; P = .048).

Table 2 lists the adverse events observed in more than 1 patient in each group of studies. The most frequent adverse event was conjunctival hyperemia, with incidence rates of 65.4% and 55.9%, respectively, in the ripasudil-timolol and ripasudil-latanoprost studies. In almost all cases, the investigators assessed hyperemia as study drug related. Even though these findings recurred after each instillation, the hyperemia was mild in all cases. In addition, the hyperemia resolved before the next instillation in most cases. In the ripasudil-timolol study, 6 (5.8%) of 104 patients had transient hyperemia and none had nontransient hyperemia in the placebo group, and 66 (63.5%) of 104 had transient hyperemia and 2 (1.9%) of 104 had nontransient hyperemia in the ripasudil group. In the ripasudil-latanoprost study, 2 (1.9%) of 103 had transient hyperemia and 7 (6.8%) of 103 had nontransient hyperemia in the placebo group, and 53 (52.0%) of 102 had transient hyperemia and 4 (3.9%) of 102 had nontransient hyperemia in the ripasudil group. No additional medical treatments were required for this adverse event. The adverse events that led to discontinuation from the study were bile duct stone, increased IOP, and asthma in the ripasudil-timolol study and increased IOP in the ripasudil-latanoprost study; all these events were reported in the placebo groups. Conjunctival hemorrhage was observed in 1 (1.0%) of 104 patients in the placebo group in the ripasudil-timolol study and 1 (1.0%) of 103 patients in the placebo group in the ripasudil-latanoprost study. No clinically meaningful changes were found in the results of ocular examinations (except for conjunctival hyperemia), blood pressure, pulse rate, or any other general conditions, including hematologic and biochemical tests.

Discussion

In this series of phase 3 clinical studies for ripasudil, a novel rho kinase inhibitor, our results revealed significant IOP-lowering effects in patients with POAG and OHT. On the basis of our previous results in the phase 2 study,10 ripasudil is expected to be an effective additive therapy with β-blockers and/or prostaglandin analogues; therefore, we conducted studies of ripasudil in combination with timolol and latanoprost. The mean IOP reductions from baseline at trough and peak (2 hours after instillation) levels were −2.4 and −2.9 mm Hg and −2.2 and −3.2 mm Hg, respectively, in the ripasudil-timolol and ripasudil-latanoprost groups. In the placebo-controlled comparison study, primary efficacy analyses revealed significant IOP reduction at peak and trough levels in both combination groups (P < .001), except for the trough level in the ripasudil-latanoprost group (P = .06). However, secondary efficacy analysis, including week 2 data in addition to other time points, suggested the presence of IOP-lowering effects even at trough level in the ripasudil-latanoprost group (P = .048). A meta-analysis of the efficacy of commonly used antiglaucoma medications revealed that the additive IOP reduction to prostaglandin analogues was −2.01 and −3.16 mm Hg for brimonidine, −3.12 and −2.51 mm Hg for β-blockers, and −2.98 and −2.68 mm Hg for topical carbonic anhydrase inhibitors, respectively, at trough and peak levels.11 In addition, in another clinical study of Japanese patients with POAG or OHT, Kitazawa and Araie12 reported that the mean additive IOP reduction at peak level for timolol was −2.78 mm Hg from baseline after the instillation of 1% dorzolamide hydrochloride. Thus, from the viewpoint of additive IOP reduction, ripasudil, 0.4%, is equal to other second-line drugs in combination with latanoprost or timolol.

Previous preclinical studies5,8 found that the IOP-lowering mechanism of rho kinase inhibitors is related to improvement in the conventional aqueous outflow pathway. In addition, with the use of in vitro experiments using cultured trabecular meshwork and Schlemm canal endothelial cells, cytoskeletal redistribution and changes in cell-cell interactions in trabecular meshwork and Schlemm canal endothelial cells have been reported.4,6,13 Ripasudil has selective rho kinase inhibitory effects and IOP-lowering and outflow facility–increasing effects in animal eyes.5 Because these mechanisms of rho kinase inhibitors (including ripasudil) are different from the known IOP-lowering mechanisms for other antiglaucoma medications, additive IOP-lowering effects had been expected. From our data in the present series of phase 3 clinical studies, we conclude that ripasudil is effective in IOP reduction as an additive therapy with first-line drugs, such as prostaglandin analogues and β-blockers.

Although the incidences of conjunctival hyperemia are high in the present phase 3 studies, as has been seen in the phase 1 and phase 2 studies,9,10 addition of ripasudil to first-line drugs did not increase the incidence of conjunctival hyperemia. Furthermore, conjunctival hyperemia was mild and resolved before the next instillation. Although the exact time of the resolution of the conjunctival hyperemia was not monitored in the current studies, our phase 1 studies indicate that they resolved without treatment within several hours. From these observations, it was suggested that the occurrence of hyperemia did not prevent clinical use of ripasudil even in additive studies. We hypothesize that the occurrence of ocular hyperemia is caused by smooth muscle relaxation of the blood vessels, which is a reflection of the vasodilatory effects of rho kinase inhibitors.4,14 A variety of adverse drug reactions, such as iris pigmentation, increased eyelash growth caused by prostaglandin analogues, and cardiovascular disorder and chronic obstructive pulmonary disease caused by β-blockers,2 were not observed in our 8-week phase 3 clinical studies; therefore, ripasudil may have the potential advantages as a second-line medication in patients with glaucoma and OHT who are experiencing such adverse drug reactions.

In our present phase 3 studies, we confirmed the efficacy and safety of 8-week administration of ripasudil in Japanese patients with moderately elevated IOP. Long-term studies, studies in patients with more elevated IOP, and studies in non-Japanese populations are planned to better understand the effect of ripasudil treatment.

Conclusions

Our present series of phase 3 clinical studies 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, although a definitive difference at the trough level with latanoprost was not identified in the primary efficacy end point. Regarding safety, the most common adverse event was conjunctival hyperemia, and no new concerns were observed when ripasudil was combined with timolol or latanoprost.

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Article Information

Submitted for Publication: September 9, 2014; final revision received January 23, 2015; accepted January 31, 2015.

Corresponding Author: Hidenobu Tanihara, MD, Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto-city, Kumamoto 860-8556, Japan (tanihara@pearl.ocn.ne.jp).

Published Online: April 16, 2015. doi:10.1001/jamaophthalmol.2015.0525.

Author Contributions: Dr Suganami had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Tanihara, Yamamoto, Kuwayama, Abe, Suganami, Araie.

Acquisition, analysis, or interpretation of data: Tanihara, Inoue, Yamamoto, Kuwayama, Abe, Suganami.

Drafting of the manuscript: Tanihara, Suganami.

Critical revision of the manuscript for important intellectual content: Inoue, Yamamoto, Kuwayama, Abe, Suganami, Araie.

Statistical analysis: Inoue, Suganami.

Administrative, technical, or material support: Yamamoto.

Study supervision: All authors.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Tanihara reported receiving consulting fees from Kowa and MSD and board membership fees from Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, and Pfizer Japan. Dr Yamamoto reported receiving consulting fees from Kowa, MSD, and Otsuka Pharmaceutical; board membership fees from Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, and Pfizer Japan; and lecture fees from Alcon Japan, Kowa, MSD, Otsuka Pharmaceutical, Pfizer Japan, Santen Pharmaceutical, and Senju Pharmaceutical. Dr Kuwayama reported receiving consulting fees from Kowa, MSD, and Bausch & Lomb Japan; board membership fees from Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, and Pfizer Japan; and lecture fees from Otsuka Pharmaceutical. Dr Abe reported receiving consulting fees from Kowa and board membership fees from Alcon Japan and Pfizer Japan. Dr Suganami reported being an employee of Kowa. Dr Araie reported receiving consulting fees from Kowa, MSD, Topcon, Allergan Japan, Bausch & Lomb Japan, and Heidelberg Japan; board membership fees from Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, and Pfizer Japan; and lecture fees from Carl Zeiss Japan, Otsuka Pharmaceutical, Nitten Pharmaceutical, JFC, Alcon Japan, Santen Pharmaceutical, and MSD and having patents with Topcon. No other disclosures were reported.

Funding/Support: This study was sponsored by Kowa Company Ltd, Nagoya, Japan.

Role of the Funder/Sponsor: The funding source participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

K-115 Clinical Study Group:Steering and Writing Committee Members: Hidenobu Tanihara, Makoto Araie, Tetsuya Yamamoto, Yasuaki Kuwayama, Haruki Abe, Toshihiro Inoue, and Hideki Suganami. Ripasudil-Timolol Study Investigators: Misato Adachi, Eye Rose Clinic, Chiyoda, Tokyo; Sachi Amaki Kobayashi, Amaki Clinic, Minato, Tokyo; Takuji Kato, Dogenzaka Kato Eye Clinic, Shibuya, Tokyo; Keiji Yoshikawa, Yoshikawa Eye Clinic, Machida, Tokyo; Isao Sato, Wakabadai Eye Clinic, Inagi, Tokyo; Hideyo Shin, Ohguchi Ophthalmic Clinic, Yokohama, Kanagawa; Miyuki Sugita, Maita Eye Clinic, Yokohama, Kanagawa; Kiichiro Mitani, Mitani Eye Clinic, Ebina, Kanagawa; Masatada Mitsuhashi, Mitsuhashi Eye Clinic, Narashino, Chiba; Toshiro Itoga, Ibaraki Seinan Medical Center Hospital, Sashima, Ibaraki; Yuko Asai, Iida Hospital, Iida, Nagano; Junji Ono, Ono Ophthalmic Clinic, Numadu, Shizuoka; Tomoyuki Muramatsu, Muramatsu Eye Clinic, Susono, Shizuoka; Toru Nakajima, Nakajima Eye Clinic, Fuji, Shizuoka; Hisayoshi Namba, Namba Eye Clinic, Shizuoka, Shizuoka; Kenichi Takahashi, Takahashi Eye Clinic, Ichinomiya, Aichi; Isao Saito, Kitano Hospital The Tazuke Kofukai Medical Research Institute, Osaka, Osaka; Nami Okamoto, Seiichiro Fujii, Nishi Eye Hospital, Osaka, Osaka; Hidetaka Maeda, Maeda Eye Clinic, Osaka, Osaka; Torao Sugiura, Sugiura Eye Clinic, Osaka, Osaka; Etsuo Chihara, Sensho-Kai Eye Institute, Uji, Kyoto; Koji Taguchi, Kobe Kaisei Hospital, Kobe, Hyogo; Makiko Wakuta, Ube Industries Central Hospital, Ube, Yamaguchi; Makoto Shirao, Shirao Eye Clinic, Kurume, Fukuoka; Tsutomu Kawasaki, Ideta Eye Hospital, Kumamoto, Kumamoto; Masayoshi Migita, Migita Eye Institute, Beppu, Oita; Shoichi Sawaguchi, Hospital, University of the Ryukyus, Nakagami, Okinawa; Setsuko Hashida, Hashida Eye Clinic, Shinagawa, Tokyo; Kazuaki Nishino, Kaimeidoh Ophthalmic & Dental Clinic, Sapporo, Hokkaido. Ripasudil-Latanoprost Study Investigators: Akira Takeda, Nakanoshima Takeda Eye Clinic, Sapporo, Hokkaido; Kenji Inoue, Ryoko Okayama, Ochanomizu Inouye Eye Clinic, Chiyoda, Tokyo; Makoto Aihara, Chihiro Mayama, The University of Tokyo Hospital, Bunkyo, Tokyo; Hiroshi Matsuo, Matsuo Eye Clinic, Kita, Tokyo; Tamotsu Seki, Tamagawa Eye Clinic, Ota, Tokyo; Yoshinori Takahashi, Tachikawadori Clinic, Tachikawa, Tokyo; Kiichiro Mitani, Mitani Eye Clinic, Ebina, Kanagawa; Yasuo Niwa, Niwa Eye Clinic, Matsudo, Chiba; Hidehito Kawabata, Kawabata Eye Clinic, Urayasu, Chiba; Masaki Sato, Mito Kyodo General Hospital, Mito, Ibaraki; Tomohiro Otsuki, Kozawa Eye Hospital, Mito, Ibaraki; Naoki Hayashi, Hayashi Eye Clinic, Kumagaya, Saitama; Tomoyuki Muramatsu, Muramatsu Eye Clinic, Susono, Shizuoka; Toru Nakajima, Nakajima Eye Clinic, Fuji, Shizuoka; Hisayoshi Namba, Namba Eye Clinic, Shizuoka, Shizuoka; Takayuki Terui, Toshiya Asano, Japan Labour Health and Welfare Organization Chubu Rosai Hospital, Nagoya, Aichi; Kazuhide Kawase, Gifu University Hospital, Gifu, Gifu; Keiji Sugasawa, Sugasawa Eye Clinic, Osaka, Osaka; Nami Okamoto, Seiichiro Fujii, Nishi Eye Hospital, Osaka, Osaka; Hidetaka Maeda, Maeda Eye Clinic, Osaka, Osaka; Jun Kozaki, Kozaki Eye Clinic, Osaka, Osaka; Torao Sugiura, Sugiura Eye Clinic, Osaka, Osaka; Kiyoshi Kano, Fukushima Eye Clinic, Osaka, Osaka; Akiyasu Kanamori, Kobe University Hospital, Kobe, Hyogo; Kazuko Hijikuro, Nagata Eye Clinic, Kobe, Hyogo; Emiko Tani, Tani Eye Clinic, Kobe, Hyogo; Takashi Kanamoto, Hiroshima University Hospital, Hiroshima, Hiroshima; Toshihiro Inoue, Kumamoto University Hospital, Kumamoto, Kumamoto; Masayoshi Migita, Migita Eye Institute, Beppu, Oita; Kazuhiko Unoki, Unoki Eye Clinic, Kagoshima, Kagoshima; Shoichi Sawaguchi, Hospital, University of the Ryukyus, Nakagami, Okinawa; Kazuhisa Sugiyama, Kanazawa University Hospital, Kanazawa, Ishikawa; Toru Nakazawa, Tohoku University Hospital, Sendai, Miyagi; Yuichi Inamoto, Inamoto Eye Clinic, Osaka, Osaka; Kenji Matsushita, Osaka University Hospital, Osaka, Osaka; Shinki Chin, Hokkaido University Hospital, Sapporo, Hokkaido.

Previous Presentation: These studies were presented in part at the World Ophthalmology Congress 2014; April 3, 2014; Tokyo, Japan; and the 68th Annual Congress of Japan Clinical Ophthalmology; November 15, 2014; Kobe, Japan.

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