title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Patients were subdivided into 2 groups in each study and were treated with ripasudil or placebo twice daily for 8 weeks.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.jp Identifiers: JAPIC111700 and JAPIC111701.
authors.affiliation: Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Tanihara
authors.affiliation: Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Ophthalmology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Fukushima Eye Clinic, Osaka, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kuwayama
authors.affiliation: Department of Orthoptics and Visual Sciences, Niigata University of Health and Welfare, Niigata, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Abe
authors.affiliation: Kowa Company Ltd, Nagoya, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Suganami
authors.affiliation: The Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Araie
mesh_terms: D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005902:Glaucoma, Open-Angle / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage* / Q000009:adverse effects; D007564:Japan; D000077338:Latanoprost; D008297:Male; D008875:Middle Aged; D009798:Ocular Hypertension / Q000175:diagnosis / Q000188:drug therapy*; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000009:adverse effects; D011461:Prostaglandins F, Synthetic / Q000008:administration & dosage / Q000009:adverse effects; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D013999:Timolol / Q000008:administration & dosage* / Q000009:adverse effects; D014065:Tonometry, Ocular; D016896:Treatment Outcome; D054460:rho-Associated Kinases / Q000008:administration & dosage / Q000037:antagonists & inhibitors
chemical_list: D007546:Isoquinolines; C584679:K-115; D009883:Ophthalmic Solutions; D011461:Prostaglandins F, Synthetic; D013449:Sulfonamides; D000077338:Latanoprost; D013999:Timolol; D054460:rho-Associated Kinases