To identify the optimal dose of a novel Rho kinase inhibitor, K-115, by assessing dose dependency of the intraocular pressure (IOP)-lowering effects and the safety in patients with primary open-angle glaucoma or ocular hypertension.
Multicenter, prospective, randomized, placebo-controlled, double-masked, parallel group comparison clinical study.
After appropriate washout periods, 210 patients with primary open-angle glaucoma or ocular hypertension were subdivided into 4 groups and were treated with K-115 in concentrations of 0.1%, 0.2%, and 0.4% or placebo twice daily for 8 weeks. The dose response of IOP reduction and the incidence of adverse events by K-115 or placebo were investigated.
The mean baseline IOP was between 23.0 and 23.4 mm Hg. The mean IOP reductions of the last visit from baseline were −2.2 mm Hg, −3.4 mm Hg, −3.2 mm Hg, and −3.5 mm Hg, respectively, in the placebo, 0.1%, 0.2%, and 0.4% groups at before instillation (9:00); −2.5 mm Hg, −3.7 mm Hg, −4.2 mm Hg, and −4.5 mm Hg at 2 hours after instillation (11:00); and −1.9 mm Hg, −3.2 mm Hg, −2.7 mm Hg, and −3.1 mm Hg at 8 hours after instillation (17:00). The dose-dependent IOP-lowering effect of K-115 was statistically significant at all time points. Also, conjunctival hyperemia was found in 7 (13.0%) of 54 patients for placebo, 23 (43.4%) of 53 patients for the 0.1% group, 31 (57.4%) of 54 patients for the 0.2% group, and 32 (65.3%) of 49 patients for the 0.4% group.
On the basis of this dose-response study, K-115 0.4% has been selected to be the optimal dose and has the potential to be a promising new agent for glaucoma to control 24-hour IOP by twice-daily dosing.
Glaucoma is a progressive optic neuropathy that is characterized by a specific pattern in visual field defects and structural changes in the optic nerve head. To date, numerous drugs to reduce intraocular pressure (IOP) have been developed and used to treat glaucoma in clinical practice. In addition to currently used antiglaucoma medications, some candidate drugs are under development. Rho kinase inhibitors are one of those candidate drug classes to reduce IOP in glaucomatous patients. Accumulating experimental evidence suggests that Rho kinase inhibitors increase outflow facility by altering the conventional outflow of aqueous humor, resulting in significant IOP reduction. In experiments using cultured trabecular meshwork and Schlemm canal cells, inhibition of Rho kinase activity causes changes in actin cytoskeleton, focal adhesion, and cell-matrix and cell-cell interactions in such cells. Also, physiologic studies in animal models, including ours, have demonstrated increased outflow in a pressure-dependent manner, suggesting that the IOP reduction is caused by the modulation of conventional outflow of aqueous humor. Previous clinical trials have shown that eye drops of Rho kinase inhibitors are useful in controlling IOP in human eyes with and without glaucoma.
K-115 is a novel Rho kinase inhibitor with potent IOP-lowering effects in rabbits and monkeys (Mizuno K, et al. IOVS 2007;48:ARVO E-Abstract 4805; Mizuno K, et al. IOVS 2008;49:ARVO E-Abstract 1640). Preclinical studies have demonstrated that K-115 has outflow-increasing effects, suggesting improvement in the conventional outflow by this Rho kinase inhibitor. Before the current clinical trial, we conducted phase 1 clinical trials for the estimation of safety and efficacy of K-115 in concentrations of up to 0.8% administered twice daily in healthy volunteers, which showed significant IOP-lowering effects of K-115. Also, the following phase 2a clinical trial showed IOP-lowering effects of K-115 over 24 hours in concentrations of 0.2% and 0.4% administered twice daily for 1 day in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT); the main adverse event was mild conjunctival hyperemia (Yamamoto T, et al. IOVS 2011;52:ARVO E-Abstract 216). Based on these findings, a phase 2 clinical trial was conducted to identify the optimal dose of K-115 by assessing the dose dependency of the efficacy and safety of K-115 in concentrations of 0.1% to 0.4% in patients with POAG or OHT.
A multicenter, prospective, randomized, placebo-controlled, double-masked, parallel-group comparison clinical study was conducted at 29 clinical centers in Japan. The institutional review board review was prospective and the study protocol was approved by each institutional review board (Appendix, Supplemental Material). Candidate patients for the clinical trial received complete information regarding the protocol, and written informed consent was obtained from each participant before entry to the study. This study is registered with www.clinicaltrials.jp as study number 101015 .
Inclusion criteria mandated that the patients be men or women (excluding women of childbearing potential who were pregnant, nursing, or planning a pregnancy) with POAG or OHT who were 20 years of age or older. Untreated IOP (after washout) was 21 mm Hg or more and IOP differences were within 3 mm Hg in at least 1 eye at 2 eligibility visits (9:00), 2 to 14 days apart. Untreated IOP was less than 35 mm Hg in both eyes. Patients with narrow angles defined as grade 2 or less of the Shaffer classification by gonioscopy or who had undergone ocular surgery (other than cataract surgery more than 1 year ago, retinal laser treatment and yttrium–aluminun–garnet laser posterior capsulotomy more than 90 days ago, and eyelid surgery more than 120 days ago) in either eye were excluded from the study. Patients with severe visual field defects or with a corrected visual acuity of worse than 0.3 (decimal fraction) in either eye also were excluded. During the trial, subjects were prohibited from receiving other IOP-lowering agents, receiving any ophthalmic agents (excluding artificial tears) or steroids, wearing contact lenses, and changing dosages of any systemic medications that may affect IOP if patients were taking these medications.
After appropriate washout periods (prostaglandin analogs and sympatholytic agents, 4 weeks or more; other antiglaucoma medications, 2 weeks or more), IOPs for eligibility were measured (9:00) at 2 separate visits (a run-in period) and the IOPs (obtained at 9:00, 11:00, and 17:00) for the second visit (week 0) were used as the baseline. Patients fulfilling the above criteria were assigned randomly to 4 groups and were treated with K-115 in concentrations of 0.1%, 0.2%, or 0.4% or with placebo, according to the permuted blocks method, which treated clinical sites as strata. The block size was 4 and the allocation ratio of 4 groups was 1:1:1:1; site investigators were not informed about the block size throughout the study period. After randomization, 1 drop of study drug was instilled into each eye twice daily at 9:00 and 21:00 for 8 weeks. The dose response of IOP reduction and the incidence of adverse events by K-115 or placebo from baseline were investigated. IOP was measured with Goldmann tonometry every 2 weeks at 9:00 and 11:00 and every 4 weeks at 17:00.
To evaluate the safety of K-115, ophthalmologic findings and physiologic parameters were examined during the trial. The palpebral and bulbar conjunctiva, cornea, anterior chamber, iris, and lens were examined with slit-lamp microscopy during the trial. In particular, conjunctival hyperemia was scored according to the following criteria: 0, no significant hyperemia; 1, mild changes (dilation in several blood vessels); 2, moderate changes (dilation in many blood vessels or ciliary vessels); and 3, severe changes (dilation in total blood vessels). Other ocular examinations including visual acuity, ocular fundus examination, and visual field also were conducted.
One eye per patient—the one with greater IOP at baseline—was included in the analysis of this study. If the IOPs were the same, the right eye was chosen as the study eye. The change in IOP at the last visit from the baseline at time-matched points was calculated as the primary efficacy end point. IOP data were expressed as the mean ± standard deviation. The analysis of covariance model including terms for baseline and group was applied to the change in IOP data, and the significance of dose dependency was assessed on the basis of a maximum contrast method. The contrast coefficient vectors were set to be (3, 1, −1, −3), (5, 1, −3, −3), and (3, −1, −1, −1) to search where to reach the plateau of the dose-response curve. The Dunnett test was conducted to compare the adjusted means based on analysis of covariance of K-115 and placebo groups. In all analyses, a 2-sided significance level of .05 was used. To avoid the multiplicity of analyses, we evaluated significance of the Dunnett test results only when the maximum contrast method was significant. Furthermore, the multiplicity of 3 time points (9:00, 11:00, and 17:00) was adjusted by defining significance to be only when all the results for 3 time points were significant. Because this study was intended for exploration, we calculated the sample size only for assuring the precision of the estimate. The standard deviation of the difference from baseline was estimated to be 2.37 mm Hg, and the correlation between time points (peak, trough, and 8 hours) was estimated to be 0.56 from the previous phase 2a clinical trial. We assumed that the true dose-response structure was the contrast, (3, 1, −1, −3), and that the treatment difference between any adjacent doses (higher dose − lower dose) was −1. Then 41 subjects per group were required to achieve the probability of the estimates of treatment differences between any pairs of doses with different means (higher dose – lower dose) being lower than 0 for all 3 time points (9:00,11:00, and 17:00) to be larger than 0.8. For this sample size, the corresponding probabilities for the other contrasts also were larger than 0.8. The number of subjects in each group was determined to be 50 subjects per group taking dropouts into account. All statistical analyses were performed by using SAS software version 9.1.3 (SAS Institute, Cary, North Carolina, USA) at Kowa Company, Ltd, Nagoya, Japan. All patients, physicians and technicians were masked to treatment assignment during the study period.
The enrollment of patients began in February 2010 and was completed in May 2010. In this phase 2 clinical trial, 232 patients with POAG or OHT were enrolled and 210 patients who fulfilled the eligibility criteria were subdivided randomly into 4 groups: 54 patients were assigned to placebo, 53 were assigned to 0.1% K-115, 54 were assigned to 0.2% K-115, and 49 were assigned to 0.4% K-115 and were subjected to the analyses on safety. A total of 7 patients were excluded from analyses because of adverse events (2 patients in the placebo group and 1 patient in the 0.1% group were excluded for drug unrelated adverse events. 2 patients in the 0.1% group and 1 patient in the 0.2% group were excluded for drug related adverse events) in 6 and protocol deviations in 1. In the remaining 203 patients, 52 in the placebo group, 50 in the 0.1% group, 52 in the 0.2% group, and 49 in the 0.4% group, subsequent statistical analyses were conducted for the estimation of efficacy in IOP reduction ( Figure 1 ).
The baseline characteristics of the included population and eye complications before treatment are shown in Table 1 . The mean IOP at baseline of efficacy population at 9:00 was 23.0 ± 2.1 mm Hg for the placebo group and, for the groups treated with K-115, 23.4 ± 2.5 mm Hg for 0.1%, 23.2 ± 2.0 mm Hg for 0.2%, and 23.2 ± 1.9 mm Hg for 0.4% concentrations. After 8 weeks with K-115 or placebo treatments, the adjusted means of the change in IOP from baseline were −2.2 mm Hg, −3.4 mm Hg, −3.2 mm Hg, and −3.5 mm Hg, respectively, in the placebo, 0.1%, 0.2%, and 0.4% groups before the last instillation (9:00); −2.5 mm Hg, −3.7 mm Hg, −4.2 mm Hg, and −4.5 mm Hg at 2 hours after instillation (11:00); and −1.9 mm Hg, −3.2 mm Hg, −2.7 mm Hg, and −3.1 mm Hg at 8 hours after instillation (17:00). The dose-dependent IOP-lowering effect of K-115 was statistically significant at all of the contrasts and the time points after 8 weeks of treatment by the maximum contrast method ( P < .05). The selected contrasts were (3, −1, −1, −1) at 9:00 and 17:00 and (5, 1, −3, −3) at 11:00. Statistical analysis showed significant differences in the adjusted mean of the change in IOP between eyes administered K-115 and placebo for all time points for the 0.1% and 0.4% groups and at 2 hours after instillation for the 0.2% group ( P < .05, Dunnett test; Figure 2 ).
|Placebo (n = 54)||0.1% (n = 53)||0.2% (n = 54)||0.4% (n = 49)||Total (n = 210)|
|Male||21 (39)||27 (51)||19 (35)||20 (41)||87 (41)|
|Female||33 (61)||26 (49)||35 (65)||29 (59)||123 (59)|
|Age||63 ± 14||58 ± 14||59 ± 15||58 ± 17||60 ± 15|
|POAG||25 (46)||20 (38)||22 (41)||20 (41)||87 (41)|
|OHT||29 (54)||33 (62)||32 (59)||29 (59)||123 (59)|
|At 9:00||23.0 ± 2.1||23.3 ± 2.4||23.2 ± 2.0||23.2 ± 1.9||23.2 ± 2.1|
|At 11:00||22.5 ± 2.3||22.6 ± 2.5||22.5 ± 2.4||22.7 ± 2.1||22.6 ± 2.3|
|At 17:00||22.1 ± 2.4||22.1 ± 2.6||21.8 ± 2.2||22.0 ± 2.7||22.0 ± 2.5|
|Pretreatment drug||29 (54)||29 (55)||31 (57)||32 (65)||121 (58)|
|Eye complications (5% or more)|
|Cataract||25 (46)||18 (34)||24 (44)||19 (39)||86 (41)|
|Asthenopia||5 (9)||7 (13)||6 (11)||6 (12)||24 (11)|
|Punctate keratitis||7 (13)||5 (9)||4 (7)||5 (10)||21 (10)|
|Dry eye||1 (2)||4 (8)||8 (15)||4 (8)||17 (8)|
|Allergic conjunctivitis||3 (6)||2 (4)||5 (9)||2 (4)||12 (6)|
|Keratoconjunctivitis sicca||3 (6)||4 (8)||4 (7)||1 (2)||12 (6)|