Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Department of Ophthalmology, Gifu University Graduate School of Medicine, Gifu, Japan.
JAMA Ophthalmol. 2015 Jul;133(7):755-61. doi: 10.1001/jamaophthalmol.2015.0525.
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.
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.
Patients were subdivided into 2 groups in each study and were treated with ripasudil or placebo twice daily for 8 weeks.
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.
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.
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.
clinicaltrials.jp Identifiers: JAPIC111700 and JAPIC111701.
盐酸利匹司特水合物（K-115）是一种新型的 rho 激酶抑制剂，具有统计学显著的降眼压（IOP）作用，且安全性良好。然而，尚无研究评估利匹司特联合β受体阻滞剂和前列腺素类似物的效果。
评估利匹司特（0.4%）联合噻吗洛尔（0.5%）或拉坦前列素（0.005%）对原发性开角型青光眼或高眼压症患者的眼压降低作用和安全性。
设计、地点和参与者：我们分别在 29 个和 36 个日本临床中心进行了两项多中心、随机、双盲、平行组比较研究，评估利匹司特-噻吗洛尔和利匹司特-拉坦前列素的效果。分析基于意向治疗原则。在适当的噻吗洛尔或拉坦前列素导入期后，分别有 208 名和 205 名眼压为 18 mmHg 或更高的患者纳入利匹司特-噻吗洛尔组和利匹司特-拉坦前列素组。入组时间为 2011 年 12 月 1 日，利匹司特-噻吗洛尔研究的随访于 2012 年 9 月 7 日结束，利匹司特-拉坦前列素研究的随访于 2012 年 9 月 27 日结束。
在每项研究中，患者被分为两组，分别接受利匹司特或安慰剂，每日两次，治疗 8 周。
在第 4、6 和 8 周时，使用重复测量方差模型分析利匹司特和安慰剂组的眼压降低情况，在谷值（滴注前 9 点）和峰值（滴注后 2 小时 11 点）水平。
在利匹司特-噻吗洛尔研究中，利匹司特组和安慰剂组在 9 点时的平均眼压降幅分别为-2.4 和-1.5 mmHg，差值为 0.9 mmHg（95%CI，0.4-1.3 mm Hg；P<0.001），在 11 点时的平均眼压降幅分别为-2.9 和-1.3 mmHg，差值为 1.6 mm Hg（95%CI，1.1-2.1 mm Hg；P<0.001）。在利匹司特-拉坦前列素研究中，9 点时的平均眼压降幅分别为-2.2 和-1.8 mmHg，差值为 0.4 mmHg（95%CI，-0.0 至 0.9 mm Hg；P=0.06），11 点时的平均眼压降幅分别为-3.2 和-1.8 mmHg，差值为 1.4 mm Hg（95%CI，0.9-1.9 mm Hg；P<0.001）。最常见的不良反应是结膜充血，为轻度，大多数情况下在下一次滴注前无需治疗即可自行缓解。
这些临床试验发现，利匹司特与噻吗洛尔联合使用时，在谷值和峰值水平，以及与拉坦前列素联合使用时，在峰值水平上具有显著的降眼压作用。然而，在谷值水平上，利匹司特联合安慰剂与拉坦前列素联合使用的效果差异并未得到明确确定。
clinicaltrials.jp 标识符：JAPIC111700 和 JAPIC111701。
