PURPOSE To compare the efficacy, safety, and tolerability of waterfree cyclosporine formulation (CyclASol) at 2 concentrations (0.1% and 0.05% of cyclosporine [CsA]) to vehicle when applied twice daily for 16 weeks in patients with dry eye disease (DED). An open-label Restasis (Allergan, Irvine, CA) arm was included to allow a direct comparison with an approved therapy. DESIGN An exploratory phase II, multicenter, randomized, vehicle-controlled clinical trial, double-masked between CyclASol and vehicle with an open-label comparator. PARTICIPANTS Two hundred and seven eligible patients with a history of dry eye disease were randomized 1:1:1:1 to 1 of 4 treatment arms (CyclASol 0.05%, n = 51; CyclASol 0.1%, n = 51; vehicle, n = 52, and Restasis, n = 53). METHODS After a 2-week run-in period with twice-daily dosing of Systane Balance (Alcon, Fort Worth, TX), patients were randomized to the respective treatment arm and dosed twice daily for 16 weeks. MAIN OUTCOME MEASURES The study was set up to explore efficacy on a number of sign and symptom end points including total and subregion corneal fluorescein staining, conjunctival staining, visual analog scale (VAS) for dry eye symptoms VAS severity, and Ocular Surface Disease Index (OSDI) questionnaire. RESULTS CyclASol showed a consistent reduction in corneal and conjunctival staining compared with both vehicle and Restasis over the 16-week treatment period, with an early onset of effect (at day 14). A mixed-effects model-based approach demonstrated that the CyclASol drug effect was statistically significant over vehicle (total corneal staining P < 0.1, central corneal staining P < 0.001, conjunctival staining P < 0.01). This model-based analysis suggests a significant CyclASol effect for OSDI as symptom parameter (P < 0.01). The numbers of ocular adverse events were low in all treatment groups. CONCLUSIONS CyclASol showed efficacy, safety, and tolerability at 2 concentrations in moderate-to-severe DED. In a direct head-to-head against open-label Restasis, CyclASol was found to have an earlier onset of action, as early as after 2 weeks of treatment, in relieving the signs of DED, as measured by corneal and conjunctival staining. The central region of the cornea, an important area for visual function in dry eye sufferers, was shown to have the most benefit from treatment. Excellent safety, tolerability, and comfort profile supports this new CsA formulation as having a positive benefit-to-risk ratio.

中文翻译：

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评估无水环孢菌素制剂治疗干眼病的疗效、安全性和耐受性的临床 II 期研究。

目的 比较 2 种浓度（0.1% 和 0.05% 的环孢菌素 [CsA]）的无水环孢菌素制剂 (CyclASol) 与媒介物在干眼病 (DED) 患者中每天使用两次，持续 16 周的疗效、安全性和耐受性. 包括一个开放标签 Restasis（艾尔建，欧文，加利福尼亚州）手臂，以允许与批准的治疗进行直接比较。设计 一项探索性 II 期、多中心、随机、载体对照临床试验，在 CyclASol 和载体之间使用开放标签比较器进行双重掩蔽。参与者 207 名有干眼病史的合格患者按 1:1:1:1 的比例随机分配到 4 个治疗组中的 1 个（CyclASol 0.05%，n = 51；CyclASol 0.1%，n = 51；赋形剂，n = 52 和 Restasis，n = 53）。方法 在为期 2 周的磨合期后，每天服用两次 Systane Balance（Alcon，Fort Worth, TX)，患者被随机分配到各自的治疗组，每天给药两次，持续 16 周。主要观察指标 本研究旨在探讨多个体征和症状终点的疗效，包括总和亚区域角膜荧光素染色、结膜染色、干眼症状视觉模拟量表 (VAS)、VAS 严重程度和眼表疾病指数（ OSDI) 问卷。结果 在 16 周的治疗期内，与载体和 Restasis 相比，CyclASol 的角膜和结膜染色持续减少，并且起效较早（第 14 天）。基于混合效应模型的方法表明，CyclASol 药物效应相对于载体具有统计学意义（总角膜染色 P < 0.1，中央角膜染色 P < 0.001，结膜染色 P < 0.01）。这种基于模型的分析表明，作为症状参数的 OSDI 具有显着的 CyclASol 效应 (P < 0.01)。在所有治疗组中，眼部不良事件的数量都很低。结论 CyclASol 在 2 个浓度的中度至重度 DED 中显示出有效性、安全性和耐受性。在与开放标签 Restasis 的直接正面交锋中，发现 CyclASol 在缓解 DED 迹象方面具有更早的作用，最早在治疗 2 周后，通过角膜和结膜染色进行测量。角膜的中央区域是干眼症患者视觉功能的重要区域，被证明从治疗中获益最大。出色的安全性、耐受性和舒适度支持这种新的 CsA 配方，因为它具有积极的收益风险比。