ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis
ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis
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DOI：
10.3389/fneur.2019.00293
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发表时间：
2019-03-27
影响因子：
3.4
通讯作者：
Zielke, Eirini
中科院分区：
文献类型：
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作者：
Lingor, Paul;Weber, Markus;Zielke, Eirini
目的：肌萎缩侧索硬化症（ALS）的疾病改善治疗仍然不令人满意。Rho激酶（ROCK）抑制剂法舒地尔已在ALS的细胞培养和动物模型中显示出有益作用。多年来，法舒地尔已在日本获批用于治疗蛛网膜下腔出血患者的血管痉挛，具有良好的安全性。在这里，我们描述了一项临床试验方案，重新将法舒地尔作为ALS患者的疾病改善疗法。方法：ROCK-ALS是一项多中心、双盲、随机、安慰剂对照的ALS患者IIa期试验（EudraCT：2017-003676-31，NCT：03792490）。安全性和耐受性是主要终点。疗效是次要终点，将通过ALSFRS-R、ALSAQ-5、慢肺活量（SVC）、ECAS和运动单位数量指数（MUNIX）的变化以及生存率进行评估。将在输注治疗前（基线）和输注治疗后立即以及第90天和第180天评估疗效指标。患者将接受30或60 mg法舒地尔或安慰剂的每日剂量，分两次静脉注射，共20天。将在整个治疗期间以及随访期间直至第180天进行定期安全性评估。此外，我们将收集生物体液以评估靶点参与并评估疾病进展的潜在生物标志物。在德国、瑞士和法国的16个中心共纳入了120例可能或明确的ALS（修订后的埃尔埃斯科里亚标准）且在虚弱发作6-18个月内的患者。结果和结论：ROCK-ALS试验是一项评估ROCK抑制剂法舒地尔在早期ALS患者中的IIa期试验，于2019年开始招募患者。
Objectives: Disease-modifying therapies for amyotrophic lateral sclerosis (ALS) are still not satisfactory. The Rho kinase (ROCK) inhibitor fasudil has demonstrated beneficial effects in cell culture and animal models of ALS. For many years, fasudil has been approved in Japan for the treatment of vasospasm in patients with subarachnoid hemorrhage with a favorable safety profile. Here we describe a clinical trial protocol to repurpose fasudil as a disease-modifying therapy for ALS patients.Methods: ROCK-ALS is a multicenter, double-blind, randomized, placebo-controlled phase IIa trial of fasudil in ALS patients (EudraCT: 2017-003676-31, NCT: 03792490). Safety and tolerability are the primary endpoints. Efficacy is a secondary endpoint and will be assessed by the change in ALSFRS-R, ALSAQ-5, slow vital capacity (SVC), ECAS, and the motor unit number index (MUNIX), as well as survival. Efficacy measures will be assessed before (baseline) and immediately after the infusion therapy as well as on days 90 and 180. Patients will receive a daily dose of either 30 or 60 mg fasudil, or placebo in two intravenous applications for a total of 20 days. Regular assessments of safety will be performed throughout the treatment period, and in the follow-up period until day 180. Additionally, we will collect biological fluids to assess target engagement and evaluate potential biomarkers for disease progression. A total of 120 patients with probable or definite ALS (revised El Escorial criteria) and within 6-18 months of the onset of weakness shall be included in 16 centers in Germany, Switzerland and France.Results and conclusions: The ROCK-ALS trial is a phase IIa trial to evaluate the ROCK-inhibitor fasudil in early-stage ALS-patients that started patient recruitment in 2019.