Lingor Paul, Weber Markus, Camu William, Friede Tim, Hilgers Reinhard, Leha Andreas, Neuwirth Christoph, Günther René, Benatar Michael, Kuzma-Kozakiewicz Magdalena, Bidner Helen, Blankenstein Christiane, Frontini Roberto, Ludolph Albert, Koch Jan C
Department of Neurology, Technical University of Munich, Munich, Germany.
Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
Front Neurol. 2019 Mar 27;10:293. doi: 10.3389/fneur.2019.00293. eCollection 2019.
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. 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. 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.
肌萎缩侧索硬化症（ALS）的疾病修饰疗法仍不尽人意。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效果。多年来，法舒地尔在日本已被批准用于治疗蛛网膜下腔出血患者的血管痉挛，安全性良好。在此，我们描述一项临床试验方案，将法舒地尔重新用作ALS患者的疾病修饰疗法。ROCK-ALS是一项在ALS患者中进行的多中心、双盲、随机、安慰剂对照的IIa期试验（欧盟临床试验注册号：2017-003676-31，美国国立医学图书馆临床试验注册号：03792490）。安全性和耐受性是主要终点。疗效是次要终点，将通过肌萎缩侧索硬化功能评定量表修订版（ALSFRS-R）、肌萎缩侧索硬化症生活质量问卷-5（ALSAQ-5）、慢肺活量（SVC）、欧洲ALS协作组评估量表（ECAS）、运动单位数量指数（MUNIX）的变化以及生存率来评估。疗效指标将在输注治疗前（基线）、输注治疗后即刻以及第90天和第180天进行评估。患者将接受每日剂量为30毫克或60毫克的法舒地尔，或安慰剂，分两次静脉给药，共20天。在整个治疗期间以及直至第180天的随访期内，将定期进行安全性评估。此外，我们将收集生物体液以评估靶点结合情况，并评估疾病进展的潜在生物标志物。德国、瑞士和法国的16个中心将共纳入120例可能或确诊的ALS患者（修订的埃尔埃斯科里亚尔标准），且肌无力发病在6至18个月内。ROCK-ALS试验是一项IIa期试验，旨在评估ROCK抑制剂法舒地尔在早期ALS患者中的疗效，该试验于2019年开始招募患者。
