Morimoto Satoru, Takahashi Shinichi, Fukushima Komei, Saya Hideyuki, Suzuki Norihiro, Aoki Masashi, Okano Hideyuki, Nakahara Jin
Department of Physiology, Keio University School of Medicine, Japan.
Department of Neurology, Keio University School of Medicine, Japan.
Regen Ther. 2019 Jul 26;11:143-166. doi: 10.1016/j.reth.2019.07.002. eCollection 2019 Dec.
Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial.
The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years.
Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020.
Current controlled trials UMIN000034954 and JMA-IIA00397.
version 1.6 (Date; 5/Apr/2019).
肌萎缩侧索硬化症（ALS）是一种难治且无法治愈的神经疾病。它是一种进行性疾病，其特征是上、下运动神经元的选择性易损性导致肌肉萎缩和无力。在疾病研究中，使用携带家族性ALS相关基因突变的小鼠模型作为ALS的病理模型很常见。然而，尚无模型能够重现人类脊髓病理的实际情况。因此，我们开发了一种利用人类诱导多能干细胞（iPSC）生成人类脊髓运动神经元的方法以及一种用于药物筛选的创新实验技术。结果，在考虑到盐酸罗匹尼罗在大脑中的良好传递性和耐受性（包括可能的不良反应）等结果后，最终发现了盐酸罗匹尼罗。因此，我们在这项临床试验中探索盐酸罗匹尼罗作为ALS治疗药物的安全性、耐受性和疗效。
ROPALS试验是一项单中心双盲随机平行组对照试验，旨在研究盐酸罗匹尼罗缓释片（Requip CR）在2至16毫克剂量下对ALS患者的安全性、耐受性和疗效。将招募20名患者，分为活性药物组（15名患者）和安慰剂组（5名患者）。如果在本试验期间未改变剂量，所有患者都将能够接受利鲁唑的标准ALS治疗。主要结局将是随机分组日期起24周时的安全性和耐受性。次要结局将是疗效，包括ALS功能评定量表修订版（ALSFRS-R）的任何变化、功能与生存综合评估（CAFS）的变化以及各种临床项目Z转换分数总和的复合终点。值得注意的是，我们将使用患者来源的iPSC进行探索性药物效果评估，以证明该试验概念。符合条件的患者将患有埃尔埃斯科里亚尔可能型、临床可能型且有实验室支持型、临床很可能型或临床确诊型肌萎缩侧索硬化症，病程小于60个月（含），所有项目的ALSFRS-R评分≥2分，年龄在20至80岁之间。
患者招募于2018年12月开始，预计最后一名患者将于2020年11月完成试验方案。
当前受控试验UMIN000034954和JMA-IIA00397。
版本1.6（日期：2019年4月5日）。
