Background

Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis.

Methods

ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18–80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6–24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed.

Findings

Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI –0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (–0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI –0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and –0·03 (–0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group.

Interpretation

Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug.

Funding

Framework of the E-Rare Joint Transnational Call 2016 “Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases”.

中文翻译：

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法舒地尔在肌萎缩侧索硬化症 （ROCK-ALS） 中的安全性、耐受性和有效性：一项 2 期、随机、双盲、安慰剂对照试验

 背景

Fasudil 是一种 Rho 相关激酶 （ROCK） 的小分子抑制剂，被批准用于治疗蛛网膜下腔出血。在临床前研究中，法舒地尔已被证明可以减轻神经退行性变、调节神经炎症并促进轴突再生。我们旨在研究法舒地尔在肌萎缩侧索硬化症患者中的安全性、耐受性和有效性。

 方法

ROCK-ALS 是一项 2 期、随机、双盲、安慰剂对照试验，在德国、法国和瑞士的 19 个肌萎缩侧索硬化症中心进行。至少可能患有肌萎缩侧索硬化症（根据修订后的 El Escorial 标准）、病程为 6-24 个月且慢肺活量大于预测正常值的 65% 的个体（18-80 岁）符合纳入条件。患者被随机分配 （1：1：1） 接受 30 mg （15 mg， 每日两次） 或 60 mg （30 mg， 每日两次） 法舒地尔或匹配的安慰剂，持续 4 周，持续 20 天。在治疗开始后 45 、 90 和 180 天进行随访评估。共同主要终点是第 180 天之前的安全性（定义为没有药物相关严重不良事件的比例）和治疗期间的耐受性（定义为因疑似药物相关不良事件而未停止治疗的比例）。主要分析是在意向治疗人群中进行的，其中包括所有进入治疗阶段的参与者。该试验已在 ClinicalTrials.gov （NCT03792490） 和 Eudra-CT （2017-003676-31） 注册，现已完成。

 发现

在 2019 年 2 月 20 日至 2022 年 4 月 20 日期间，120 名参与者被纳入并随机分组;两名分配法舒地尔 30 mg 的个体在基线访视前撤回同意。因此，意向治疗人群包括 35 名法舒地尔 30 毫克组、39 名法舒地尔 60 毫克组和 44 名安慰剂组。无药物相关严重不良事件的估计比例为安慰剂组 1·00 （95% CI 0·91 至 1·00），法舒地尔 30 mg 组为 1·00 （0·89 至 1·00），法舒地尔 60 mg 组为 1·00 （0·90 至 1·00）;法舒地尔 30 mg 与安慰剂的比例差异为 0·00（95% CI -0·11 至 0·10;p>0·99），法舒地尔 60 mg 与安慰剂的比例差异为 0·00（-0·10 至 0·10;p>0·99）。安慰剂组的治疗耐受性（未停药的估计比例）为 0·93（95% CI 0·81 至 0·99），30 mg 法舒地尔为 1·00（0·90 至 1·00），60 mg 法舒地尔为 0·90（0·76 至 0·97）;30 mg 法舒地尔与安慰剂的比例差异为 0·07（95% CI -0·05 至 0·20;p=0·25），60 mg 法舒地尔与安慰剂的比例差异为 -0·03（-0·18 至 0·10;p=0·70）。发生了 8 例死亡：安慰剂组 2 例，法舒地尔 30 mg 组 4 例，法舒地尔 60 mg 组 2 例。最常见的严重不良事件为呼吸衰竭 （7 例）、胃造口术 （5 例）、肺炎 （4 例） 和吞咽困难 （4 例）。没有严重的不良事件或死亡归因于研究治疗。不良事件主要与疾病进展有关，安慰剂组有 139 名参与者，法舒地尔 30 毫克组有 108 名，法舒地尔 60 毫克组有 105 名。

 解释

Fasudil 在肌萎缩侧索硬化症患者中具有良好的耐受性和安全性。应在更大规模的临床试验中探讨法舒地尔对疗效结局的影响，这些试验具有更长的治疗持续时间、口服给药和可能更高的试验药物剂量。

 资金

2016 年 E-Rare 联合跨国电话会议的框架“罕见病中现有分子新治疗用途的临床研究（再利用）”。