Background

There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function.

Methods

The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178) has also been completed, but will be reported separately.

Findings

Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis.

Interpretation

Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation.

Funding

Orion Corporation.

中文翻译：

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肌萎缩侧索硬化患者口服左西孟旦的安全性和有效性（REFALS 研究）：一项随机、双盲、安慰剂对照的 3 期试验

背景

肌萎缩侧索硬化症的新疗法迫切需要得到满足。在一项针对健康志愿者的临床研究中，一种钙增敏剂左西孟旦被证明可以提高人体横膈膜的神经机械效率和收缩功能。我们旨在评估口服左西孟旦对肌萎缩侧索硬化症患者的安全性和有效性，重点是呼吸功能。

方法

REFALS 研究是一项随机、双盲、安慰剂对照的 3 期试验，在全球 14 个国家的 99 个肌萎缩侧索硬化症专科中心开展。患有肌萎缩侧索硬化症的人如果年满 18 岁且坐姿缓慢肺活量 (SVC) 为 60-90% 的预测值，则有资格参与。参与者通过交互式网络响应系统随机分配（2:1）接受左西孟旦或安慰剂。用于口服给药的胶囊在外观上是相同的，以保持参与者和研究人员的盲目性。主要终点是 12 周时仰卧位 SVC 从基线的变化，评估为预测的正常坐位 SVC 的百分比。关键的次要终点是长达 48 周的功能和生存期综合评估 (CAFS)。在意向治疗人群中进行了分析，包括随机分配的所有参与者。该试验已在 ClinicalTrials.gov (NCT03505021) 注册并已完成。一项扩展研究（REFALS-ES；NCT03948178）也已完成，但将单独报告。

发现

在 2018 年 6 月 21 日至 2019 年 6 月 28 日期间，该研究筛选了 871 人，其中 496 人被随机分配左西孟旦（n=329）或安慰剂（n=167）。在 2018 年 6 月 27 日至 2020 年 6 月 26 日期间对参与者进行了随访，中位持续时间为 50·1（IQR 37·5-51·1）周。中位治疗时间为 47·9 (IQR 26·4–48·1) 周。12 周时仰卧位 SVC 与基线的变化分别为 –6·73% 和安慰剂组 –6·99%，治疗之间没有显着差异（估计治疗差异 0·26%，95% CI –2·03 至2·55, p=0·83)。同样，在第 48 周，治疗组之间的 CAFS 没有差异（最小二乘均值从基线 10·69 的变化，95% CI –15·74 到 37·12；标称 p 值=0·43）。最常见的不良事件是心率加快（接受左西孟旦治疗的 326 人中有 106 [33%]166人中有 12 [7%] 人接受安慰剂）、跌倒（85 [26%] vs 48 [29%]）、头痛（93 [29%] vs 36 [22%]）和呼吸困难（59 [18%]对比32 [19%]）。33 名（10%）分配左西孟旦的参与者和 20 名（12%）分配安慰剂的参与者在试验期间死亡，主要是由于呼吸衰竭或肌萎缩侧索硬化症的进展。

解释

在患有肌萎缩侧索硬化症的广泛人群中，左西孟旦在维持呼吸功能方面并不优于安慰剂。尽管左西孟旦通常耐受性良好，但与安慰剂相比，左西孟旦的心率增加和头痛发生率更高。临床相关的响应个体亚组的可能性需要进一步评估。

资金

猎户座公司。