Shefner Jeremy M, Cudkowicz Merit E, Genge Angela, Hardiman Orla, Al-Chalabi Ammar, Andrews Jinsy A, Chio Adriano, Corcia Philippe, Couratier Philippe, de Carvalho Mamede, Heiman-Patterson Terry, Henderson Robert D, Ingre Caroline, Johnston Wendy, Ludolph Albert, Maragakis Nicholas J, Miller Timothy M, Mora Jesus S, Petri Susanne, Simmons Zachary, van den Berg Leonard H, Zinman Lorne, Kupfer Stuart, Malik Fady I, Meng Lisa, Simkins Tyrell J, Wei Jenny, Wolff Andrew A, Rudnicki Stacy A
Department of Neurology, Barrow Neurological Institute, University of Arizona, Phoenix.
Creighton University, Phoenix, Arizona.
JAMA Neurol. 2025 May 1;82(5):477-485. doi: 10.1001/jamaneurol.2025.0241.
Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression.
To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS.
DESIGN, SETTING, AND PARTICIPANTS: A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted.
Oral reldesemtiv, 300 mg, or placebo twice daily.
The primary end point was change in ALSFRS-R total score from baseline to week 24.
Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI, -2.17 to -0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11).
This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS.
ClinicalTrials.gov Identifier: NCT04944784.
肌萎缩侧索硬化症（ALS）的治疗选择仍不尽人意。一项关于relldesemtiv治疗ALS的2期研究结果表明，它可能会减缓疾病进展。
评估relldesemtiv与安慰剂对ALS功能结局的影响。
设计、地点和参与者：一项评估relldesemtiv对肌萎缩侧索硬化症患者疗效和安全性的研究（COURAGE-ALS）是一项双盲、安慰剂对照的3期随机临床试验，于2021年8月至2023年7月在16个国家的83个ALS中心进行。第一个24周期间为安慰剂对照与relldesemtiv对比。所有参与者在第二个24周期间接受relldesemtiv治疗，并进行4周的随访。计划进行两次中期分析，第一次用于评估无效性，第二次用于评估无效性和可能的样本量调整。这是一项混合去中心化试验，约一半的试验访视通过远程进行，其余访视在诊所进行。符合条件的参与者符合经改良的埃斯科里亚尔标准确定的、可能的或疑似的ALS且伴有下运动神经元体征，ALS症状持续24个月或更短时间，ALS功能评定量表修订版（ALSFRS-R）总分44分或更低，且用力肺活量大于或等于预测值的65%。
口服relldesemtiv，300毫克，或安慰剂，每日两次。
主要终点是从基线到第24周ALSFRS-R总分的变化。
在696名筛查的参与者中，207名筛查未通过。共有486名参与者（平均[标准差]年龄，59.4[10.9]岁；309名男性[63.6%]）被随机分配至relldesemtiv组（n = 325）或安慰剂组（n = 161）；3名随机分组的患者未给药。随机分组后24周的第二次中期分析纳入了256名参与者。数据监测委员会建议因无效性而终止试验，申办方表示同意。从基线到第24周，ALSFRS-R评分的平均（标准误）组间差异为-1.1（0.53；95%置信区间，-2.17至-0.08；P = 0.04，支持安慰剂）。鉴于早期终止导致的数据缺失过多，综合评估显得更为重要；综合评估也未显示relldesemtiv治疗有获益（relldesemtiv的获胜概率为0.44，安慰剂为0.49，获胜比为0.91；获胜比调整后的95%置信区间，0.77 - 1.10；P = 0.11）。
这项随机临床试验未能证明relldesemtiv在减缓ALS功能衰退方面的疗效。
ClinicalTrials.gov标识符：NCT04944784。
