Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.
Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.
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DOI：
10.1056/nejmoa1916945
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发表时间：
2020-09-03
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在实验模型中，苯丁酸钠和牛磺酸二醇已被发现可以减少神经元死亡。这两种化合物联合治疗肌萎缩侧索硬化症(ALS)的有效性和安全性尚不清楚。在这项多中心、随机、双盲试验中，我们招募了在过去18个月内出现症状的确诊为ALS的参与者。参与者被按2：1的比例随机分配给苯丁酸钠-牛磺酸二醇组(苯丁酸钠3g和牛磺酸二醇1g，连续3周每天一次，然后每天两次)或安慰剂。主要结果是在24周内肌萎缩侧索硬化症功能评定量表(ALSFRS-R；范围从0到48，分数越高，表明功能更好)总分的下降率。次要结果是等长肌力、血浆磷酸化轴索神经丝H亚单位水平和肺活量减慢的比率；死亡、气管切开或永久机械通气的时间；以及死亡、气管切开、永久机械通气或住院的时间。共有177名ALS患者接受了资格筛选，137人被随机分配接受苯丁酸钠牛磺酸二醇(89名参与者)或安慰剂(48名参与者)。在改进的意向治疗分析中，活性药物组和安慰剂组ALSFRS-R评分的平均变化率分别为−1.24分/月和−1.66分/月(差异为0.42分/月；95%可信区间为0.03~0.81分；P=0.03)。二次结局在两组之间没有显著差异。活性药物的不良反应主要是胃肠道反应。根据ALSFRS-R评分，在24周的时间里，苯丁酸钠-牛磺酸二醇导致的功能下降慢于安慰剂。二次结局在两组之间没有显著差异。有必要进行更长时间和更大规模的试验来评估苯丁酸钠-牛磺酸二醇对ALS患者的疗效和安全性。(由Amylyx PharmPharmticals和其他公司资助；Centaur ClinicalTrials.gov编号，NCT03127514。)
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate–taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate–taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was −1.24 points per month with the active drug and −1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. Sodium phenylbutyrate–taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR Clinicaltrials.gov number, NCT03127514.)