安全性和有效性的cipaglucosidase阿尔法+ miglustat与alglucosidase阿尔法+安慰剂在晚发性疾病筛(推动):一个国际,随机,双盲,与这些相应平行的组织,第三阶段试验。

文章的细节

引用 复制到剪贴板

罗伯茨Schoser B, M,伯恩BJ, Sitaraman年代,江H, Laforet P, Toscano, Castelli J, Diaz-Manera J,高盛M, van der Ploeg, Bratkovic D,反观年代,Mozaffar T, Kishnani PS

柳叶刀神经。2021;12月20 (12):1027 - 1037。doi: 10.1016 / s1474 - 4422 (21) 00331 - 8。

PubMed ID

34800400 (在PubMed

]

文摘

背景:筛症是一种罕见的疾病,特点是进步的损失由于酸alpha-glucosidase缺乏肌肉和呼吸功能。酶替代疗法与重组人类酸alpha-glucosidase alglucosidase阿尔法,是第一个批准治疗疾病,但有些病人不回应,许多没有显示持续受益。我们旨在评估一个临床实验的双组分治疗的安全性和有效性(cipaglucosidase阿尔法,小说重组人类酸alpha-glucosidase + miglustat酶稳定器)对晚发性疾病筛。方法:我们做了一个随机、双盲、与这些相应平行的组织,3期临床试验在24个国家的62个神经肌肉和代谢医学中心在美洲、亚太地区和欧洲。合格的参与者与晚发性疾病筛18岁或以上,并被接收alglucosidase阿尔法至少2年或酶替代therapy-naive。参与者被随机分配(2:1)使用交互式响应技术软件,分层的6分钟步行距离和前酶替代疗法的地位,对静脉cipaglucosidase阿尔法(20毫克/公斤)+口服miglustat或静脉alglucosidase阿尔法(20毫克/公斤)+口服安慰剂为52周每隔2周。患者、调查和评估结果被蒙面的治疗任务。主要终点是改变从基线到52周6分钟步行距离,评估使用重复测量的混合效应模型分析比较优势的意向处理人口(所有病人至少一剂研究药物)。这项研究现在已经完成,并在ClinicalTrials.gov注册,NCT03729362。发现:2018年12月3日之间,11月26日,2019年,130名患者筛查合格,125人注册和随机分配接受cipaglucosidase阿尔法+ miglustat (n = 85)或alglucosidase阿尔法+安慰剂(n = 40)。 Two patients in the alglucosidase alfa plus placebo group did not receive any dose due to absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group, five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At week 52, mean change from baseline in 6-min walk distance was 20.8 m (SE 4.6) in the cipaglucosidase alfa plus miglustat group versus 7.2 m (6.6) in the alglucosidase alfa plus placebo group using last observation carried forward (between-group difference 13.6 m [95% CI -2.8 to 29.9]). 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events were fall (25 [29%] patients in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%]) vs 5 [13%]). 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group; only one event (anaphylaxis) was deemed related to study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was deemed unrelated to study drug. There were no deaths. INTERPRETATION: Cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-min walk distance in our overall population of patients with late-onset Pompe disease. Further studies should investigate the longer-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than 2 years, as suggested by our secondary and subgroup analyses. FUNDING: Amicus Therapeutics.

DrugBank数据引用了这篇文章

药物: Cipaglucosidase阿尔法