在 UNC13A 基因 SNP rs12608932 位点纯合 C 等位基因的肌萎缩侧索硬化症患者中使用碳酸锂：一项确证性、随机、分组序贯、事件驱动、双盲、安慰剂对照试验的方案。
Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial.
机构信息
Department of Neurology, UMC Utrecht, Utrecht, The Netherlands.
Department of Health Evidence, Radboud UMC, Nijmegen, The Netherlands.
出版信息
Trials. 2022 Dec 5;23(1):978. doi: 10.1186/s13063-022-06906-5.
BACKGROUND
Given the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A.
METHODS
A randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between -6.0 and -2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events.
DISCUSSION
Lithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup.
TRIAL REGISTRATION
EudraCT number 2020-000579-19 . Registered on 29 March 2021.
背景
鉴于肌萎缩侧索硬化症 (ALS) 的遗传异质性较大，遗传亚组可能会因治疗而受益不同。一项探索性荟萃分析发现，在 UNC13A 基因中的 SNP rs12608932 处为 C 等位基因纯合的患者，在接受碳酸锂治疗时具有统计学意义上的生存获益。我们旨在确认 SNP rs12608932 处为 UNC13A 的 C 等位基因纯合的 ALS 患者使用碳酸锂对死亡或呼吸衰竭时间的疗效。
方法
将在欧洲和澳大利亚的 15 个地点进行一项随机、分组序贯、事件驱动、双盲、安慰剂对照试验。患者将进行 UNC13A 基因分型；那些在 SNP rs12608932 处为 C 等位基因纯合的患者将有资格参加。患者必须根据修订后的埃尔埃斯科里亚尔标准诊断为 ALS，并且 TRICALS 风险评分在-6.0 至-2.0 之间。预计将筛选 1200 名患者，以招募 171 名目标样本量的患者。患者将以 2:1 的比例随机分配至碳酸锂或匹配的安慰剂组，并接受最长 24 个月的治疗。主要终点是死亡或呼吸衰竭的时间，以先发生者为准。关键次要终点包括功能下降、呼吸功能、生活质量、耐受性和安全性。在发生 41 例事件后，将进行中期无效性和疗效分析。
讨论
碳酸锂已被证明在 ALS 患者中安全且耐受良好。鉴于良好的安全性概况，潜在的益处被认为超过了与研究参与相关的负担和风险。这项研究可能为碳酸锂在遗传 ALS 亚组中的延长生命潜力提供确凿的证据。
试验注册
EudraCT 编号 2020-000579-19。于 2021 年 3 月 29 日注册。
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