Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.
Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.
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DOI：
10.1002/ana.21743
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发表时间：
2009-08
影响因子：
11.2
通讯作者：
Levin, Bruce
中科院分区：
文献类型：
--
作者：
Kaufmann, Petra;Thompson, John L. P.;Levy, Gilberto;Buchsbaum, Richard;Shefner, Jeremy;Krivickas, Lisa S.;Katz, Jonathan;Rollins, Yvonne;Barohn, Richard J.;Jackson, Carlayne E.;Tiryaki, Ezgi;Lomen-Hoerth, Catherine;Armon, Carmel;Tandan, Rup;Rudnicki, Stacy A.;Rezania, Kourosh;Sufit, Robert;Pestronk, Alan;Novella, Steven P.;Heiman-Patterson, Terry;Kasarskis, Edward J.;Pioro, Erik P.;Montes, Jacqueline;Arbing, Rachel;Vecchio, Darleen;Barsdorf, Alexandra;Mitsumoto, Hiroshi;Levin, Bruce
肌萎缩侧索硬化症(ALS)是一种毁灭性的、目前无法治愈的神经肌肉疾病，氧化应激和线粒体损伤导致神经元丢失。辅酶Q10(CoQ10)是一种抗氧化剂和线粒体辅助因子，已在ALS转基因小鼠以及ALS以外的神经退行性疾病的临床试验中显示出前景。我们的目标是在ALS的两种高剂量辅酶Q10之间进行选择，并确定它是否值得在第三阶段临床试验中进行测试。我们设计并实施了一项多中心试验，采用适应性、两阶段、偏差调整、随机、安慰剂对照、双盲、II期设计(n=185)。两个阶段的主要结果都是9个月后ALS功能评定量表(ALSFRsr)评分下降。阶段1(剂量选择，每组35名参与者)比较了每天1,800和2,700毫克的辅酶Q10剂量。第二阶段(无效性试验，每组75名患者)将第一阶段选择的剂量与安慰剂进行比较。第一阶段选择2700毫克剂量。在第二阶段，该剂量优于安慰剂的预先指定的主要无效假设没有被拒绝。然而，在附带的预先指定的敏感性测试和进一步的补充分析中，它被拒绝了。预先指定的二次分析显示，每天2,700毫克的辅酶Q10与安慰剂没有显著差异。没有安全方面的顾虑。连续9个月每天2,700毫克的辅酶Q10显示出不足以保证第三阶段测试的承诺。考虑到这一结果，结合了剂量选择和无效性测试的适应性第二阶段设计避免了需要更大规模的常规第三阶段试验。
Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial. We designed and implemented a multi-center trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n=185). The primary outcome in both stages was decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo. Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying pre-specified sensitivity test, and further supplementary analyses. Pre-specified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns. CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial.
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