Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial.
Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial.
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DOI：
10.1016/j.ebiom.2015.11.022
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发表时间：
2015-12
期刊：
影响因子：
11.1
通讯作者：
Kiernan MC
中科院分区：
文献类型：
--
作者：
Park SB;Vucic S;Cheah BC;Lin CS;Kirby A;Mann KP;Zoing MC;Winhammar J;Kiernan MC
肌萎缩侧索硬化症（ALS）的特征是膜兴奋性和Na+通道功能的降低。我们的目的是检查ALS中Na+通道阻滞剂和膜稳定剂氟卡尼的神经保护潜力、安全性和耐受性。在从多个澳大利亚中心招募的可能或明确的ALS受试者中进行了一项为期32周的氟卡尼（200 mg/天）双盲、安慰剂对照、随机临床试验，其中包括12周的导入期（ANZCT注册号ACTRN 12608000338369）。由心脏病专家对患者进行审查，以排除心脏禁忌症。中心药房使用分层排列区组将参与者随机分配（1：1）接受氟卡尼或安慰剂。主要结局指标是治疗期间ALS功能评定量表修订版（ALS FRS-r）的下降斜率。在2008年3月11日至2010年7月1日期间，筛选了67例患者，其中54例随机分配接受氟卡尼（26例患者）或安慰剂（28例患者）。氟卡尼组的4名患者和安慰剂组的3名患者退出研究。氟卡尼组1例患者在研究期间死亡，原因是疾病进展。氟卡尼一般耐受良好，两组均未报告严重不良事件。安慰剂和氟卡尼治疗患者之间的主要结局指标ALS-FRS-r下降率无显著差异（氟卡尼0.65 [95% CI 0.49至0.98];安慰剂0.81 [0.49至2.12] P = 0.50）。然而，氟卡尼组的神经生理学指数下降率显著降低（氟卡尼0.06 [0.01 - 0.11];安慰剂0.14 [0.09 - 0.19]，P = 0.02）。在基线CMAP振幅降低的患者亚组中，安慰剂治疗患者在研究过程中表现出更大的CMAP振幅降低（氟卡尼：− 15 ± 12%;安慰剂− 59 ± 12%; P = 0.03）。与安慰剂相比，氟卡尼治疗的患者在研究期间维持稳定的外周轴突兴奋性。这项初步研究表明，氟卡尼是安全的，并在ALS的潜在生物学有效。有证据表明，氟卡尼稳定外周轴突膜功能的ALS。虽然该研究没有把握度检测氟卡尼对ALS-FRS-r下降的益处的证据，但进一步的研究可能证明氟卡尼在ALS中的临床疗效。为了确定安全性和神经保护潜力，在ALS患者中进行了一项钠离子通道阻断剂氟卡尼的双盲、安慰剂对照、随机试验。氟卡尼耐受性良好，无严重不良事件。虽然有一些证据表明氟卡尼稳定外周轴突膜功能，但该研究不能提供对功能下降有益的证据。肌萎缩侧索硬化症（ALS）患者神经兴奋性功能发生变化。我们进行了一项双盲、安慰剂对照、随机临床试验，以检查膜/神经稳定剂（氟卡尼）对ALS患者的影响。尽管有一些证据表明氟卡尼稳定了ALS患者的外周轴突膜功能，但该研究没有找到氟卡尼有益于患者功能的证据。
Abnormalities in membrane excitability and Na+ channel function are characteristic of amyotrophic lateral sclerosis (ALS). We aimed to examine the neuroprotective potential, safety and tolerability of the Na+ channel blocker and membrane stabiliser flecainide in ALS. A double-blind, placebo-controlled, randomised clinical trial of flecainide (200 mg/day) for 32-weeks with a 12-week lead-in phase was conducted in participants with probable or definite ALS recruited from multiple Australian centres (ANZCT Registry number ACTRN12608000338369). Patients were reviewed by a cardiologist to rule out cardiac contraindications. Participants were randomly assigned (1:1) to flecainide or placebo using stratified permuted blocks by a central pharmacy. The primary outcome measure was the slope of decline of the ALS Functional Rating Scale-revised (ALS FRS-r) during the treatment period. Between March 11, 2008 and July 1, 2010, 67 patients were screened, 54 of whom were randomly assigned to receive flecainide (26 patients) or placebo (28 patients). Four patients in the flecainide group and three patients in the placebo group withdrew from the study. One patient in the flecainide group died during the study, attributed to disease progression. Flecainide was generally well tolerated, with no serious adverse events reported in either group. There was no significant difference in the rate of decline in the primary outcome measure ALS-FRS-r between placebo and flecainide treated patients (Flecainide 0.65 [95% CI 0.49 to 0.98]; Placebo 0.81 [0.49 to 2.12] P = 0.50). However, the rate of decline of the neurophysiological index was significantly reduced in the flecainide group (Flecainide 0.06 [0.01 to 0.11]; Placebo 0.14 [0.09 to 0.19], P = 0.02). Placebo-treated patients demonstrated greater CMAP amplitude reduction during the course of the study in the subset of patients with a reduced baseline CMAP amplitude (Flecainide: − 15 ± 12%; Placebo − 59 ± 12%; P = 0.03). Flecainide-treated patients maintained stabilized peripheral axonal excitability over the study compared to placebo. This pilot study indicated that flecainide was safe and potentially biologically effective in ALS. There was evidence that flecainide stabilized peripheral axonal membrane function in ALS. While the study was not powered to detect evidence of benefit of flecainide on ALS-FRS-r decline, further studies may demonstrate clinical efficacy of flecainide in ALS. To determine safety and neuroprotective potential, a double-blind, placebo-controlled, randomised trial of the Na+ channel blocking agent flecainide was conducted in ALS. Flecainide was well tolerated, with no serious adverse events. Although there was some evidence that flecainide stabilised peripheral axonal membrane function, the study was not powered to provide evidence of benefit on functional decline. Changes in nerve excitability function occur in patients with amyotrophic lateral sclerosis (ALS). We conducted a double-blind, placebo-controlled, randomised clinical trial to examine the impact of a membrane/nerve stabilizer (flecainide) in ALS patients. Although there was some evidence that flecainide stabilised peripheral axonal membrane function in ALS, the study was not powered to find evidence that flecainide benefited patient function.