High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study
High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study
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DOI：
10.1007/s00702-004-0220-1
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发表时间：
2005-05-01
影响因子：
3.3
通讯作者：
Ludolph, AC
中科院分区：
文献类型：
--
作者：
Graf, M;Ecker, D;Ludolph, AC
越来越多的证据表明，氧化应激可能参与肌萎缩侧索硬化症（ALS）的发病机制。抗氧化剂维生素E（α-生育酚）已被证明可以减缓转基因小鼠瘫痪的发作和进展，转基因小鼠表达了在某些形式的家族性ALS中发现的超氧化物歧化酶基因突变。目前的研究是一项双盲、安慰剂对照、随机、分层、平行组临床试验，旨在确定维生素E（5000 mg/天）与利鲁唑联合使用是否可有效减缓疾病进展。方法.本研究纳入了6个德国中心的160例可能或明确的ALS患者（根据埃尔埃斯科里亚标准），病程少于5年，接受利鲁唑治疗，并随机分配接受α-生育酚（5000 mg/天）或安慰剂治疗18个月。根据临床试验的WFN标准，主要结局指标是生存率，计算至死亡、气管造口术或永久辅助通气的时间。次要结局指标为通过改良Norris肢体和延髓量表、手动肌肉测试（BMRC）、痉挛量表、痉挛功能和疾病影响特征（SIP ALS/19）评估的功能恶化率。在入组时和此后研究期间每4个月评估一次患者，直至第16个月，并在第18个月末次访视时评估患者。采集维生素E样本用于试验的依从性检查和质量控制。对于安全性，在基线时进行体格检查，然后在每次访视时进行体格检查，直至第18个月停止治疗。基线时记录身高和体重，随访访视时仅记录体重。在每次访视时记录神经系统检查以及生命体征（心率和血压）、ECG和VEP。此外，记录自发报告的不良事件和严重不良事件，并进行标准实验室检查，包括肝功能检查。对于统计分析，考虑用于主要结局指标的人群是“意向治疗”（ITT）人群，包括接受至少一次治疗剂量的所有随机化患者（n = 160例患者）。对于次要结局指标，对患者人群进行了双向方差分析，该患者人群包括入选后至少进行了一次评估的所有随机化患者。结果关于主要终点，使用分层对数秩或Wilcoxon检验均未检测到安慰剂组和治疗组之间的显著差异。功能评估显示支持维生素E的边际趋势，但未达到显著性。结论主要和次要结局指标均不能确定大剂量维生素E作为利鲁唑的辅助治疗是否能有效减缓ALS的疾病进展。可能需要更大或更长的研究。然而，这种大剂量给药似乎在该患者人群中没有任何显著的副作用。
Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole. Methods. 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP's were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an "intent-to-treat" (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. Results. Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. Conclusion. Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.