促红细胞生成素治疗肌萎缩侧索硬化症：一项多中心、随机、双盲、安慰剂对照的III期研究

Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study.

作者信息

Lauria Giuseppe, Dalla Bella Eleonora, Antonini Giovanni, Borghero Giuseppe, Capasso Margherita, Caponnetto Claudia, Chiò Adriano, Corbo Massimo, Eleopra Roberto, Fazio Raffaella, Filosto Massimiliano, Giannini Fabio, Granieri Enrico, La Bella Vincenzo, Logroscino Giancarlo, Mandrioli Jessica, Mazzini Letizia, Monsurrò Maria Rosaria, Mora Gabriele, Pietrini Vladimiro, Quatrale Rocco, Rizzi Romana, Salvi Fabrizio, Siciliano Gabriele, Sorarù Gianni, Volanti Paolo, Tramacere Irene, Filippini Graziella

机构信息

Neuromuscular Disease, IRCCS Foundation, "Carlo Besta" Neurological Institute, Milan, Italy.

NESMOS Department, Neuromuscular Disease Unit, Sant'Andrea Hospital and University of Rome "Sapienza", Rome, Italy.

出版信息

J Neurol Neurosurg Psychiatry. 2015 Aug;86(8):879-86. doi: 10.1136/jnnp-2014-308996. Epub 2015 Jan 16.

OBJECTIVE

To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS).

METHODS

Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91.

RESULTS

We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes.

CONCLUSIONS

RhEPO 40,000 IU fortnightly did not change the course of ALS.

目的

评估重组人促红细胞生成素（rhEPO）治疗肌萎缩侧索硬化症（ALS）的疗效。

方法

25个意大利中心招募了可能有实验室支持、可能或确诊的ALS患者，并将其随机分配（1:1），接受静脉注射rhEPO 40,000国际单位或安慰剂，每两周一次，作为每日100毫克利鲁唑的附加治疗，持续12个月。主要复合结局为生存、气管切开或无创通气（NIV）时间>23小时。次要结局为ALS功能评定量表修订版（ALSFRS-R）、慢肺活量（sVC）和生活质量（ALSAQ-40）下降情况。通过分析导致停药的不良事件（AE）来评估耐受性。随机化序列由计算机按区组生成，按中心、疾病严重程度（ALSFRS-R临界评分为33）和起病类型（脊髓型或延髓型）分层。主要结局分析在所有随机分组的患者中进行，并对整个人群以及按严重程度和起病类型分层的患者进行意向性分析。该研究已注册，欧洲临床试验数据库编号为EudraCT 2009-016066-91。

结果

我们随机分配了208例患者，其中5例（1例rhEPO组和4例安慰剂组）撤回同意书，3例（安慰剂组）在接受治疗前不符合入选标准（视网膜血栓形成、呼吸功能不全、超氧化物歧化酶1基因突变）；103例接受rhEPO治疗和97例接受安慰剂治疗的患者符合分析条件。在12个月时，两组的年化死亡率（rhEPO组为0.11，95%置信区间为0.06至0.20；安慰剂组为0.08，置信区间为0.04至0.17）、气管切开或无创通气时间>23小时的发生率（rhEPO组为0.16，置信区间为0.10至0.27；安慰剂组为0.18，置信区间为0.11至0.30）无差异，按起病类型和基线时的ALSFRS-R分层后也是如此。rhEPO组因AE停药的比例为16.5%，安慰剂组为8.3%。次要结局未发现差异。