University Hospitals Leuven, Leuven, Belgium.
Institut de Myologie, Université Pierre et Marie Curie INSERM UMR 974, CNRS FRE 3617, Groupe Hospitalier de la Pitié Salpetrière, Paris, France.
Lancet. 2015 May 2;385(9979):1748-1757. doi: 10.1016/S0140-6736(15)60025-3. Epub 2015 Apr 20.
Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids.
In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10-18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884.
31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (-3·05%p [95% CI -7·08 to 0·97], p=0·134, vs placebo -9·01%p [-13·18 to -4·84], p=0·0001; difference 5·96%p [0·16 to 11·76], p=0·044) and ITT populations (-2·57%p [-6·68 to 1·54], p=0·215, vs -8·84%p [-12·73 to -4·95], p<0·0001; difference 6·27%p [0·61 to 11·93], p=0·031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients).
Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy.
Santhera Pharmaceuticals.
心肺衰竭是杜氏肌营养不良症患者的主要致死原因。基于临床前和 2 期证据，我们评估了艾地苯醌在未同时接受糖皮质激素治疗的年轻杜氏肌营养不良症患者中的疗效和安全性。
在一项多中心 3 期临床试验中，比利时、德国、荷兰、瑞士、法国、瑞典、奥地利、意大利、西班牙和美国的患者（年龄 10-18 岁）以 1:1 的比例随机分配，使用中央交互式网络响应系统进行分配，采用区组随机化设计，每个区组 4 例患者，接受艾地苯醌（300 mg，每日 3 次）或匹配的安慰剂口服治疗，持续 52 周。研究人员和患者对治疗分配均设盲。主要终点是通过肺活量计测量的从基线到第 52 周时的最大呼气峰流速（PEF）占预计值的百分比（PEF%p）的变化，分析基于意向治疗（ITT）和改良意向治疗（mITT），mITT 预先定义为排除每年 PEF%p 变化至少有 20%差异的患者，使用基于医院和每周家庭的肺活量计进行测量。这项研究在 ClinicalTrials.gov 注册，编号为 NCT01027884。
在 ITT 人群中，艾地苯醌组有 31 例患者，安慰剂组有 33 例患者；在 mITT 人群中，艾地苯醌组有 30 例患者，安慰剂组有 27 例患者。在 mITT 人群中，艾地苯醌组从基线到第 52 周时 PEF%p 的下降明显低于安慰剂组（-3.05%p [95%CI -7.08 至 -4.84]，p=0.134，与安慰剂组 -9.01%p [-13.18 至 -4.84]相比，p=0.0001；差异 5.96%p [0.16 至 11.76]，p=0.044）和 ITT 人群（-2.57%p [-6.68 至 1.54]，p=0.215，与安慰剂组 -8.84%p [-12.73 至 -4.95]相比，p<0.0001；差异 6.27%p [0.61 至 11.93]，p=0.031）。艾地苯醌对 PEF（L/min）、每周家庭 PEF、FVC 和 FEV1 也有显著影响。艾地苯醌对有既往皮质激素使用史和无皮质激素使用史患者的呼吸功能结局的影响相似。艾地苯醌治疗安全且耐受良好，两组不良反应发生率相似。鼻咽炎和头痛是最常见的不良反应（艾地苯醌组分别有 8 例[25%]和 6 例[19%]，安慰剂组分别有 9 例[26%]和 7 例[21%]）。艾地苯醌组比安慰剂组更常出现短暂和轻度腹泻（8 例[25%]比 4 例[12%]）。
艾地苯醌减少了呼吸功能的丧失，为杜氏肌营养不良症患者提供了一种新的治疗选择。
Santhera 制药公司。
