Kappos Ludwig, Gold Ralf, Miller David H, Macmanus David G, Havrdova Eva, Limmroth Volker, Polman Chris H, Schmierer Klaus, Yousry Tarek A, Yang Minhua, Eraksoy Mefkûre, Meluzinova Eva, Rektor Ivan, Dawson Katherine T, Sandrock Alfred W, O'Neill Gilmore N
University Hospital Basel, Basel, Switzerland.
Lancet. 2008 Oct 25;372(9648):1463-72. doi: 10.1016/S0140-6736(08)61619-0.
Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis.
257 patients, aged 18-55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4-24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701.
Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1.4 vs 4.5, p<0.0001). It also reduced number of new or enlarging T2-hyperintense (p=0.0006) and new T1-hypointense (p=0.014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0.44 vs 0.65 for placebo; p=0.272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot.
The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups.
口服富马酸盐（BG00012）可能具有双重抗炎和神经保护作用。我们的目的是评估BG00012在复发缓解型多发性硬化症患者中的疗效和安全性。
257例年龄在18至55岁之间的复发缓解型多发性硬化症患者被随机分配，分别接受每日一次120毫克（n = 64）、每日三次120毫克（n = 64）或每日三次240毫克（n = 64）的BG00012，或安慰剂（n = 65），为期24周。在为期24周的安全性评估延长期内，接受安慰剂治疗的患者改为每日三次服用240毫克BG00012。主要终点是在第12、16、20和24周时脑部MRI扫描上新出现的钆增强（GdE）病灶总数。其他终点包括新出现的GdE病灶累积数（第4至24周）、新出现或扩大的T2高信号病灶、第24周时新出现的T1低信号病灶以及年化复发率。分析是在可进行疗效评估的人群中进行的。同时也评估了安全性和耐受性。本研究已在ClinicalTrials.gov注册，编号为NCT00168701。
与安慰剂相比，每日三次服用240毫克BG00012治疗使第12周至24周新出现的GdE病灶平均总数减少了69%（分别为1.4个和4.5个，p < 0.0001）。与安慰剂相比，它还减少了新出现或扩大的T2高信号病灶数量（p = 0.0006）以及新出现的T1低信号病灶数量（p = 0.014）。BG00012使年化复发率降低了32%（安慰剂组为0.65，BG00012组为0.44；p = 0.272）。接受BG00012治疗的患者比接受安慰剂治疗的患者更常见的不良事件包括腹痛、脸红和潮热。服用BG00012的患者中与剂量相关的不良事件有头痛、疲劳和感觉发热。
BG00012的抗炎作用和良好的安全性值得在大型患者群体中进一步开展长期III期研究。
