Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH 44195, USA.
N Engl J Med. 2012 Sep 20;367(12):1087-97. doi: 10.1056/NEJMoa1206328.
BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate).
In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate.
At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.
In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).
BG-12（富马酸二甲酯）正在开发中，作为治疗复发性多发性硬化症的口服药物，复发性多发性硬化症通常采用注射用药物（干扰素或醋酸格拉替雷）治疗。
在这项 3 期、随机研究中，我们调查了口服 BG-12（每日两次或三次，每次 240mg）与安慰剂治疗复发性多发性硬化症患者的疗效和安全性。活性药物醋酸格拉替雷也被用作参考对照。主要终点是 2 年内的年复发率。该研究的设计并非旨在测试 BG-12 与醋酸格拉替雷的优越性或非劣效性。
在 2 年时，每日两次 BG-12（0.22）、每日三次 BG-12（0.20）和醋酸格拉替雷（0.29）的年复发率明显低于安慰剂（0.40）（相对降低：每日两次 BG-12，44%，P<0.001；每日三次 BG-12，51%，P<0.001；醋酸格拉替雷，29%，P=0.01）。每日两次 BG-12、每日三次 BG-12 和醋酸格拉替雷与安慰剂相比（分别为 21%、24%和 7%），残疾进展的减少并不显著。与安慰剂相比，每日两次 BG-12、每日三次 BG-12 和醋酸格拉替雷均显著减少新的或扩大的 T2 加权高信号病变（均 P<0.001）和新的 T1 加权低信号病变（P<0.001、P<0.001 和 P=0.002）。在 BG-12 与醋酸格拉替雷的事后比较中，除年复发率（每日三次 BG-12）、新的或扩大的 T2 加权高信号病变（两种 BG-12 剂量）和新的 T1 加权低信号病变（每日三次 BG-12）外，差异无统计学意义（每次比较的名义 P<0.05）。与安慰剂相比，活性药物治疗出现的不良反应发生率更高，包括潮红和胃肠道事件（与 BG-12 有关）和注射相关事件（与醋酸格拉替雷有关）。BG-12 未报告恶性肿瘤或机会性感染。淋巴细胞计数随 BG-12 而降低。
在复发性多发性硬化症患者中，BG-12（两种剂量）和醋酸格拉替雷与安慰剂相比，均显著降低了复发率，并改善了神经影像学结果。（由 Biogen Idec 资助；CONFIRM ClinicalTrials.gov 编号，NCT00451451）。
