Department of Neurology, University Hospital, University of Basel, Switzerland.
N Engl J Med. 2010 Feb 4;362(5):387-401. doi: 10.1056/NEJMoa0909494. Epub 2010 Jan 20.
BACKGROUND: Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis. METHODS: In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point). RESULTS: A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension. CONCLUSIONS: As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.)
背景：与安慰剂或肌内注射干扰素-β-1a 相比，口服 fingolimod（一种能够阻止淋巴细胞从淋巴结迁出的鞘氨醇-1-磷酸受体调节剂）在多发性硬化症的 2 期和 3 期研究中，能显著降低复发率和磁共振成像（MRI）测量的终点。
方法：在我们这项为期 24 个月、双盲、随机研究中，我们纳入了患有复发缓解型多发性硬化症、年龄在 18 岁至 55 岁之间、扩展残疾状况量表（EDSS）评分为 0 至 5.5 分（范围为 0 至 10 分，分数越高表示残疾程度越严重）且在过去 1 年中至少有 1 次复发或在过去 2 年中有 2 次或更多次复发的患者。患者接受每日口服 fingolimod 0.5mg 或 1.25mg 或安慰剂治疗。主要终点是年化复发率（首要终点）和残疾进展时间（次要终点）。
结果：共有 1272 例患者中的 1033 例（81.2%）完成了研究。接受 fingolimod 0.5mg 和 1.25mg 治疗的患者年化复发率分别为 0.18 和 0.16，而接受安慰剂治疗的患者为 0.40（两种剂量与安慰剂相比均 P<0.001）。接受 fingolimod 0.5mg 和 1.25mg 治疗的患者在 24 个月期间残疾进展的风险分别降低了 30%（风险比分别为 0.70 和 0.68；P=0.02 与安慰剂相比，两者均有统计学意义）。接受 fingolimod 0.5mg 和 1.25mg 治疗的患者确认在 3 个月后发生残疾进展的累积概率分别为 17.7%和 16.6%，而接受安慰剂治疗的患者为 24.1%。接受 fingolimod 治疗的患者在 MRI 相关指标（T2 加权图像上新出现或扩大的病变数量、钆增强病变和脑容量损失）方面均优于安慰剂（在第 24 个月时所有比较均 P<0.001）。导致研究停药和 fingolimod 相关的不良事件包括 fingolimod 起始时的心动过缓和房室传导阻滞、黄斑水肿、肝酶水平升高和轻度高血压。
结论：与安慰剂相比，两种剂量的口服 fingolimod 均能改善复发率、残疾进展风险和 MRI 终点。这些获益需要与可能的长期风险进行权衡。（临床试验.gov 注册号，NCT00289978）
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