Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital, University of Basel, Basel, Switzerland.
Center for Neuroinflammation and Neurotherapeutics, and Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6. Epub 2018 Mar 23.
No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor modulator, on disability progression in patients with SPMS.
This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18-60 years) with SPMS and an Expanded Disability Status Scale score of 3·0-6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144.
1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65-0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.
Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.
Novartis Pharma AG.
在继发进展型多发性硬化症（SPMS）患者中，没有一种治疗方法能持续显示出减缓残疾进展的疗效。我们评估了选择性鞘氨醇 1-磷酸（S1P）受体调节剂西尼莫德对 SPMS 患者残疾进展的影响。
这是一项事件驱动和暴露驱动的、双盲、III 期临床试验，在 31 个国家的 292 家医院诊所和专门的多发性硬化症中心进行。使用交互式反应技术为治疗臂分配与数字相关联的号码，将年龄在 18-60 岁之间、扩展残疾状况量表评分 3.0-6.5 的 SPMS 患者（Expanded Disability Status Scale）随机分为每日口服西尼莫德 2mg 组或安慰剂组，为期 3 年或直至发生预定数量的确认残疾进展（CDP）事件。主要终点是 3 个月 CDP 的时间。对全分析集（即所有随机分配和治疗的患者）进行疗效评估；对安全性集进行安全性评估。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01665144。
2013 年 2 月 5 日至 2015 年 6 月 2 日期间，1651 名患者被随机分配，其中 1105 名患者接受西尼莫德治疗，546 名患者接受安慰剂治疗。一名患者未签署知情同意书，五名患者未接受研究药物治疗，均在西尼莫德组。1645 名患者被纳入分析（西尼莫德组 1099 名，安慰剂组 546 名）。基线时，首次多发性硬化症状出现后的平均时间为 16.8 年（标准差 8.3），从转化为 SPMS 到开始治疗的平均时间为 3.8 年（标准差 3.5）；1055 名（64%）患者在过去 2 年内没有复发，1651 名患者中有 918 名（56%）需要行走辅助。1096 名接受西尼莫德治疗的患者中有 903 名（82%）和 545 名接受安慰剂治疗的患者中有 424 名（78%）完成了研究。1096 名接受西尼莫德治疗的患者中有 288 名（26%）和 545 名接受安慰剂治疗的患者中有 173 名（32%）发生了 3 个月 CDP（风险比 0.79，95%CI 0.65-0.95；相对风险降低 21%；p=0.013）。1099 名接受西尼莫德治疗的患者中有 975 名（89%）和 546 名接受安慰剂治疗的患者中有 445 名（82%）发生了不良事件；西尼莫德组有 197 名（18%）患者发生严重不良事件，安慰剂组有 83 名（15%）患者发生严重不良事件。与安慰剂相比，西尼莫德组更常发生淋巴细胞减少症、肝转氨酶浓度升高、心动过缓、心动过缓性心律失常、黄斑水肿、高血压、水痘带状疱疹再激活和癫痫发作。起始剂量滴定减轻了心脏的首剂量效应。感染、恶性肿瘤和死亡率的发生率在两组之间没有差异。
西尼莫德降低了残疾进展的风险，其安全性与其他 S1P 调节剂相似，可能是 SPMS 的一种有用治疗方法。
诺华制药公司。
