Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study
Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study
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DOI：
10.1016/s0140-6736(18)30475-6
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发表时间：
2018-03-31
期刊：
影响因子：
168.9
通讯作者：
Dahlke, Frank
中科院分区：
文献类型：
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作者：
Kappos, Ludwig;Bar-Or, Amit;Dahlke, Frank
背景：没有一种治疗在减缓继发性进展型多发性硬化（SPMS）患者的残疾进展方面一直有效。我们评估了辛波莫德，选择性鞘氨醇1-磷酸（S1 P）受体1，5调制剂，残疾进展SPMS.Methods患者的影响，这一事件驱动的和治疗驱动的，双盲，3期试验在31个国家的292家医院诊所和专门的多发性硬化症中心。使用交互式应答技术分配与治疗组相关的数字，将患有SPMS且扩展残疾状态量表评分为3.0-6.5的患者（年龄18-60岁）随机分配（2：1）至每日一次口服辛波莫德2 mg或安慰剂，持续长达3年或直至发生预定数量的确认残疾进展（CDP）事件。主要终点是至3个月CDP的时间。评估了全分析集（即，所有随机分配和接受治疗的患者）的疗效;评估了安全性集的安全性。本试验已在ClinicalTrials注册。在2013年2月5日至2015年6月2日期间，1651名患者被随机分配（1105名分配到辛波莫德组，546名分配到安慰剂组）。1名患者未签署知情同意书，5名患者未接受研究药物，均为辛波莫德组。1645名患者被纳入分析（辛波莫德组1099名，安慰剂组546名）。基线时，自首次出现多发性硬化症状的平均时间为16.8年（SD 8.3），自转换为SPMS的平均时间为3.8年（SD 3.5）; 1055例（64%）患者在过去2年内未复发，1651例患者中有918例（56%）需要行走辅助。903名（82%）接受辛波莫德的患者和424名（78%）接受安慰剂的患者完成了研究。1096例辛波莫德治疗患者中288例（26%）和545例安慰剂治疗患者中173例（32%）出现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名接受辛波莫德的患者中有975名（89%）发生不良事件，而546名接受安慰剂的患者中有445名（82%）发生不良事件;辛波莫德组有197名（18%）患者报告了严重不良事件，而安慰剂组有83名（15%）患者报告了严重不良事件。辛波莫德组淋巴细胞减少症、肝转氨酶浓度升高、治疗开始时心动过缓和缓慢性心律失常、黄斑水肿、高血压、水痘带状疱疹再激活和惊厥的发生率高于安慰剂组。初始剂量滴定可缓解心脏首次给药效应。感染，恶性肿瘤和死亡率的频率在组间没有差异。解释辛波莫德降低了残疾进展的风险，其安全性与其他S1 P调节剂相似，可能是SPMS的有效治疗。
Background 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 1,5 modulator, on disability progression in patients with SPMS.Methods 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.Findings 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.Interpretation 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.