Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial
Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s0140-6736(15)01314-8
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发表时间：
2016-03-12
期刊：
影响因子：
168.9
通讯作者：
Kappos, Ludwig
中科院分区：
文献类型：
--
作者：
Lublin, Fred;Miller, David H.;Kappos, Ludwig
背景：目前还没有治疗原发性进展型多发性硬化症的药物被批准。芬戈莫德是一种口服1-磷酸鞘氨醇受体调节剂，对复发性多发性硬化症有效，但尚未在原发性进展性多发性硬化症中进行评估。我们评估了芬戈莫德在原发性进展型多发性硬化症患者中的安全性和有效性。方法在INFORMS中，一项多中心、双盲、安慰剂对照平行组研究，将18个国家148个中心招募的原发性进展型多发性硬化症患者随机分配（1：1）使用计算机生成的区块，接受口服芬戈莫德或安慰剂至少36个月，最长5年。患者最初被分配至芬戈莫德1.25 mg/天或安慰剂组（队列1）;然而，在2009年11月19日的方案修订后，患者以设盲方式转换至芬戈莫德0.5 mg，而安慰剂组患者继续接受匹配的安慰剂。从那时起，患者被分配接受芬戈莫德0.5 mg/天或安慰剂（队列2）。关键入选标准为年龄25 - 65岁，临床诊断为原发性进行性多发性硬化，疾病进展1年或以上，以及以下标准中的两项：脑MRI阳性;脊髓MRI阳性;或脑脊液阳性。其他合格标准包括2 - 10年的病程和过去2年内残疾进展的客观证据。患者和研究者对分组设盲。我们使用了一种新的主要复合终点，该终点基于扩展残疾状态量表（EDSS）、25 '计时步行试验或九孔钉试验较基线的变化，以评估治疗至少3年的研究参与者至3个月确认残疾进展的时间。所有随机化患者均接受了至少一剂研究药物。主要疗效分析包括队列2中的所有患者和队列1中分配至安慰剂组的患者。安全性分析包括队列1和队列2中的所有患者。本研究注册于www.example.com，编号NCT 00731692。结果970例患者在2008年9月3日至2011年8月30日期间被随机分配（队列1中147例接受芬戈莫德1.25 mg治疗，133例接受安慰剂治疗;队列2中336例接受芬戈莫德0.5 mg治疗，354例接受安慰剂治疗）。疗效分析集（n = 823）包括336例随机分配至芬戈莫德0.5 mg组和487例随机分配至安慰剂组的患者。各组的基线特征相似，代表了原发性进展型多发性硬化人群（48%的女性，平均年龄48.5岁[SD 8.4]，平均EDSS 4.67 [SD 1.03]，87%无钆增强病变）。研究结束时，芬戈莫德组和安慰剂组分别有232例和338例患者发生3个月确认的残疾进展，Kaplan-Meier估计值为77.2%。（95% CI 71.87 - 82.51）与80.3%（95% CI 71.87 - 82.51）相比，（73.31 - 87.25）（风险降低5.05%;风险比0.95，95% CI 0.80 - 1.12; p = 0.544）。安全性结果与芬戈莫德在复发性多发性硬化患者中的研究结果基本一致。芬戈莫德组19例（6%）患者发生淋巴细胞减少，安慰剂组0例，心动过缓5例（1%），
Background No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis.Methods In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1: 1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1.25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0.5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0.5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25-65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2-10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed.Findings 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1.25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0.5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n= 823) consisted of 336 patients randomly allocated to fingolimod 0.5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48.5 years [SD 8.4], mean EDSS 4.67 [SD 1.03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77.2% (95% CI 71.87-82.51) of patients in the fingolimod group versus 80.3% (73.31-87.25) of patients in the placebo group (risk reduction 5.05%; hazard ratio 0.95, 95% CI 0.80-1.12; p= 0.544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (