The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Queen Square MS Centre, UCL Institute of Neurology, London, UK.
Lancet. 2016 Mar 12;387(10023):1075-1084. doi: 10.1016/S0140-6736(15)01314-8. Epub 2016 Jan 28.
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.
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.
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 (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%).
The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis.
Novartis Pharma AG.
目前尚无用于原发性进展型多发性硬化症的治疗方法。芬戈莫德是一种口服鞘氨醇 1-磷酸受体调节剂，在复发性多发性硬化症中有效，但尚未在原发性进展型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疗效。
在 INFORMS 多中心、双盲、安慰剂对照平行组研究中，来自 18 个国家的 148 个中心的原发性进展型多发性硬化症患者随机（1:1）分配，接受口服芬戈莫德或安慰剂治疗至少 36 个月，最长 5 年。患者最初按 1.25mg/天或安慰剂（队列 1）随机分组；然而，在 2009 年 11 月 19 日的方案修正案之后，患者以盲法方式转换为 0.5mg/天的芬戈莫德，而安慰剂组继续使用匹配的安慰剂。从那时起，患者被分配接受 0.5mg/天的芬戈莫德或安慰剂（队列 2）。主要纳入标准为年龄 25-65 岁、临床诊断为原发性进展型多发性硬化症、疾病进展 1 年或以上、以下标准中的两项：阳性脑 MRI；阳性脊髓 MRI；或阳性脑脊液。其他纳入标准包括病程 2-10 年和前 2 年内有客观证据表明残疾进展。患者和研究研究者对分组均不知情。我们使用基于扩展残疾状况量表（EDSS）、25'定时行走测试或 9 孔钉测试的基线变化的新型主要复合终点，评估至少治疗 3 年的研究参与者 3 个月确认的残疾进展时间。所有随机患者至少服用了一剂研究药物。主要疗效分析包括队列 2 中的所有患者和队列 1 中接受安慰剂的患者。安全性分析包括队列 1 和 2 中的所有患者。该研究在 ClinicalTrials.gov 上注册，编号为 NCT00731692。该研究现已结束。
2008 年 9 月 3 日至 2011 年 8 月 30 日期间，970 名患者被随机分配（队列 1 中，147 名接受芬戈莫德 1.25mg 治疗，133 名接受安慰剂；队列 2 中，336 名接受芬戈莫德 0.5mg 治疗，354 名接受安慰剂）。疗效分析集（n=823）包括 336 名随机分配至芬戈莫德 0.5mg 组和 487 名接受安慰剂组的患者。各组的基线特征相似，代表原发性进展型多发性硬化症患者人群（48%女性，平均年龄 48.5 岁[标准差 8.4]，平均 EDSS 4.67[标准差 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 名和 338 名患者发生 3 个月确认的残疾进展，Kaplan-Meier 估计芬戈莫德组患者的残疾进展率为 77.2%（95%CI 71.87-82.51），安慰剂组为 80.3%（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症患者中的研究结果基本一致。芬戈莫德组有 19 名（6%）患者出现淋巴细胞减少，安慰剂组无此情况，5 名（1%）患者出现心动过缓，1 名（<1%）患者出现一度房室传导阻滞，3 名（1%）患者出现一度房室传导阻滞。芬戈莫德组 84 名（25%）患者和安慰剂组 117 名（24%）患者发生严重不良事件，包括 6 名（2%）患者出现黄斑水肿，6 名（1%）患者出现基底细胞癌。
芬戈莫德的抗炎作用并未减缓原发性进展型多发性硬化症的疾病进展。原发性进展型多发性硬化症的治疗策略可能需要与复发性多发性硬化症不同的方法。
诺华制药公司。
