Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis
Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis
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原发性进行性多发性硬化症患者的富马酸二甲酯治疗
DOI：
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
F. Sellebjerg
中科院分区：
文献类型：
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作者：
Helene Højsgaard Chow;J. Talbot;H. Lundell;Camilla Gøbel Madsen;Lisbet Marstrand;T. Lange;M. Mahler;Sophie Buhelt;Rikke Holm Hansen;M. Blinkenberg;J. Romme Christensen;P. Soelberg Sørensen;Marina Rode von Essen;H. Siebner;F. Sellebjerg
背景与目的研究富马酸二甲酯在降低原发性进展型多发性硬化（PPMS）患者脑脊液神经丝轻链（NFL）浓度方面是否优于安慰剂（上级）。方法在富马酸二甲酯治疗进展性多发性硬化（FUMAPMS）的双盲、安慰剂对照II期研究中，PPMS患者以1：1的比例随机分配至富马酸二甲酯240 mg或安慰剂治疗48周。主要终点是CSF中NFL浓度的变化。次要终点包括其他CSF生物标志物以及临床和MRI指标。通过多重插补评价全数据集的疗效，以解释缺失数据。评估了完整数据集的安全性。结果54例患者（平均年龄54.9岁[SD 6.1]，中位扩展残疾状态量表4.0 [四分位数间距4.0-6.0]，疾病持续时间14.1 [SD 9.4]，21例[39%]女性）随机接受安慰剂（n = 27）或富马酸二甲酯（n = 27）治疗。在筛选CSF浓度，调整年龄和性别，NFL，髓鞘碱性蛋白（MBP），可溶性CD 27，几丁质酶3样1，和B细胞成熟抗原高于一组症状对照。富马酸二甲酯组26例患者（96%）和安慰剂组24例患者（89%）完成了随机化阶段。两组间NFL CSF浓度的平均变化无差异（平均差异99 ng/L; 95% CI −292至491 ng/L）。治疗组CSF中的MBP降低（与安慰剂相比，−182 ng/L，95% CI −323至−41 ng/L）。在符合方案分析中，在多重插补数据集中观察到的差异不显著。这在多重插补数据集中名义上具有显著性，但在符合方案分析中不具有显著性。在符合方案分析中未发现这一点。其他次要和三级结局不受影响。富马酸二甲酯组中各种感染、淋巴细胞减少症、潮红和胃肠道副作用更常见。两组之间的严重不良事件相似。讨论富马酸二甲酯治疗48周对PPMS患者的任何研究疗效指标均无影响。我们未观察到富马酸二甲酯治疗未预期的不良事件。试验注册信息Clinicaltrials.gov标识符NCT 02959658。证据分类本研究提供了I类证据，证明对于PPMS患者，与安慰剂治疗相比，富马酸二甲酯治疗对CSF NFL水平无影响。
Background and Objective To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS). Methods In the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set. Results Fifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0–6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI −292 to 491 ng/L). MBP in CSF decreased in the treatment group (−182 ng/L, 95% CI −323 to −41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more frequent in the dimethyl fumarate group. Serious adverse events were similar between groups. Discussion Dimethyl fumarate treatment for 48 weeks had no effect on any of the investigated efficacy measures in patients with PPMS. We did not observe adverse events not anticipated for dimethyl fumarate treatment. Trial Registration Information Clinicaltrials.gov identifier NCT02959658. Classification of Evidence This study provides Class I evidence that for patients with PPMS, dimethyl fumarate treatment has no effect on CSF NFL levels compared with placebo treatment.