Fingolimod for the Treatment of Intracerebral Hemorrhage A 2-Arm Proof-of-Concept Study
Fingolimod for the Treatment of Intracerebral Hemorrhage A 2-Arm Proof-of-Concept Study
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芬戈莫德治疗脑出血的 2 臂概念验证研究
DOI：
10.1001/jamaneurol.2014.1065
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发表时间：
2014-09-01
期刊：
影响因子：
29
通讯作者：
Shi, Fu-Dong
中科院分区：
文献类型：
--
作者：
Fu, Ying;Hao, Junwei;Shi, Fu-Dong
重要的是，脑出血(ICH)后不久发生的炎症反应有助于血肿周围水肿(Phe)和继发性脑损伤的形成和发展。我们假设调节脑部炎症可以减少脑水肿，从而改善多发性硬化症患者的临床预后。目的研究口服Fingolimod是否安全有效。Fingolimod是美国食品和药物管理局(FDA)批准的一种治疗多发性硬化症的1-磷酸鞘氨醇受体调节剂，用于缓解ICH患者的Phe和神经功能障碍。临床和神经影像特征匹配的患者接受标准护理，使用或不使用口腔指状物。研究在天津医科大学总医院进行。干预：所有患者均接受标准治疗(对照组)或联合芬托莫特(FTY720，Gilenya)，0.5 mg，口服，连续3天。治疗开始于基线CT扫描后1小时内，不迟于症状出现后72小时。临床评估和磁共振成像分别监测3个月的神经功能状态和血肿和Phe体积(EV)和相对Phe(EV除以血肿体积)。结果与对照组相比，接受Fingolimod治疗的患者神经功能损害减轻，第7天恢复格拉斯哥昏迷评分15分(100%对50%，P=.01)，美国国立卫生研究院卒中评分减少7.5vs0.5(P<；.001)。这些患者的神经功能在第一周得到改善，同时循环中的淋巴细胞数量减少。3个月后，接受Fingolimod治疗的患者达到神经功能完全恢复的比例更大(改良Barthel指数评分范围95-100；63%vs0%；P=.001；改良Rankin评分范围0-1；63%vs0%；P=.001)，报告的脑出血相关肺部感染较少。治疗组血肿周围水肿体积和rPhe显著小于对照组(第7天EV，47mLvs 108mL，P=0.04；第14天EV，55mLvs 124mL，P=0.07；第7天rPhe，2.5vs6.4，P&t；.001；第14天rPhe，2.6vs7.7，P=.003)。两组间不良事件的发生率无差异。结论与相关的是，在中小规模的幕上深部脑出血患者中，发病72小时内口服Fingolimod是安全的，减少了Phe，减轻了神经功能障碍，促进了康复。Fingolimod预防脑出血患者继发性脑损伤的疗效值得在后期试验中进一步研究。
IMPORTANCE Pronounced inflammatory reactions occurring shortly after intracerebral hemorrhage (ICH) contribute to the formation and progression of perihematomal edema (PHE) and secondary brain injury. We hypothesized that modulation of brain inflammation reduces edema, thus improving clinical outcomes in patients with ICH.OBJECTIVE To investigate whether oral administration of fingolimod, a Food and Drug Administration-approved sphingosine 1-phosphate receptor modulator for multiple sclerosis, is safe and effective in alleviating PHE and neurologic deficits in patients with ICH.DESIGN, SETTING, AND PARTICIPANTS In this 2-arm, evaluator-blinded study, we included 23 patients with primary supratentorial ICH with hematomal volume of 5 to 30mL. Clinical and neuroimaging feature-matched patients were treated with standard care with or without oral fingolimod. The study was conducted in Tianjin Medical University General Hospital, Tianjin, China.INTERVENTIONS All patients received standard management alone (control participants) or combined with fingolimod (FTY720, Gilenya), 0.5mg, orally for 3 consecutive days. Treatment was initiated within 1 hour after the baseline computed tomographic scan and no later than 72 hours after the onset of symptoms.MAIN OUTCOMES AND MEASURES Neurologic status and hematomal and PHE volumes (Ev) and relative PHE, defined as Ev divided by hematomal volume, were monitored by clinical assessment and magnetic resonance imaging, respectively, for 3 months.RESULTS Patients treated with fingolimod exhibited a reduction of neurologic impairment compared with control individuals, regained a Glasgow Coma Scale score of 15 by day 7 (100% vs 50%, P = .01), and had a National Institutes of Health Stroke Scale score reduction of 7.5 vs 0.5 (P < .001). Neurologic functions improved in these patients in the first week coincident with a reduction of circulating lymphocyte counts. At 3 months, a greater proportion of patients receiving fingolimod achieved full recovery of neurologic functions (modified Barthel Index score range, 95-100; 63% vs 0%; P = .001; modified Rankin Scale score range, 0-1; 63% vs 0%; P = .001), and fewer reported ICH-related lung infections. Perihematomal edema volume and rPHE were significantly smaller in fingolimod-treated patients than in control individuals (Ev at day 7, 47 mL vs 108 mL, P = .04; Ev at day 14, 55 mL vs 124 mL, P = .07; rPHE at day 7, 2.5 vs 6.4, P < .001; rPHE at day 14, 2.6 vs 7.7, P = .003, respectively). We recorded no differences between groups in the occurrence of adverse events.CONCLUSIONS AND RELEVANCE In patients with small-to moderate-sized deep primary supratentorial ICH, administration of oral fingolimod within 72 hours of disease onset was safe, reduced PHE, attenuated neurologic deficits, and promoted recovery. The efficacy of fingolimod in preventing secondary brain injury in patients with ICH warrants further investigation in late-phase trials.