Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke
Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke
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DOI：
10.1161/strokeaha.119.026318
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发表时间：
2019-10-01
期刊：
影响因子：
8.3
通讯作者：
Cramer, Steven C.
中科院分区：
文献类型：
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作者：
Levy, Michael L.;Crawford, John R.;Cramer, Steven C.
背景和目的-中风是导致长期残疾的主要原因。慢性卒中和严重功能缺陷患者的治疗选择有限。目前的研究检查了静脉注射同种异体间充质干细胞在这一人群中的安全性和初步疗效估计。方法-进入标准包括缺血性卒中>6个月前和实质性损害（国立卫生研究院卒中量表评分>= 6）和残疾。入组者接受单次静脉注射同种异体缺血耐受间充质干细胞。I期采用剂量递增设计（3层，每层n=5）。II期是一个扩展的安全性队列。主要终点是1年内的安全性。结果-在第1阶段（n=15）中，发现每种剂量（0.5、1.0和1.5百万细胞/kg体重）是安全的，因此第2阶段受试者（n=21）接受1.5百万细胞/kg。基线时，受试者（n=36）平均卒中后4.24.6年，年龄61.110.8岁，国立卫生研究院卒中量表评分8（6.5-10），Barthel指数65 +/- 29。2例失访，1例退出，2例死亡（与研究治疗无关）。在15起严重不良事件中，无一可能或很可能与研究治疗相关。两起轻度不良事件可能与研究治疗有关，尿路感染和静脉注射部位刺激。根据系列检查、心电图、实验室检查和胸部/腹部/骨盆计算机断层扫描，治疗是安全的。在12个月的随访中，所有行为终点均显示出显着改善。比如说，Barthel指数评分增加6.8 +/- 11.4分6个月时（平均值+/- SD）（P=0.002）和12个月时的10.8 +/- 15.5分（P= 95）从基线时的11.4%增加到6个月时的27.3%和12个月时的35.5%。耐受性间充质干细胞在慢性中风和实质性功能缺陷患者中是安全的，并提示行为改善。这些数据支持在该人群中进行该疗法的随机、安慰剂对照研究。
Background and Purpose-Stroke is a leading cause of long-term disability. Limited treatment options exist for patients with chronic stroke and substantial functional deficits. The current study examined safety and preliminary efficacy estimates of intravenous allogeneic mesenchymal stem cells in this population.Methods-Entry criteria included ischemic stroke >6 months prior and substantial impairment (National Institutes of Health Stroke Scale score >= 6) and disability. Enrollees received a single intravenous dose of allogeneic ischemia-tolerant mesenchymal stem cells. Phase 1 used a dose-escalation design (3 tiers, n=5 each). Phase 2 was an expanded safety cohort. The primary end point was safety over 1-year. Secondary end points examined behavioral change.Results-In phase 1 (n=15), each dose (0.5, 1.0, and 1.5 million cells/kg body weight) was found safe, so phase 2 subjects (n=21) received 1.5 million cells/kg. At baseline, subjects (n=36) averaged 4.24.6 years poststroke, age 61.110.8 years, National Institutes of Health Stroke Scale score 8 (6.5-10), and Barthel Index 65 +/- 29. Two were lost to follow-up, one was withdrawn and 2 died (unrelated to study treatment). Of 15 serious adverse events, none was possibly or probably related to study treatment. Two mild adverse events were possibly related to study treatment, a urinary tract infection and intravenous site irritation. Treatment was safe based on serial exams, electrocardiograms, laboratory tests, and computed tomography scans of chest/abdomen/pelvis. All behavioral end points showed significant gains over the 12-months of follow-up. For example, Barthel Index scores increased by 6.8 +/- 11.4 points (mean +/- SD) at 6-months (P=0.002) and by 10.8 +/- 15.5 points at 12-months (P= 95) increased from 11.4% at baseline to 27.3% at 6-months and to 35.5% at 12-months.Conclusions-Intravenous transfusion of allogeneic ischemia-tolerant mesenchymal stem cell in patients with chronic stroke and substantial functional deficits was safe and suggested behavioral gains. These data support proceeding to a randomized, placebo-controlled study of this therapy in this population.