Randomized Placebo-Controlled Phase II Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis

ObjectiveUncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study.MethodsPatients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0–6.5 were randomized to receive IV 1–2×106 bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects.ResultsAt baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1–8.8 vs 12.3, 95% CI = 4.4–34.5, p = 0.064), and at the end of study to reduced mean GEL (−2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients.ConclusionBone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties.ClinicalTrials.gov NCT01228266

研究目的：既往针对多发性硬化患者的间充质干细胞 (mesenchymal stem cells, MSCs) 开展的非对照研究显示其具有一定获益效果。本项随机双盲安慰剂对照交叉II期临床试验，旨在探讨间充质干细胞在复发缓解型多发性硬化患者中的安全性与有效性。有效性评价以治疗6个月及试验结束时，磁共振成像 (magnetic resonance imaging, MRI) 检出的钆增强病灶 (gadolinium-enhancing lesions, GEL) 累积数量为指标。

研究方法：将对常规治疗应答不佳的患者纳入本研究，纳入标准为：过去12个月内至少出现1次复发和/或MRI检出GEL，病程2~10年，扩展残疾状态量表 (Expanded Disability Status Scale, EDSS) 评分3.0~6.5。符合入组标准的患者被随机分为两组，分别接受静脉输注1~2×10^6个骨髓来源间充质干细胞每千克体重，或安慰剂治疗。治疗6个月后，两组患者交叉接受对照治疗，并继续随访6个月。次要终点包括临床结局指标（复发情况、经EDSS评分及多发性硬化功能复合评分评估的残疾状态）、多项脑部MRI指标及光学相干断层扫描检测指标。本研究同时开展免疫学检测以评估间充质干细胞的免疫调节作用。

研究结果：基线时共9名患者被随机分组，其中间充质干细胞组5例，安慰剂组4例。1名安慰剂组患者在前5个月出现3次复发后退出研究。本研究未观察到严重不良事件。治疗6个月时，间充质干细胞治疗组的平均GEL累积数呈降低趋势（3.1，95%置信区间[CI] 1.1~8.8 vs 安慰剂组12.3，95%CI 4.4~34.5，p=0.064）；试验结束时，该组平均GEL累积数同样呈降低趋势（-2.8±5.9 vs 3±5.4，p=0.075）。次要终点未检测到显著组间差异。间充质干细胞治疗组患者血液中Th1（CD4+ IFN-γ+）细胞频率呈非显著性降低。

研究结论：骨髓来源间充质干细胞安全性良好，可降低炎性MRI相关参数，支持其免疫调节特性。本试验注册号为ClinicalTrials.gov NCT01228266