Background

Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, have been proposed as a promising therapeutic option for people with multiple sclerosis on the basis of their immunomodulatory and neuroprotective properties. The MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study was devised to evaluate the safety, tolerability, and activity of autologous MSCs derived from bone marrow and infused intravenously in patients with active multiple sclerosis.

Methods

MESEMS is a randomised phase 2 trial done at 15 sites in nine countries. Patients (aged 18–50 years) with active relapsing-remitting or progressive multiple sclerosis were included if they had a disease duration of 2–15 years since onset of multiple sclerosis and an Expanded Disability Status Scale score of 2·5–6·5. Patients were randomly assigned (1:1), according to a crossover design, to receive a single intravenous dose of autologous bone marrow-derived MSCs followed by placebo at week 24, or to receive placebo followed by autologous MSCs at week 24, with a follow-up visit at week 48. Primary objectives were to test safety and activity of MSC treatment. The primary safety endpoint was to assess the number and severity of adverse events within each treatment arm. The primary efficacy endpoint was the number of gadolinium-enhancing lesions (GELs) counted over week 4, 12, and 24 compared between treatment groups. The primary efficacy endpoint was assessed in the full analyis set, after all participants completed the week 24 visit. Efficacy endpoints were evaluated using a predefined statistical testing procedure. Safety was monitored throughout the study by recording vital signs and adverse events at each visit.

Findings

From July 16, 2012, until July 31, 2019, 144 patients were randomly assigned to first receive early intravenous infusion of autologous bone marrow-derived MSCs (n=69) or placebo (n=75). MSC treatment did not meet the primary endpoint of efficacy on the total number of GELs accumulated from baseline to week 24 (rate ratio [RR] 0·94, 95% CI 0·58–1·50; p=0·78). 213 adverse events were recorded, similarly distributed between groups (93 cases recorded in 35 [51%] of 69 patients treated first with MSCs vs 120 cases in 42 [56%] of 75 patients infused first with placebo). The most frequent adverse events reported were infection and infestations, with a total of 54 (25%) of 213 adverse events (18 [19%] of 93 in the early-MSC group and 36 [30%] of 120 in the delayed-MSC group). Nine serious adverse events were reported in seven patients treated with placebo versus none in the MSC group. All serious adverse events were considered to be unrelated to the treatment infusion. No deaths were reported during the study.

Interpretation

Bone marrow-derived MSC treatment was safe and well tolerated but did not show an effect on GELs, an MRI surrogate marker of acute inflammation, in patients with active forms of multiple sclerosis, at week 24. Thus, this study does not support the use of bone marrow-derived MSCs to treat active multiple sclerosis. Further studies should address the effect of MSCs on parameters related to tissue repair.

Funding

Fondazione Italiana Sclerosi Multipla (FISM), the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), and the Multiple Sclerosis International Federation (MSIF) for centralised activities. Individual trials participating in the MESEMS network are funded by the following agencies: FISM and Compagnia di San Paolo (Italy); The Danish Multiple Sclerosis Society, The Toyota Foundation, and Danish Blood Donors’ Research Foundation (Denmark); the Spanish Health Research Institute Carlos 3 and the Andalusian Public Foundation Progreso y Salud (Spain); the Royan Institute for Stem Cell Biology and Technology (Iran); the Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Paracelsus Medical University, and Salzburg (Austria); the Fondation pour l’aide à la recherche sur la sclérose en plaques (ARSEP), French Muscular Dystrophy Association (AFM)-Telethon (France); the UK Multiple Sclerosis Society and the UK Stem Cell Foundation (UK); and the Multiple Sclerosis Society of Canada and The Multiple Sclerosis Scientific Research Foundation and Research Manitoba (Canada).

中文翻译：

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间充质干细胞与安慰剂在多发性硬化症 (MESEMS) 中的安全性、耐受性和活性：2 期、随机、双盲交叉试验

背景

间充质干细胞 (MSCs)，也称为间充质基质细胞，基于其免疫调节和神经保护特性，已被提议作为多发性硬化症患者的一种有前途的治疗选择。用于多发性硬化症的间充质干细胞 (MESEMS) 研究旨在评估自体骨髓间充质干细胞在活动性多发性硬化症患者中静脉输注的安全性、耐受性和活性。

方法

MSEMS 是一项在 9 个国家的 15 个地点进行的随机 2 期试验。如果自多发性硬化症发病后病程为 2-15 年且扩展残疾状态量表评分为 2·5-6·5 . 根据交叉设计，患者被随机分配（1:1），在第 24 周接受单次静脉注射自体骨髓来源的 MSCs，然后是安慰剂，或者在第 24 周接受安慰剂，然后是自体 MSCs。在第 48 周进行随访。主要目标是测试 MSC 治疗的安全性和活性。主要安全终点是评估每个治疗组内不良事件的数量和严重程度。主要疗效终点是治疗组之间在第 4、12 和 24 周内计算的钆增强病变 (GEL) 的数量。在所有参与者完成第 24 周访问后，在完整分析集中评估主要疗效终点。使用预定义的统计测试程序评估功效终点。通过在每次就诊时记录生命体征和不良事件来监测整个研究的安全性。

发现

从 2012 年 7 月 16 日至 2019 年 7 月 31 日，144 名患者被随机分配首先接受早期静脉输注自体骨髓来源的 MSC（n=69）或安慰剂（n=75）。MSC 治疗未达到从基线到第 24 周累积的 GEL 总数的主要疗效终点（比率 [RR] 0·94，95% CI 0·58–1·50；p=0·78）。记录了 213 起不良事件，在各组之间分布相似（第一次接受 MSCs 治疗的 69 名患者中有 35 名 [51%] 记录了 93 例，对比75 名患者中的 42 名 [56%] 中的 120 名患者首先输注安慰剂）。报告的最常见的不良事件是感染和侵染，总共 213 起不良事件中的 54 起 (25%) （早期 MSC 组 93 起中的 18 起 [19%] 和延迟治疗组 120 起中的 36 起 [30%] MSC 组）。7 名接受安慰剂治疗的患者报告了 9 例严重不良事件，而 MSC 组则没有。所有严重的不良事件都被认为与治疗输注无关。研究期间没有死亡报告。

解释

骨髓来源的 MSC 治疗安全且耐受性良好，但在第 24 周对活动性多发性硬化症患者的 GEL（急性炎症的 MRI 替代标志物）没有显示效果。因此，本研究不支持使用骨髓来源的间充质干细胞治疗活动性多发性硬化症。进一步的研究应该解决 MSCs 对与组织修复相关的参数的影响。

资金

Fondazione Italiana Sclerosi Multipla (FISM)、欧洲多发性硬化症治疗和研究委员会 (ECTRIMS) 和多发性硬化症国际联合会 (MSIF) 的集中活动。参与 MESEMS 网络的个别试验由以下机构资助：FISM 和 Compagnia di San Paolo（意大利）；丹麦多发性硬化症协会、丰田基金会和丹麦献血者研究基金会（丹麦）；西班牙健康研究所 Carlos 3 和安达卢西亚公共基金会 Progreso y Salud（西班牙）；Royan 干细胞生物学和技术研究所（伊朗）；萨尔茨堡脊髓损伤和组织再生中心、帕拉塞尔苏斯医科大学和萨尔茨堡（奥地利）；The Fondation pour l'aide à la recherche sur la sclérose enplas (ARSEP) 法国肌营养不良协会（AFM）-Telethon（法国）；英国多发性硬化症协会和英国干细胞基金会（英国）；以及加拿大多发性硬化症协会和多发性硬化症科学研究基金会和马尼托巴研究中心（加拿大）。