Randomized Double-Blind Placebo-Controlled Adaptive Design Trial of Intrathecally Administered Autologous Mesenchymal Stem Cells in Multiple System Atrophy

项目摘要/摘要 摘要多系统萎缩(MSA)是一种罕见、进展迅速且总是致命的神经退行性疾病。 目前还没有治疗疾病的方法。对病理生理机制的最新见解表明 剥夺间充质分泌的神经营养因子的关键作用 干细胞(MSCs)。在最近的I/II期研究中，将脂肪来源的自体MSCs移植到鞘内 对于早期MSA患者，采用剂量递增设计。在50×106的MSCs剂量下，注射 一般耐受性良好，但观察到马尾神经根增厚，这是 无症状的或与下腰痛有关的。使用统一的 MSA评定量表(UMSARS)明显慢于匹配对照组。一个更多的 在接受附加治疗的队列中，可以看到良好的副作用概况和几乎没有疾病进展 每次注射25×106骨髓间充质干细胞。作为中枢轴索变性指标的神经丝轻链在ALL中减少 接受该剂量的患者。MSC给药导致显著的、剂量依赖性的增加 脑脊液中的神经营养因子。2年存活率显著高于自然病史队列中的观察结果。 基于这些发现，我们提出了一项双盲、安慰剂对照、适应性设计的II期试验。 脂肪源性鞘内自体骨髓间充质干细胞在MSA中的应用 同时获得安慰剂对照的疗效和安全性数据，为多中心III阶段做准备 审判。多达76名患有MSA的成年受试者将被登记。为了确保患者群体的同质性， 类似的疾病进展速度，我们将把研究限制在早期病例，但仍然是最严格的 诊断共识标准。参与者将接受皮下脂肪活检以获得自体MSCs， 在梅奥的细胞治疗实验室进行培养、扩增和准备交付。在第一阶段， 受试者将以1：1：1的比例随机接受25x106骨髓间充质干细胞注射，注射间隔为两次(每6个月一次 或每隔3个月)作为两个主动臂或作为安慰剂臂的乳酸林格氏溶液。招聘暂停 在一半的受试者被登记后，将允许进行临时的无效性和有效性分析，以选择 “赢家”的积极治疗假设无效标准没有得到满足。然后，该研究将重新开始招募第二名 采用2：1随机化的受试者中有一半(“赢家”有效：安慰剂)。患者在医院接受临床评估 基线，3、6、9和12个月，以得出主要终点，即评估的疾病进展率 采用UMSARS总效应和混合效应回归模型。头部和腰椎的核磁共振成像将是 在基线和12个月时完成，以扩展安全数据并评估选定大脑的萎缩速度 使用形态测量测量作为疾病进展的替代标记的地区。术前和术后的脊髓液 给药后，将收集干细胞产品培养液，以进一步探索生物学特性 和MSCs的作用，并探索选定的脊髓液标志物作为疾病进展的生物标志物。

Project Summary/Abstract Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurodegenerative disease for which there is no disease-modifying treatment. Recent insights into pathophysiologic mechanisms suggest a crucial role of deprivation of neurotrophic factors which have been shown to be secreted by mesenchymal stem cells (MSCs). In a recent phase I/II study adipose-derived autologous MSCs were delivered intrathecally to patients with early MSA utilizing a dose-escalation design. At a dose of 50x106 MSCs, injections were generally well tolerated, but thickening of cauda equina nerve roots was observed which was either asymptomatic or associated with low back pain. The rate of disease progression assessed using the Unified MSA Rating Scale (UMSARS) was markedly slower compared to a matched control group. An even more favorable side effect profile and virtually lack of disease progression was seen in an add-on cohort receiving 25x106 MSCs per injection. Neurofilament light chain, an index of central axonal degeneration, decreased in all patients receiving that dose. MSC administrations resulted in a marked, dose-dependent increase of neurotrophic factors in CSF. 2-year survival was significantly higher than observed in natural history cohorts. Based on these findings we propose a double-blind, placebo-controlled, adaptive design phase II trial of adipose-derived intrathecal autologous MSCs in MSA with the goal to establish optimal treatment frequency and simultaneously derive placebo-controlled efficacy and safety data in preparation for a multicenter phase III trial. Up to 76 adult subjects with MSA will be enrolled. To ensure a homogenous patient population with comparable rates of disease progression, we will restrict the study to early cases but still fulfilling strictest diagnostic consensus criteria. Participants will undergo a subcutaneous fat biopsy to derive autologous MSCs, which are cultured, expanded, and prepared for delivery in Mayo's Cell Therapeutics Lab. In a first phase, subjects will be randomized 1:1:1 to receive 25x106 MSCs at two different injection intervals (every 6 months or every 3 months) as the two active arms or lactated Ringer's solution as the placebo arm. A recruitment hold after half the subjects have been enrolled will allow for an interim futility and efficacy analysis to select the “winner” active treatment assuming futility criteria are not met. The study will then restart recruiting the second half of subjects utilizing 2:1 randomization (“winner” active: placebo). Patients undergo clinical assessments at baseline, 3, 6, 9, and 12 months to derive the primary endpoint, the rate of disease progression assessed using UMSARS total and a mixed effects regression model. MRI of the head and lumbar spine will be completed at baseline and 12 months to expand safety data and to assess the rate of atrophy of selected brain regions using morphometric measures as surrogate markers of disease progression. Spinal fluid before and after administrations, as well as stem cell product media will be collected to further explore biological properties and effects of MSCs and to explore selected spinal fluid markers as biomarkers of disease progression.