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

项目总结/摘要 多系统萎缩症是一种罕见的、进展迅速且总是致命的神经退行性疾病 没有改善疾病的治疗方法。对病理生理机制的最新见解表明， 剥夺神经营养因子的关键作用，这些因子已被证明是由间充质分泌的， 干细胞（MSC）。在最近的一项I/II期研究中， 使用剂量递增设计的早期MSA患者。在50 × 106个MSC的剂量下， 一般耐受性良好，但观察到马尾神经根增厚， 无症状或与腰痛有关。使用统一评估标准评估的疾病进展率 MSA评定量表（UMSRS）与匹配的对照组相比明显较慢。一个更 在一个接受联合化疗的附加队列中观察到了有利的副作用特征和几乎没有疾病进展。 每次注射25x106个MSC。神经丝轻链，一个中枢轴突变性的指标，在所有的 患者接受该剂量。MSC给药导致显著的剂量依赖性增加， CSF中的神经营养因子。2-年生存率显著高于自然史队列中观察到的。 基于这些发现，我们提出了一个双盲，安慰剂对照，适应性设计的II期试验， MSA中脂肪来源的鞘内自体MSC，目的是建立最佳治疗频率 同时获得安慰剂对照的疗效和安全性数据，为多中心III期研究做准备。 审判最多将入组76例患有MSA的成人受试者。为了确保同质的患者人群， 疾病进展的速度相当，我们将把研究限制在早期病例，但仍然满足最严格的要求。 诊断共识标准。参与者将接受皮下脂肪活检以获得自体MSC， 这些细胞在马约的细胞治疗实验室中培养、扩增并准备递送。在第一阶段， 受试者将以1：1：1的比例随机分配，以两种不同的注射间隔（每6个月）接受25 × 106个MSC 或每3个月一次）作为两个活性组或乳酸林格氏溶液作为安慰剂组。 在一半受试者入组后，将允许进行中期无效性和有效性分析，以选择 "优胜者"积极治疗，假设不符合无效标准。然后，该研究将重新开始招募第二个 一半受试者采用2：1随机化（"优胜者"活性药物：安慰剂）。患者接受临床评估， 基线、3、6、9和12个月，以得出主要终点，评估疾病进展率 使用UMSRS总和混合效应回归模型。头部和腰椎的MRI将 在基线和12个月时完成，以扩展安全性数据并评估选定脑萎缩率 使用形态测量作为疾病进展的替代标记的区域。脊髓液之前， 给药后，将收集干细胞产物培养基，以进一步探索生物学特性 和骨髓间充质干细胞的影响，并探讨选定的脊髓液标记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.