Phase 2 Pediatric Autologous BMMNC for Severe TBI

治疗严重 TBI 的 2 期儿童自体 BMMNC

• 批准号: 8500878
• 负责人: Charles S Cox
• 金额: $ 74.28万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500878
• 关键词: 14 year old; Adaptive Behaviors; Adult; Age; Albumins; Animal Model; Anisotropy; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Attention; Autologous; Biological; Biological Markers; Biological Preservation; Blinded; Body Weight; Bone Marrow; Brain; Brain Injuries; Caregivers; Cause of Death; Cell Therapy; Cells; Child; Childhood; Childhood Injury; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Cognitive; Corpus Callosum; Corticospinal Tracts; Data; Dose; Future; Hour; Inflammation; Infusion procedures; Injury; Interleukin-10; Interleukin-4; Interleukin-6; Intracranial Pressure; Intravenous; Intravenous infusion procedures; Magnetic Resonance Imaging; Measurement; Measures; Memory; Mental Health; Metric; Microscopic; Microvascular Permeability; Mononuclear; Motor; Nervous System Trauma; Neurocognitive; Neurocognitive Deficit; Neurons; Outcome; Outcome Measure; Outcomes Research; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Placebo Control; Placebos; Plasma; Pre-Clinical Model; Randomized; Regimen; Risk; Safety; Sample Size; Short-Term Memory; Statistical Methods; Stem cells; Stroke; Structure; Testing; Therapeutic; Time; Tonga; Traumatic Brain Injury; United States National Institutes of Health; Variant; Vascular Permeabilities; base; brain tissue; brain volume; central nervous system injury; design; disability; effective therapy; follow-up; functional improvement; functional outcomes; gray matter; improved; indexing; inflammatory marker; injured; interest; neuroinflammation; neuropsychological; pediatric traumatic brain injury; pre-clinical; primary outcome; processing speed; prospective; public health relevance; response; response to injury; white matter

DESCRIPTION (provided by applicant): Pediatric severe traumatic brain injury (TBI) is the leading cause of death and disability in children ages 1-14 years old. There are no effective therapies to treat secondary brain injury. Pre-clinical and Phase I clinical progenitor cell therapies have shown promise in TBI/stroke. This proposed study is a follow-up trial from a previously performed Phase I trial (IND BB12620/NCT00254722) that demonstrated the safety and potential CNS structural preservation effect of intravenous autologous bone marrow mononuclear cells (BMMNC) after severe TBI in children. Pre-clinical data suggest that BMMNCs alter the global neuroinflammatory response to traumatic brain injury, serving to preserve injured/"at-risk" neurons that would otherwise die. Functional improvement has been demonstrated in two animal models of CNS injury: TBI and stroke. Further, structural integrity/preservation is associated with improved functional outcomes. For these reasons, a cell based therapeutic approach is proposed. Autologous cells eliminate the possibility of rejection, and obviate the need for anti- rejection medications. The purpose of this study is to determine the effect of intravenous infusion of autologous BMMNCs on brain structure and neurocognitive/functional outcomes after severe TBI in children. The study is designed as a prospective, randomized, placebo controlled blinded, Phase 2 safety/biological activity study. [A Bayesian adaptive dose escalation design is planned to assess doses of 6 X106 and 10 X106 cells/kg body weight vs. placebo. Aim 1: Determine the effect of autologous BMMNC on CNS white matter (WM), gray matter (GM) structural preservation. Volumetric and DTMRI will be performed acutely (first clinically stable time point), and at one month, 6 (primary outcome) and 12 months (safety) post-injury. Quantitative indices of both macro- and microscopic integrity (e.g. volume and fractional anisotropy/mean diffusivity) will be evaluated over time and compared to baseline measurements (immediate post- injury) and non-treated controls. Aim 2: Determine if autologous BMMNC infusion preserves structural integrity of GM and WM regions of interest [and improves functional and neurocognitive deficits in children after TBI.] We will examine the effect of BMMNC infusion on 1) FA and MD in regions of interest in WM and GM, and 2) specific global, adaptive behavior, psychological health, and neuropsychological outcomes. Aim 3: Determine if autologous BMMNC infusion reduces the neuroinflammatory response to TBI. CNS inflammation will be determined by plasma: CSF ratios of albumin (surrogate for micro vascular permeability), IL-1a, IL-4, Tonga, IL-6, and IL-10, measured every 12 hours for the first 7 days post-injury.

描述(申请人提供)：儿童严重创伤性脑损伤(TBI)是1-14岁儿童死亡和残疾的主要原因。目前还没有有效的治疗继发性脑损伤的方法。临床前和I期临床祖细胞疗法在脑外伤/卒中中显示出良好的前景。这项拟议的研究是先前进行的I期试验(IND BB12620/NCT00254722)的后续试验，该试验证实了儿童重型颅脑损伤后静脉注射自体骨髓单个核细胞(BMMNC)的安全性和潜在的中枢神经系统结构保留效应。临床前数据表明，BMMNC改变了创伤性脑损伤的全局神经炎性反应，保护了原本会死亡的受损/“危险”神经元。在两种中枢神经系统损伤的动物模型中，已经证明了功能的改善：脑外伤和中风。此外，结构完整性/保存与功能结果的改善有关。基于这些原因，提出了一种基于细胞的治疗方法。自体细胞消除了排斥的可能性，并消除了抗排斥药物的需要。本研究的目的是确定静脉输注自体骨髓单个核细胞对儿童重型颅脑损伤后脑结构和神经认知/功能结果的影响。这项研究是一项前瞻性、随机、安慰剂对照、盲法、2期安全性/生物活性研究。[贝叶斯适应性剂量递增设计计划评估6x106和10x106细胞/千克体重与安慰剂相比的剂量。目的1：探讨自体BMMNC对中枢神经系统白质(WM)、灰质(GM)结构的影响。在伤后1个月、6个月(主要结果)和12个月(安全)分别进行急性(第一个临床稳定时间点)、1个月、6个月(主要结果)和12个月(安全)的容量和DTMRI检查。宏观和微观完整性的量化指标(例如体积和各向异性分数/平均扩散率)将随着时间的推移进行评估，并与基线测量(损伤后立即)和未治疗的对照组进行比较。目的2：确定自体BMMNC输注是否保留了GM和WM感兴趣区的结构完整性[并改善了脑外伤后儿童的功能和神经认知障碍]。我们将检验BMMNC输注对1)西医和GM感兴趣区域的FA和MD的影响，以及2)特定的整体、适应行为、心理健康和神经心理结果的影响。目的3：探讨自体骨髓单个核细胞输注是否能降低脑外伤后的神经炎性反应。中枢神经系统炎症将通过血浆：脑脊液白蛋白(微血管通透性替代物)、IL-1a、IL-4、Thoma、IL-6和IL-10的比率来确定，在损伤后的前7天，每12小时测量一次。