Phase 2 Pediatric Autologous BMMNC for Severe TBI

治疗严重 TBI 的 2 期儿童自体 BMMNC

• 批准号: 9012117
• 负责人: Charles S Cox
• 金额: $ 74.13万
• 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/9012117
• 关键词: 14 year old; Adaptive Behaviors; Adult; Age; Albumins; Animal Model; Anisotropy; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Attention; Autologous; Biological; 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; Cognitive; Corpus Callosum; Corticospinal Tracts; Data; Dose; Future; Health; 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; Microscopic; Microvascular Permeability; Mononuclear; Motor; Nervous System Trauma; Neurocognitive; Neurocognitive Deficit; Neurons; Outcome; Outcome Measure; Outcomes Research; Patients; Pharmaceutical Preparations; Phase; 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; Traumatic injury; United States National Institutes of Health; Variant; Vascular Permeabilities; base; brain tissue; brain volume; central nervous system injury; clinical biomarkers; design; disability; effective therapy; follow-up; functional improvement; functional outcomes; gray matter; improved; improved outcome; indexing; inflammatory marker; injured; interest; neuroinflammation; neuropsychological; pediatric traumatic brain injury; phase I trial; pre-clinical; primary outcome; processing speed; prospective; response; response to injury; trial design; 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（由申请人提供）：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。目前还没有治疗继发性脑损伤的有效方法。临床前和I期临床祖细胞疗法在TBI/卒中中显示出前景。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，该试验证明了静脉注射自体骨髓单个核细胞（BMMNC）在儿童严重TBI后的安全性和潜在的中枢神经系统结构保存效果。临床前数据表明，bmmnc改变了对创伤性脑损伤的整体神经炎症反应，有助于保护受伤/“危险”神经元，否则它们将死亡。两种CNS损伤动物模型：脑外伤和脑卒中已证实功能改善。此外，结构完整性/保存与功能预后的改善有关。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反应的可能性，也避免了抗排斥药物的需要。本研究的目的是确定静脉输注自体bmmnc对儿童严重TBI后脑结构和神经认知/功能结局的影响。该研究是一项前瞻性、随机、安慰剂对照的盲法2期安全性/生物活性研究。[计划采用贝叶斯自适应剂量递增设计来评估6 X106和10 X106细胞/公斤体重与安慰剂的剂量。]目的1：确定自体BMMNC对中枢神经系统白质（WM）、灰质（GM）结构保存的影响。将在急性（第一个临床稳定时间点）、损伤后1个月、6个月（主要结局）和12个月（安全）进行体积测量和DTMRI。随着时间的推移，将评估宏观和微观完整性的定量指标（例如体积和分数各向异性/平均扩散系数），并将其与基线测量（损伤后立即）和未治疗对照进行比较。目的2：确定自体BMMNC输注是否能保持GM和WM感兴趣区域的结构完整性，并改善TBI后儿童的功能和神经认知缺陷。我们将研究BMMNC输注对1)WM和GM感兴趣区域FA和MD的影响，以及2)特定的全局、适应性行为、心理健康和神经心理结果。目的3：确定自体BMMNC输注是否能减轻TBI的神经炎症反应。CNS炎症将通过血浆：脑脊液白蛋白（微血管通透性的替代品）、IL-1a、IL-4、Tonga、IL-6和IL-10的比值来确定，在损伤后的前7天每12小时测量一次。