Phase 2 Pediatric Autologous BMMNC for Severe TBI

治疗严重 TBI 的 2 期儿童自体 BMMNC

• 批准号: 8638992
• 负责人: Charles S Cox
• 金额: $ 73.08万
• 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/8638992
• 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（由申请人提供）：小儿严重创伤性脑损伤 (TBI) 是 1-14 岁儿童死亡和残疾的主要原因。没有有效的疗法来治疗继发性脑损伤。临床前和 I 期临床祖细胞疗法在 TBI/中风方面已显示出前景。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，该试验证明了儿童严重 TBI 后静脉自体骨髓单核细胞 (BMMNC) 的安全性和潜在的 CNS 结构保存作用。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/“高危”神经元，否则这些神经元就会死亡。功能改善已在两种中枢神经系统损伤动物模型（TBI 和中风）中得到证实。此外，结构完整性/保存与功能结果的改善相关。由于这些原因，提出了基于细胞的治疗方法。自体细胞消除了排斥的可能性，并且不需要抗排斥药物。本研究的目的是确定静脉输注自体 BMMNC 对儿童严重 TBI 后大脑结构和神经认知/功能结果的影响。该研究被设计为一项前瞻性、随机、安慰剂对照、盲法、2 期安全/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。目标 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。将在急性期（第一个临床稳定时间点）以及受伤后 1 个月、6 个月（主要结果）和 12 个月（安全性）进行容量测定和 DTMRI。将随着时间的推移评估宏观和微观完整性的定量指数（例如体积和分数各向异性/平均扩散率），并与基线测量（受伤后立即）和未治疗的对照进行比较。目标 2：确定自体 BMMNC 输注是否能保留 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]。我们将检查 BMMNC 输注对 1) WM 和 GM 感兴趣区域中的 FA 和 MD 的影响，以及 2) 特定的整体适应性行为、心理健康和神经心理学结果。目标 3：确定自体 BMMNC 输注是否会降低对 TBI 的神经炎症反应。 CNS 炎症将通过血浆：脑脊液中白蛋白（微血管通透性的替代）、IL-1a、IL-4、Tonga、IL-6 和 IL-10 的比率来确定，在受伤后的前 7 天每 12 小时测量一次。