Biomarkers in the Hyperbaric Oxygen in Brain Injury Treatment Trial

脑损伤治疗试验中高压氧的生物标志物

• 批准号: 10252915
• 负责人: Frederick Kofi Korley
• 金额: $ 56.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10252915
• 关键词: Achievement; Address; Affect; Astrocytes; Biological; Biological Markers; Blood; Blood Circulation; Brain Injuries; C-reactive protein; Caring; Cause of Death; Clinical; Clinical Trials; Complement 3a; Dose; Enrollment; Glasgow Coma Scale; Glasgow Outcome Scale; Glial Fibrillary Acidic Protein; Human; Hyperbaric Oxygen; Hyperbaric Oxygenation; Individual; Inflammatory; Injury; Intensive Care Units; Intervention; Knowledge; Light; Measures; Methods; Monitor; Nerve Degeneration; Neurogenic Inflammation; Neurological outcome; Neuronal Injury; Neurons; Neuroprotective Agents; Observational Study; Outcome; Pathway interactions; Patients; Persons; Phase; Population; Proteins; Randomized; Research Personnel; Severities; Structural Protein; Subgroup; Subjects Selections; Testing; Therapeutic; Therapeutic Agents; Titrations; Traumatic Brain Injury; Traumatic Brain Injury recovery; United States; Validation; Valproic Acid; Work; brain cell; clinical examination; clinical outcome measures; cohort; control trial; disability; experience; improved; improved outcome; individual patient; inflammatory marker; insight; mortality; neurofilament; neurological recovery; neuroprotection; novel; phase III trial; porcine model; predict clinical outcome; predictive marker; prognostic; prognostic model; repository; response; success; systemic inflammatory response; tool; treatment effect; treatment response; treatment trial

Project Summary / Abstract Traumatic Brain Injury (TBI) is a major cause of death and disability both in the United States and worldwide. This proposal focuses on persons with severe TBI (those with prolonged unresponsiveness [Glasgow Coma Scale < 8]). Severe TBI affects nearly 27,000 persons in the United States each year. These patients experience high mortality and require sophisticated care in intensive care units estimated at up to $244 billion dollars each year. There are no therapeutic agents that have been shown to improve outcomes from severe traumatic brain injury (TBI). Critical barriers to progress in developing treatments for severe TBI are the lack of: 1) monitoring biomarkers for assessing individual patient response to treatment; 2) predictive biomarkers for identifying patients likely to benefit from a promising intervention. Currently, clinical examination remains the fundamental tool for monitoring severe TBI patients and for subject selection in clinical trials. However, these patients are typically intubated and sedated, limiting the utility of clinical examinations. Validated monitoring and predictive biomarkers will allow titration of the dose of promising therapeutics to individual subject response, as well as make clinical trials more efficient by enabling the enrollment of subjects likely to benefit. Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and high sensitivity c-reactive protein (hsCRP) are promising biomarkers that may be useful as 1) monitoring biomarkers; 2) predictive biomarkers in severe TBI trials. Although the biological rationale supporting their use is strong, significant knowledge gaps remain. To address these gaps in knowledge, we propose an ancillary observational study leveraging an ongoing severe TBI clinical trial that is not funded to collect biospecimen. The Hyperbaric Oxygen in Brain Injury Treatment (HOBIT) trial, a phase II randomized control clinical trial that seeks to determine the dose of hyperbaric oxygen therapy (HBOT) that that has the highest likelihood of demonstrating efficacy in a phase III trial. The proposed study will: 1) validate the accuracy of candidate monitoring biomarkers for predicting clinical outcome; 2) determine the treatment effect of different doses of HBOT on candidate monitoring biomarkers; and 3) determine whether there is a biomarker defined subset of severe TBI that responds favorably to HBOT. This proposal will: 1) inform a go/no-go decision for a phase III trial of HBOT by providing adjunctive evidence of the effect of HBOT on key biological pathways through which HBOT is hypothesized to affect outcome; 2) provide evidence to support further study of the first monitoring biomarkers of severe TBI; 3) increase the likelihood of success of a phase III trial by identifying the sub-population of severe TBI likely to benefit from HBOT; 4) create a repository of TBI biospecimen which may be accessed by other investigators.

项目摘要/摘要 创伤性脑损伤(TBI)是美国和世界范围内死亡和残疾的主要原因。 这项建议侧重于严重脑外伤患者(那些长期无反应[格拉斯哥昏迷 Scale&lt；8])。在美国，每年有近27,000人受到严重的脑外伤的影响。这些病人 死亡率高，需要在重症监护病房接受复杂的护理，估计高达2440亿美元 每年1美元。目前还没有治疗药物被证明可以改善重症患者的预后。 创伤性脑损伤(TBI)。严重脑外伤的治疗进展的关键障碍是缺乏： 1)监测生物标记物，以评估个体患者对治疗的反应；2)预测生物标记物 确定可能从前景看好的干预措施中受益的患者。目前，临床检查仍是 监测重型脑外伤患者和临床试验中选择受试者的基本工具。然而，这些 患者通常需要插管和镇静，这限制了临床检查的效用。经过验证的监控 预测性生物标记物将允许滴定个别受试者有希望的治疗药物的剂量。 反应，以及通过允许登记可能受益的受试者使临床试验更有效率。 胶质纤维酸性蛋白(GFAP)、神经丝轻链(NFL)和高敏C反应蛋白 (HsCRP)是很有前景的生物标记物，可用作1)监测生物标记物；2)预测生物标记物 严重的脑外伤试验。尽管支持使用它们的生物学原理是强有力的，但重大的知识差距 留下来。为了解决这些知识上的差距，我们建议进行一项辅助的观察性研究，利用 正在进行的严重颅脑损伤临床试验没有获得资金来收集生物胺。大脑中的高压氧 伤害治疗(HOBIT)试验，一项II期随机对照临床试验，旨在确定 高压氧疗法(HBOT)，在第三阶段显示疗效的可能性最高的疗法 审判。这项拟议的研究将：1)验证候选监测生物标志物预测临床的准确性 结果：2)确定不同剂量HBOT对候选监测生物标志物的治疗效果； 以及3)确定是否存在对HBOT有良好反应的重度脑外伤的生物标志物定义的子集。 该提案将：1)通过提供辅助证据，为HBOT第三阶段试验提供通过/不通过的决定 高压氧对假设高压氧影响结局的关键生物学途径的影响；2) 为进一步研究重型颅脑损伤的首批监测生物标志物提供证据；3)增加 通过确定可能受益于以下方面的严重脑损伤亚群，III期试验成功的可能性 HBOT；4)创建一个可供其他研究人员访问的TBI生物样品储存库。