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: 10689546
• 负责人: Frederick Kofi Korley
• 金额: $ 5.2万
• 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/10689546
• 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 Controlled Clinical Trials; Randomized Controlled Trials; 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; 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.

项目概要/摘要 创伤性脑损伤 (TBI) 是美国和全世界死亡和残疾的主要原因。 该提案重点关注患有严重 TBI 的人（长期无反应的人 [格拉斯哥昏迷] 规模 < 8]）。在美国，每年有近 27,000 人受到严重 TBI 的影响。这些患者 死亡率很高，需要在重症监护病房接受精密护理，估计耗资高达 2,440 亿美元 每年美元。目前尚无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 TBI 治疗方法的开发取得进展的关键障碍是缺乏： 1) 监测生物标志物以评估个体患者对治疗的反应； 2) 预测生物标志物 识别可能从有希望的干预措施中受益的患者。目前，临床检查仍然是 监测严重 TBI 患者和临床试验受试者选择的基本工具。然而，这些 患者通常需要插管并服用镇静剂，这限制了临床检查的实用性。经验证的监控 预测性生物标志物将允许对个体受试者调整有前途的治疗药物的剂量 响应，以及通过允许招募可能受益的受试者来提高临床试验的效率。 胶质纤维酸性蛋白 (GFAP)、神经丝轻链 (NfL) 和高灵敏度 C 反应蛋白 (hsCRP) 是有前途的生物标志物，可用于 1) 监测生物标志物； 2) 预测生物标志物 严重的 TBI 试验。尽管支持其使用的生物学原理很充分，但仍存在重大知识差距 保持。为了解决这些知识差距，我们提出了一项辅助观察研究，利用 正在进行的严重 TBI 临床试验没有资助收集生物样本。大脑中的高压氧 损伤治疗 (HOBIT) 试验，一项 II 期随机对照临床试验，旨在确定损伤治疗的剂量 最有可能在 III 期临床试验中显示疗效的高压氧治疗 (HBOT) 审判。拟议的研究将：1）验证候选监测生物标志物用于预测临床的准确性 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； 3) 确定是否存在生物标志物定义的严重 TBI 子集对 HBOT 有良好反应。 该提案将：1）通过提供辅助证据，为 HBOT III 期试验的进行/不进行决定提供信息 HBOT 对关键生物学途径的影响，假设 HBOT 通过这些途径影响结果； 2） 提供证据支持进一步研究严重 TBI 的第一个监测生物标志物； 3）增加 通过确定可能受益的严重 TBI 亚群来确定 III 期试验成功的可能性 HBOT； 4) 创建可供其他研究人员访问的 TBI 生物样本存储库。