Biomarkers of Injury and Outcome in Pro-TECT III (BIO-ProTECT)

Pro-TECT III (BIO-ProTECT) 中损伤和结果的生物标志物

• 批准号: 8258750
• 负责人: MICHAEL Ross FRANKEL
• 金额: $ 41.58万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258750
• 关键词: Acute; Ancillary Study; Animal Model; Apoptosis; Biological Markers; Blood; Blood Circulation; Brain Injuries; Cause of Death; Cerebral Edema; Cessation of life; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Data; Diagnostic; Disease; Double-Blind Method; Early treatment; Edema; Enrollment; Event; Favorable Clinical Outcome; Functional disorder; Future; Glasgow Coma Scale; Glasgow Outcome Scale; Glial Fibrillary Acidic Protein; Goals; Hour; Human; Hydrolase; In Vitro; Injury; Intervention; Intracranial Pressure; Intravenous; Link; Measures; Methodology; Modeling; Motion; Multi-Institutional Clinical Trial; Necrosis; Outcome; Outcome Measure; Patients; Phase III Clinical Trials; Placebo Control; Progesterone; Proteins; Proteolysis; Proxy; Randomized; Risk; Sampling; Serum; Severities; Spectrin; Structural Protein; TBI Patients; Tissues; Traumatic Brain Injury; Treatment outcome; Ubiquitin C; United States National Institutes of Health; Validation; X-Ray Computed Tomography; arm; brain cell; cell injury; clinical effect; design; disability; evidence base; follow-up; improved; in vivo; innovation; insight; neurotrophic protein S100beta; outcome forecast; predictive modeling; prognostic; response; tool; treatment effect; treatment response; treatment strategy; treatment trial; young adult

DESCRIPTION (provided by applicant): Traumatic Brain Injury (TBI) is the leading cause of death and disability among young adults in the US and worldwide. The pathophysiology of acute TBI is characterized by a cascade of primary and secondary cellular events set in motion by the initial injury, and ultimately leading to cerebral edema, cellular disruption and death. Tissue breakdown in TBI results in the release of structural proteins into the bloodstream, including S100B, GFAP, UCH-L1 and SBDP150. These proteins may serve as useful biomarkers of the severity of the injury and perhaps provide useful information about response to treatment. Preliminary data from our group suggest that serum levels of S100B, GFAP, UCH-L1 and SBDP150 are more accurate predictors of the extent of injury than the Glasgow Coma Scale and computed tomography. However, none of these potential biomarkers are sufficiently validated to assess their clinical utility. The studies proposed here will follow up and extend these initial studies with the goal of providing proof that one or more of these proteins is a useful diagnostic tool for assessing injury severity, guiding treatment decisions, and developing innovative TBI interventions. This proposal, "Biomarkers of Injury and Outcome in ProTECT III" (BIO-ProTECT), is designed to validate our preliminary findings by prospectively assessing biomarker levels in patients who are enrolled in the NIH sponsored double blind randomized, placebo-controlled multicenter Phase III clinical trial of intravenous progesterone in acute TBI entitled, "Progesterone for Traumatic Brain Injury: Experimental Clinical Treatment Trial (ProTECT III; D. Wright, PI). ProTECT III will randomize 1,140 patients at 17 centers in the US with the goal of determining if administration of progesterone is effective in improving outcome measured 6 months after injury. ProTECT III provides an ideal opportunity to a) validate the ability of promising biomarkers to predict outcome in TBI, b) demonstrate the utility of biomarkers as proxy indicators of the clinical effects of treatment with progesterone, and c) provide better definition of treatment outcome in ProTECT III by defining an optimal serum concentration of progesterone in the treatment of TBI. In our primary aim we will determine whether serum biomarkers of structural brain injury are independent predictors of clinical outcome assessed 6 months after moderate and severe TBI. We will develop a prognostic model to predict outcome and validate this predictive model using subjects enrolled in the ProTECT III trial. We will also assess whether biomarker levels measured 24 and 48 hours after randomization will be predictive of outcome at 6 months. In our secondary aim we will define the relationship between serum progesterone levels and treatment effect. We will evaluate whether steady state progesterone levels, measured 24 and 48 hours after randomization, correlate with a favorable outcome at 6 months. We will also explore whether diminished release of S100b, GFAP, UCH-L1 and SBDP150, measured at 24 and 48 hours, can serve as a readily identifiable surrogate measure of early treatment response to progesterone.

描述（由申请人提供）：创伤性脑损伤 (TBI) 是美国和全世界年轻人死亡和残疾的主要原因。急性 TBI 的病理生理学特征是最初损伤引发的一系列原发性和继发性细胞事件，最终导致脑水肿、细胞破坏和死亡。 TBI 中的组织分解导致结构蛋白释放到血流中，包括 S100B、GFAP、UCH-L1 和 SBDP150。这些蛋白质可以作为损伤严重程度的有用生物标志物，并可能提供有关治疗反应的有用信息。我们小组的初步数据表明，与格拉斯哥昏迷量表和计算机断层扫描相比，S100B、GFAP、UCH-L1 和 SBDP150 的血清水平是更准确的损伤程度预测指标。然而，这些潜在的生物标志物都没有经过充分验证来评估其临床效用。这里提出的研究将跟进并扩展这些初步研究，目的是提供证据证明这些蛋白质中的一种或多种是评估损伤严重程度、指导治疗决策和开发创新 TBI 干预措施的有用诊断工具。这项名为“ProTECT III 损伤和结果的生物标志物”(BIO-ProTECT) 的提案旨在通过前瞻性评估参加 NIH 资助的急性 TBI 静脉注射孕酮双盲随机、安慰剂对照多中心 III 期临床试验的患者的生物标志物水平来验证我们的初步结果，该试验题为“孕酮治疗创伤性脑损伤：实验性临床” 治疗试验（ProTECT III；D. Wright，PI）。 ProTECT III 将对美国 17 个中心的 1,140 名患者进行随机分组，目的是确定服用黄体酮是否能有效改善受伤后 6 个月测量的结果。 ProTECT III 提供了一个理想的机会：a) 验证有前途的生物标志物预测 TBI 结果的能力，b) 证明生物标志物作为治疗临床效果的代理指标的实用性 孕酮，c) 通过定义 TBI 治疗中孕酮的最佳血清浓度，更好地定义 ProTECT III 中的治疗结果。我们的主要目标是确定结构性脑损伤的血清生物标志物是否是中度和重度 TBI 后 6 个月评估的临床结果的独立预测因子。我们将开发一个预后模型来预测结果，并使用参加 ProTECT III 试验的受试者验证该预测模型。我们还将评估 随机化后 24 小时和 48 小时测量的生物标志物水平是否可以预测 6 个月时的结果。在我们的次要目标中，我们将定义血清黄体酮水平与治疗效果之间的关系。我们将评估随机分组后 24 小时和 48 小时测量的稳态孕酮水平是否与 6 个月时的良好结果相关。我们还将探讨 S100b、GFAP、UCH-L1 和 SBDP150 的释放是否减少， 在 24 小时和 48 小时测量，可以作为黄体酮早期治疗反应的易于识别的替代指标。