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: 8868178
• 负责人: MICHAEL Ross FRANKEL
• 金额: $ 25万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868178
• 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; clinical predictors; design; disability; evidence base; follow-up; improved; in vivo; innovation; insight; neurotrophic protein S100beta; outcome forecast; phase III trial; predictive modeling; response; tool; treatment effect; treatment response; treatment strategy; treatment trial; young adult; 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; clinical predictors; design; disability; evidence base; follow-up; improved; in vivo; innovation; insight; neurotrophic protein S100beta; outcome forecast; phase III trial; predictive modeling; 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）是美国和全球年轻人的死亡和残疾的主要原因。急性TBI的病理生理学的特征是一系列由初始损伤开始运动的原发性和次级细胞事件，并最终导致脑水肿，细胞破坏和死亡。 TBI的组织分解导致结构蛋白释放到血液中，包括S100B，GFAP，UCH-L1和SBDP150。这些蛋白质可能是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。来自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的血清水平更准确地预测了损伤程度。但是，这些潜在的生物标志物都没有得到足够的验证来评估其临床效用。此处提出的研究将跟进并扩展这些初步研究，目的是提供证据，证明其中一种或多种是评估伤害严重性，指导治疗决策并制定创新的TBI干预措施的有用诊断工具。该提议是“保护III中的伤害和结果的生物标志物”（生物保护），旨在通过前瞻性评估参加NIH赞助的双重盲人随机，安慰剂控制的多中度临床临床临时性的NIH盲人型临床试验的患者的生物标志物来验证我们的初步发现：治疗试验（Protect III； D. Wright，PI）。III将在美国的17个中心中随机，目的是确定孕酮的给药是否有效地改善了损伤后6个月的结果，以验证有前途的生物标志的能力。孕酮和c）通过在TBI治疗中定义孕酮的最佳血清浓度来更好地定义保护III的治疗结果。在我们的主要目的中，我们将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指标。我们将开发一个预后模型，以使用保护III试验的受试者来预测结果并验证这种预测模型。我们还将评估在随机分组后24和48小时测量的生物标志物水平是否可以预测6个月的结果。在我们的次要目标中，我们将定义血清孕激素水平与治疗效果之间的关系。我们将评估随机分组后24和48小时测量的稳态孕酮水平是否与6个月时的有利结果相关。我们还将探索在24和48小时测量的S100B，GFAP，UCH-L1和SBDP150的释放减少，是否可以用作易于识别的对孕酮的早期治疗反应的替代量度。