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

描述(由申请人提供)：创伤性脑损伤(TBI)是美国和世界各地年轻人死亡和残疾的主要原因。急性颅脑损伤的病理生理学特征是由最初的损伤引起的一系列原发和继发的细胞事件，最终导致脑水肿、细胞破坏和死亡。脑损伤的组织破坏导致结构蛋白释放到血流中，包括S100B、GFAP、UCH-L1和SBDP150。这些蛋白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显示，血清S100B、GFAP、UCH-L1和SBDP150水平比格拉斯哥昏迷评分和CT更准确地预测损伤程度。然而，这些潜在的生物标记物都没有得到充分的验证，无法评估它们的临床应用。这里提出的研究将继续和扩展这些初步研究，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、指导治疗决定和开发创新的脑外伤干预措施的有用诊断工具。这项名为“PROTECT III中损伤和结果的生物标记物”(BIO-PROTECT)的提案旨在通过前瞻性地评估参加NIH赞助的黄体酮静脉注射治疗急性脑损伤的双盲随机、安慰剂对照多中心第三阶段临床试验的患者的生物标记物水平来验证我们的初步发现。PROTECT III将对美国17个中心的1140名患者进行随机抽样，目的是确定黄体酮的管理在改善受伤后6个月的预后方面是否有效。Protecte III提供了一个理想的机会来a)验证有希望的生物标记物预测脑外伤预后的能力，b)展示生物标记物作为黄体酮治疗临床效果的替代指标的有效性，以及c)通过定义脑损伤治疗中孕酮的最佳血清浓度，在Protect III中更好地定义治疗结果。在我们的主要目标中，我们将确定结构性脑损伤的血清生物标记物是否是中、重度脑损伤后6个月评估的临床结果的独立预测因子。我们将开发一个预测模型来预测结果，并使用参加Protect III试验的受试者来验证这个预测模型。我们还将评估随机化后24小时和48小时测量的生物标记物水平是否可以预测6个月的预后。在我们的第二个目标中，我们将确定血清孕酮水平和治疗效果之间的关系。我们将评估在随机分组后24小时和48小时测量的稳态孕酮水平是否与6个月后的良好结局相关。我们还将探索在24小时和48小时测量的S100B、GFAP、UCH-L1和SBDP150的释放减少是否可以作为早期治疗对孕酮反应的容易识别的替代指标。

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.