Blood Based Biomarkers of Injury and Outcome in the Prehospital TXA for TBI Trial

 描述（由申请人提供）：TBI的有效治疗是公共卫生领域最大的未满足需求之一。TBI临床试验失败的部分原因是损伤的异质性，TBI的诊断和分类方法基于药物代谢动力学分析，以确定潜在治疗的最佳剂量。基于症状的格拉斯哥昏迷评分（GCS）是确定损伤后早期TBI存在的主要组成部分，但受到显著的限制，导致高达20%的病例中脑损伤的不准确确定。因此，结构性脑损伤的生物标志物已被越来越多地研究，以识别和分类TBI，并预测TBI后的结果。我们的总体假设是，急性中度或重度TBI后循环脑特异性生物标志物的水平反映了TBI的存在和严重程度，可用于对患者进行分层，测量治疗反应并预测结果。我们将在参加院前氨甲环酸治疗TBI试验的中度或重度急性TBI患者中检查3种有希望的脑特异性生物标志物（来自星形胶质细胞的胶质细胞酸性蛋白[GFAP]、来自神经元的泛素C-水解酶-L1 [UCH-L1]和来自轴突的150-kDA α II-血影蛋白分解产物[SBDP 150]）。这项由美国国防部和NHLBI资助的试验将随机分配1002名中度或重度TBI患者，在美国和加拿大的10个中心的院前环境中使用复苏结局联盟的基础设施接受TXA或安慰剂的两种给药方案之一。我们将通过以下具体目标来检验这一假设。1.确定连续测量的循环脑特异性生物标志物（GFAP、UCH-L1、SBDP 150）的初始值或趋势是否与中度或重度TBI后颅内出血、损伤模式和严重程度以及28天死亡率相关。2.确定循环脑特异性生物标志物（GFAP、UCH-L1、SBDP 150）是否与治疗组分配、血清TXA水平以及在中度或重度TBI损伤后6个月通过GOS-E测量的长期结局相关。3.确定循环脑特异性生物标志物（GFAP，UCH-L1，SBDP 150）是否改善中度或重度TBI后的长期预后预测。此外，我们建议利用这项大型临床试验的资源，从该患者队列损伤后非常早期的连续时间点获得的样本中创建基因组和转录组样本库。通过这项研究，我们将致力于完善TBI的诊断，以早期识别脑损伤的特定模式，这些模式可以与适当的治疗干预相联系，以便有针对性地纳入临床试验。 此外，我们可以扩展现有的预测模型，以支持临床实践和TBI研究，包括随机试验的设计和分析。最后，我们还可以建立脑特异性生物标志物作为监测TBI治疗反应的有效方法，可以在临床和干预性TBI试验中广泛使用。

 DESCRIPTION (provided by applicant): Effective treatment for TBI is one of the greatest unmet needs in public health. Failed clinical trials for TBI have been attributed in part to the heterogeneity of injury, the symptom-based diagnosis and classification methods for TBI, and the lack of pharmacokinetic analyses to determine optimal dosing of potential therapies. The symptom based Glasgow Coma Scale (GCS) is a major component of determining the presence of TBI early after injury but is subject to significant limitations resulting in inaccurat determination of brain injury in up to 20% of cases. As a result, biomarkers of structural brain injury have been increasingly studied to identify and classify TBI, and to predict outcome after TBI. Our overall hypothesis is that levels of circulating brain-specific biomarkers after acute moderate or severe TBI reflect the presence and severity of TBI and can be used to stratify patients, measure treatment response and predict outcome. We will examine 3 promising brain-specific biomarkers (glial fibrillary acidic protein [GFAP] from astrocytes, Ubiquitin C-Hydrolase-L1 [UCH-L1] from neurons, and the 150-kDA aII-spectrin breakdown product [SBDP150] from axons) in patients with moderate or severe acute TBI enrolled in the Prehospital Tranexamic Acid for TBI Trial. This trial, funded by the DoD and NHLBI, will randomize 1002 patient with moderate or severe TBI to receive one of two dosing regimens of TXA or placebo in the prehospital setting in 10 centers across the US and Canada using the infrastructure of the Resuscitation Outcomes Consortium. We will test this hypothesis with the following specific aims. 1. To determine if initial values, or trends in serially measured circulating brain-specific biomarkers (GFAP, UCH-L1, SBDP150) are associated with the presence of intracranial hemorrhage, injury pattern and severity, and 28-day mortality after moderate or severe TBI. 2. To determine if circulating brain-specific biomarkers (GFAP, UCH-L1, SBDP150) are associated with treatment arm allocation, serum TXA level, and long-term outcome as measured by the GOS-E 6 months after injury in moderate or severe TBI. 3. To determine if circulating brain-specific biomarkers (GFAP, UCH-L1, SBDP150) improve long-term outcome prediction after moderate or severe TBI. In addition, we propose to leverage the resources of this large clinical trial to create a genomic and transcriptomic specimen repository from samples obtained at sequential time points very early after injury in this patient cohort. With this study we will be ale to refine the diagnosis of TBI to enable early identification of specific patterns of brain injury hat can be linked to appropriate therapeutic interventions for targeted inclusion into clinical trials. Furthermore, we may expand upon existing prediction models to support both clinical practice and TBI research, including the design and analysis of randomized trials. Finally, we may also establish brain-specific biomarkers as an effective method of monitoring response to treatment in TBI that could have widespread use both clinically and in interventional TBI trials.