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

TBI 试验的院前 TXA 中基于血液的损伤生物标志物和结果

• 批准号: 8852242
• 负责人: Susan Rowell
• 金额: $ 38.9万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-16 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852242
• 关键词: Accident and Emergency department; Acute; Age; Astrocytes; Axon; Biological Markers; Blood; Blood Circulation; Brain; Brain Injuries; Canada; Cessation of life; Classification; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Data; Diagnosis; Diagnostic; Dose; Drug Kinetics; Early identification; Enrollment; Functional disorder; Funding; Future; Genomics; Glasgow Coma Scale; Glasgow Outcome Scale; Glial Fibrillary Acidic Protein; Head; Heterogeneity; Hour; Hydrolase; Injury; Intracranial Hemorrhages; Link; Marshal; Measures; Methods; Modeling; Monitor; Motor; National Heart, Lung, and Blood Institute; Necrosis; Neurons; Outcome; Patients; Pattern; Placebos; Pre-hospital setting; Proteins; Proteolysis; Public Health; Randomized; Regimen; Relative (related person); Research; Research Infrastructure; Resources; Resuscitation; Risk; Role; Sampling; Scanning; Serum; Severities; Specimen; Spectrin; Stratification; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Tranexamic Acid; Translating; Traumatic Brain Injury; Ubiquitin C; X-Ray Computed Tomography; abstracting; arm; base; clinical practice; cohort; design; disability; effective therapy; follow-up; improved; inclusion criteria; insight; mortality; phase III trial; prognostic; public health relevance; randomized trial; repository; response; transcriptomics; treatment effect; treatment response; trend

 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.

 描述（由适用提供）：对TBI的有效治疗是公共卫生中最大的未满足需求之一。 TBI的临床试验失败的部分原因是损伤的异质性，基于症状的诊断和TBI分类方法以及缺乏药代动力学分析来确定潜在疗法的最佳给药。基于症状的格拉斯哥昏迷量表（GCS）是确定受伤后早期TBI存在的主要组成部分，但受到重大局限性，导致多达20％的病例确定脑损伤。结果，已经增加了结构性脑损伤的生物标志物来识别和分类TBI，并在TBI后预测结果。我们的总体假设是，急性现代或重度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，测量治疗反应和预测结果。 We will examine 3 promise 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试验。该试验由DOD和NHLBI资助，将随机将1002例中度或重度TBI患者在美国和加拿大的10个中心的院前环境中接受TXA或安慰剂的两种剂量治疗方案之一。我们将以以下特定目的检验这一假设。 1。确定初始值或串行测得的循环脑特异性生物标志物（GFAP，UCH-L1，SBDP150）是否与颅内出血，损伤模式和严重程度以及28天死亡率以及缓和或重度TBI后的28天死亡率有关。 2。确定循环脑特异性生物标志物（GFAP，UCH-L1，SBDP150）是否与治疗臂分配，血清TXA水平和长期结局有关，如GOS-E在受伤后6个月在中度或重度TBI中受伤后6个月相关。 3。确定循环脑特异性生物标志物（GFAP，UCH-L1，SBDP150）是否改善了中度或重度TBI后的长期预测。此外，我们建议利用这项大型临床试验的资源来从该患者队列后很早就从顺序时间点获得的样品中的样品创建基因组和转录样品存储库。通过这项研究，我们将是ALE来完善对TBI的诊断，以便早日识别脑损伤的特定模式，可以与适当的治疗干预措施有关，将其靶向纳入临床试验。 此外，我们可能会扩展现有的预测模型，以支持临床实践和TBI研究，包括对随机试验的设计和分析。最后，我们还可以建立大脑特异性生物标志物作为监测对TBI治疗反应的有效方法，该方法可能在临床和介入的TBI试验中都可以使用宽度。