Planning a Multi-Center Trial of Interferon-gamma in Trauma Patients

描述（由申请人提供）：根据我们对入组“炎症和宿主对损伤的反应”项目的严重钝性创伤患者的分析，我们的研究者提出，通常符合严重创伤患者研究入选标准的大部分患者不需要免疫调节治疗，也不太可能从此类治疗中获益（IFN？，葡聚糖或免疫球蛋白）。相反，有一部分患者的临床病程延长，并将受益于生物反应调节剂的介入治疗。将前者患者纳入此类临床试验，这些患者不会受益于此类治疗或可能受到此类治疗的伤害，这使得很难确定这些干预措施对后者的有益影响 对这些疗法有反应的患者子集。我们认为，这种未能事先确定哪些患者实际上可能从干预（“个性化治疗”）中受益的情况是创伤和脓毒症临床试验失败的原因之一。因此，绝对有必要开发一种快速的预后方法，并用于前瞻性地识别那些严重受伤的患者，这些患者将是免疫调节干预的良好候选人。拟议的临床试验的总体目标将是确定是否管理的干扰素？将改变严重损伤患者亚组的临床轨迹，所述亚组由基于基因组签名的预后指标识别，可能具有不利的临床结果，并且将受益于这种疗法。将收集血液样本，目的是确定是否rh-IFN？治疗恢复了与更好结果相关的改善的基因组特征。一个主要的临床目标是确定是否rh-IFN？减少了“恢复时间”，并增加了“无器官衰竭天数”。 公共卫生相关性：我们建议组织一项临床试验，以确定干扰素-β的管理是否会改变一个严重受伤的亚组的临床轨迹。 患者，通过部分基于白细胞对创伤的基因组反应的预后指标鉴定为可能具有不良临床结果并从此类治疗中获益。我们的总体假设是，血液白细胞基因组的变化可用于预测远期临床结果，并检测患者对治疗的反应，而不仅仅是严重创伤和危重疾病。一个主要目标是确定是否rhIFN-？在通过预后测试确定为风险增加的患者亚组中，减少“恢复时间”并增加“无器官衰竭天数”。

DESCRIPTION (provided by applicant): Based on our analysis of severe blunt trauma patients enrolled in the "Inflammation and the Host Response to Injury" Program, our investigators propose that a large proportion of patients who would generally meet the inclusion criteria for a study of severely injured patients are not in need of immunomodulatory therapy and are unlikely to benefit from such therapies (IFN?, ¿-glucan or immunoglobulin). In contrast, there exists a subset of patients who will have a protracted clinical course, and would benefit from interventional therapies with biological-response modifiers. Inclusion of the former patients in such a clinical trial who would either not benefit or might be harmed by such therapies has made it extremely difficult to identify the beneficial effects of these interventions in the latter subset of patients who would be responsive to these therapies. We believe that this failure to identify those patients a priori who may actually benefit from intervention ("personalized therapies") is one reason that clinical trials in trauma and sepsis have failed. Therefore, it is absolutely essential that a rapid prognostic be developed and used to prospectively identify those severely injured patients who would be good candidates for the immunomodulatory intervention. The overall goal of the proposed clinical trial would be to determine whether administration of IFN? will alter the clinical trajectory in a subgroup of severely injured patient identified by a prognostic indicator based on a genomic signature likely to have an adverse clinical outcome and who would benefit from such therapies. Blood samples will be collected with the goal being to determine whether rh-IFN? treatment restores an improved genomic signature associated with better outcomes. A primary clinical goal is to determine whether rh-IFN? reduces "time to recovery" and increases "organ-failure free days" in this at-risk population. PUBLIC HEALTH RELEVANCE: We propose to organize a clinical trial to determine whether administration of interferon-¿ will alter the clinical trajectory in a subgroup of severely injured patients, identified by a prognostic indicator based in part on the leukocyte genomic response to trauma as being likely to have an adverse clinical outcome and benefit from such therapies. Our overarching hypothesis is that changes in the blood leukocyte genome can be used to predict distant clinical outcomes and to detect response to therapies in patients, not only with severe trauma and critical illness. A primary objective is to determine whether rhIFN-? reduces "time to recovery" and increases "organ-failure free days" in the subgroup of patients identified by the prognostic test to be at increased risk.