Plasma iNOS IVD Prognosticates Sepsis Prior to Organ Damage and Dysfunction

描述（由申请人提供）：该项目的目的是完成早期，准确和可靠的体外诊断（IVD）测试的开发，以识别那些患有全身性炎症反应综合征（SIRS）的严重创伤患者将发展为败血症病理。这项为期三年的临床检测开发项目的主要目标是：对560名受试者、360名在三个地区创伤中心重症监护病房（icu）住院的创伤患者和200名献血筛查后从正常健康献血者中获得的“非关联诊断标本”进行临床研究；b[2]向美国FDA提交了一份510(k)申请，以获得监管许可，将我们的IVD作为一种早期可靠的测试产品上市，可以区分创伤患者因损伤炎症引起的SIRS（未进展为败血症）和将恶化为败血症病理的SIRS。我们的临床研究将在36个月或更短的时间内完成血浆诱导型一氧化氮合酶（iNOS）的IVD检测，作为一种准确可靠的血浆生物标志物，通过将SIRS区分为两种不同的类型，一种是由未进展为败血症的损伤引起的，另一种是进展为败血症并伴有心脏、肺和肾脏损伤和功能障碍。在我们之前的临床研究中收集的数据清楚地表明，在败血症病理早期（器官损伤和功能障碍之前）血浆中iNOS水平的可测量升高，而在正常健康对照的血浆样本中iNOS要么以极低的浓度存在，要么完全不存在。这些临床数据为iNOS作为一种新的、特异性的早期血浆生物标志物用于区分炎症引起的SIRS与损伤引起的SIRS以及将发展为危及生命的败血症病理提供了坚实的科学依据。IVD开发项目的下一步是将该测试从研究实验室转移到临床实验室市场，以便广泛使用，这将允许更早地启动积极的治疗，目前由于早期预后/诊断不足而延迟。目前标准护理治疗的延误可能导致心、肺、肾和其他器官损伤和功能障碍。该提案的重点是收集所需的数据，通过在统计上显著数量的创伤患者和健康对照中证明血浆中iNOS的存在可以作为脓毒症病理发病的可靠早期生化标志物，从而获得FDA批准上市我们的新IVD测试。根据估计每年有700万SIRS患者可能恶化为败血症，准确可靠的IVD检测每年可以挽救25,000或更多的生命，并可以显着降低治疗严重败血症或感染性休克患者的巨额长期医疗保健费用。一项被批准的临床试验可以预测败血症的发病，这将是对抗这种危及生命的病理的重大医学进步。

DESCRIPTION (provided by applicant): The aim of this project is to finish the development of an early, accurate and reliable in vitro diagnostic (IVD) test that identifies those severely injured trauma patient with systemic inflammatory response syndrome (SIRS) who will develop the sepsis pathology. The primary goals of this three year clinical assay development project are [1] to conduct a clinical study on 560 subjects, 360 trauma patients admitted to intensive care units (ICUs) at three regional trauma centers and 200 exempt "unlinked, diagnostic specimens" from normal healthy blood donors after blood donation screening; and [2] to submit a De Novo 510(k) application to the USA FDA for regulatory clearance to market our IVD as an early and reliable test that can differentiate in trauma patients between SIRS due to inflammation from injury that isn't progressing to sepsis and SIRS that will deteriorate into the sepsis pathology. A clinical study which can be completed in 36 months or less will be conducted on our IVD test for plasma inducible nitric oxide synthase (iNOS) as an accurate and reliable plasma biomarker for detecting early the onset of sepsis in trauma patients by differentiating SIRS into two distinct types: one caused by injury which is not progressing to sepsis and the other which is progressing into sepsis with its associated heart, lung and kidney damage and dysfunction. Data gather during our previous clinical studies clearly demonstrate that a measurable increase in the plasma level of iNOS occurs early in the sepsis pathology (prior to organ damage and dysfunction) and that in plasma samples from normal healthy controls iNOS is either present at an extremely low concentration or completely absent. These clinical data provide a solid scientific basis for the utilization of iNOS as a new, specific, and early plasma biomarker for differentiating SIRS caused by inflammation from injury and SIRS that will progress into the life-threatening sepsis pathology. The next step in this IVD development project is to transition the test from the research laboratory onto the clinical lab market for widespread use which should allow for the earlier initiation of aggressive therapies that are currently delayed due to inadequate early prognosis/diagnosis. The delay in current Standard-of-Care treatment can result in heart, lung, kidney and other organ damage and dysfunction. The focus of this proposal is to gather the data needed to obtain FDA clearance to market our new IVD test by demonstrating in statistically significant numbers of trauma patients and healthy controls that the presence of iNOS in plasma can be used as a reliable early biochemical marker for the onset of the sepsis pathology. Based upon the estimated 7 million SIRS patients annually that can deteriorate into sepsis, an accurate and reliable IVD test could save 25,000 or more lives per year, and could significantly reduce the enormous long term healthcare cost of treating individuals who survive an episode of severe sepsis or septic shock. An approved clinical test that forecasts the onset of sepsis would be a major medical advance in fighting this life-threatening pathology. PUBLIC HEALTH RELEVANCE: Annually, more than 7 million people worldwide are affected by the hemodynamic, pulmonary and renal dysfunction associated with systemic inflammatory response syndrome (SIRS) that deteriorates into the sepsis pathology and causes more than 250,000 deaths per year in the USA and more than 750,000 worldwide. More people die each year from the organ dysfunction caused by this hyperinflammatory pathology than from stroke, lung cancer and breast cancer combined. Yet, there is no accurate and reliable clinical test available for the early detection of this life-threatening condition. In 2000, the Institute of Medicine of the National Academies of Science estimated the cost of the sepsis pathology to the US healthcare system to be $17 - 29 billion annually. Fast diagnosis and early treatment are essential to saving lives and reducing costs. Our candidate in vitro diagnostic (IVD) test can be used to differentiate trauma patients with SIRS from inflammation due to injury and those trauma patients with SIRS whose condition will deteriorate into sepsis with organ dysfunction, such as the heart, lung, and kidney dysfunction that are the hallmarks of the sepsis pathology. Data collected from our previous clinical studies show our IVD test can prognosticate the deterioration into sepsis 24 - 48 hours before the appearance of physiological symptoms. This project is focused on gathering the clinical data required to obtain FDA clearance by the De Novo 510(k) application process for a new clinical diagnostic test based upon our discovery of a plasma protein, plasma inducible nitric oxide synthase (iNOS), that is an early and specific biomarker that differentiates between SIRS from trauma and SIRS that will progress into the sepsis pathology with its associated organ damage and dysfunction.