Plasma iNOS IVD Prognosticates Sepsis Prior to Organ Damage and Dysfunction

描述（由申请人提供）：本项目的目的是完成早期、准确和可靠的体外诊断（IVD）试验的开发，该试验可识别将发展为脓毒症病理的严重创伤患者的全身炎症反应综合征（SIRS）。这项为期三年的临床检测开发项目的主要目标是[1]对560名受试者进行临床研究，其中360名创伤患者在三个地区创伤中心的重症监护室（ICU）住院，200名豁免“未链接的诊断标本”来自献血筛查后的正常健康献血者;和[2]向美国FDA提交De Novo 510（k）申请，以获得监管许可，将我们的IVD作为一种早期和可靠的检测方法上市，该检测方法可以在创伤患者中区分因炎症引起的SIRS（未进展为脓毒症的损伤）和将恶化为脓毒症病理的SIRS。一项可以在36个月或更短时间内完成的临床研究将对我们的血浆诱导型一氧化氮合酶（iNOS）IVD试验进行研究，该试验是一种准确可靠的血浆生物标志物，用于通过将SIRS分为两种不同类型来检测创伤患者败血症的早期发作：一种是由未发展为脓毒症的损伤引起的，另一种是发展为脓毒症并伴有心、肺和肾损伤和功能障碍的。在我们以前的临床研究中收集的数据清楚地表明，在脓毒症病理学早期（在器官损伤和功能障碍之前），iNOS的血浆水平出现可测量的增加，并且在来自正常健康对照的血浆样品中，iNOS以极低浓度存在或完全不存在。这些临床数据为iNOS作为一种新的、特异性的、早期的血浆生物标志物用于区分由炎症引起的SIRS与损伤以及将发展成威胁生命的脓毒症病理的SIRS提供了坚实的科学基础。该IVD开发项目的下一步是将该检测从研究实验室转移到临床实验室市场，以广泛使用，这应允许早期启动目前因早期预后/诊断不足而延迟的积极治疗。当前标准治疗的延迟可能导致心脏、肺、肾和其他器官损伤和功能障碍。该提案的重点是收集获得FDA批准以上市我们的新IVD检测所需的数据，方法是在统计学显著数量的创伤患者和健康对照中证明血浆中iNOS的存在可用作脓毒症病理学发作的可靠早期生化标志物。基于每年估计有700万SIRS患者可能恶化为脓毒症，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脓毒症或脓毒性休克发作幸存者的巨大长期医疗保健成本。一项经批准的预测败血症发作的临床试验将是对抗这种危及生命的病理学的重大医学进步。 公共卫生相关性：每年，全世界有超过700万人受到与全身炎症反应综合征（SIRS）相关的血液动力学、肺和肾功能障碍的影响，SIRS恶化为脓毒症病理学，并在美国每年导致超过250，000人死亡，在全球超过750，000人死亡。每年有更多的人死于由这种高度炎症病理引起的器官功能障碍，而不是死于中风，肺癌和乳腺癌的总和。然而，目前还没有准确可靠的临床测试可用于早期检测这种危及生命的疾病。2000年，美国国家科学院医学研究所估计，脓毒症病理对美国医疗保健系统的成本为每年170 - 290亿美元。快速诊断和早期治疗对于挽救生命和降低成本至关重要。我们的候选体外诊断（IVD）测试可用于区分患有SIRS的创伤患者与由于损伤引起的炎症，以及那些患有SIRS的创伤患者，其病情将恶化为脓毒症伴器官功能障碍，如心、肺和肾功能障碍，这是脓毒症病理学的标志。从我们以前的临床研究中收集的数据显示，我们的IVD测试可以在生理症状出现前24 - 48小时预测恶化为脓毒症。该项目的重点是收集通过De Novo 510（k）申请流程获得FDA批准所需的临床数据，用于基于我们发现的血浆蛋白质，血浆诱导型一氧化氮合酶（iNOS），这是区分SIRS与创伤和SIRS的早期和特异性生物标志物，所述SIRS将发展成脓毒症病理及其相关的器官损伤，功能障碍

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.