Plasma iNOS IVD Prognosticates Sepsis Prior to Organ Damage and Dysfunction

血浆 iNOS IVD 在器官损伤和功能障碍之前预测败血症

• 批准号: 7926568
• 负责人: ROBERT J WEBBER
• 金额: $ 258.6万
• 依托单位: RESEARCH AND DIAGNOSTIC ANTIBODIES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926568
• 关键词: Affect; Appearance; Basic Science; Biochemical Markers; Biological Markers; Blood; Blood Banks; Blood Donations; Blood donor; C-reactive protein; Caring; Cessation of life; Clinical; Clinical Data; Clinical Research; Consent Forms; Contracts; Cyclic GMP; Data; Detection; Deterioration; Development; Devices; Diagnosis; Diagnostic; Diagnostic tests; Early Diagnosis; Early treatment; Enrollment; Functional disorder; Goals; Grant; Health Care Costs; Healthcare Systems; Heart; Hospitals; Hour; Human; In Vitro; Individual; Inflammation; Injury; Institute of Medicine (U.S.); Intensive Care Units; Kidney; Laboratory Research; Life; Lung; Malignant neoplasm of lung; Marketing; Measurable; Measures; Medical; Medical Device; Monitor; Organ; Pathology; Patients; Physicians; Physiological; Plasma; Plasma Proteins; Predictive Value; Process; Rattus; Renal function; Reporting; Research; Research Ethics Committees; Research Personnel; Research Project Grants; Research Proposals; Sampling; Screening procedure; Sepsis; Sepsis Syndrome; Septic Shock; Site; Solid; Specificity; Specimen; Staging; Stroke; Symptoms; Testing; Training; Trauma; United States National Academy of Sciences; Urine; Work; Writing; aggressive therapy; base; clinical assay development; cost; early onset; fighting; healthy volunteer; hemodynamics; human NOS2A protein; injured; malignant breast neoplasm; meetings; member; outcome forecast; patient population; procalcitonin; product development; public health relevance; research clinical testing; septic; success; trauma centers

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.

描述(由申请人提供)：该项目的目标是完成一种早期、准确和可靠的体外诊断(IVD)测试的开发，该测试可以识别将发展为脓毒症病理的严重创伤合并全身炎症反应综合征(SIRS)患者。这个为期三年的临床分析开发项目的主要目标是[1]对560名受试者、360名住进三个地区创伤中心的重症监护病房(ICU)的创伤患者进行临床研究，并在献血筛查后免除200名正常健康献血者的“无关联的诊断标本”；以及[2]向美国FDA提交一份de Novo 510(K)申请，要求监管部门批准将我们的IVD作为一种早期且可靠的检测方法，用于区分创伤患者因炎症而产生的SIRS和不会发展为脓毒症的SIRS和将恶化为脓毒症病理的SIRS。一项可在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)检测进行临床研究，以此作为一种准确可靠的血浆生物标志物，通过将创伤患者的SIRS分为两种不同的类型：一种是由创伤引起的，不会进展为脓毒症，另一种是进展为败血症，并伴随着心、肺和肾脏的损害和功能障碍。在我们以前的临床研究中收集的数据清楚地表明，在脓毒症病理的早期(器官损伤和功能障碍之前)，血浆iNOS水平显著增加，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、特异的、早期的血浆生物标志物用于区分炎症引起的SIRS和损伤引起的SIRS以及将进展为危及生命的脓毒症病理的SIRS提供了坚实的科学基础。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，这将使目前因早期预后/诊断不充分而推迟的积极治疗更早开始。当前标准护理治疗的延迟可能导致心、肺、肾和其他器官损伤和功能障碍。这项建议的重点是收集获得FDA批准所需的数据，以将我们的新IVD测试推向市场，方法是在具有统计意义的大量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生的可靠早期生化标志物。据估计，每年有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人或更多的生命，并可以显著降低治疗严重败血症或感染性休克患者的巨额长期医疗费用。一项获得批准的临床测试可以预测脓毒症的发生，这将是在对抗这种威胁生命的病理方面的重大医学进步。 公共卫生相关性：每年，全球有700多万人受到与全身炎症反应综合征(SIRS)相关的血流动力学、肺和肾功能障碍的影响，SIRS恶化为脓毒症病理，每年在美国造成超过250,000人死亡，在全球造成超过750,000人死亡。每年死于这种高炎性病理导致的器官功能障碍的人数比死于中风、肺癌和乳腺癌的人数总和还要多。然而，目前还没有准确可靠的临床测试来早期发现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，美国医疗系统每年因脓毒症病理造成的成本为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)试验可用于区分创伤SIRS患者和创伤引起的炎症反应，以及创伤SIRS患者病情恶化为脓毒症并伴有器官功能障碍的患者，如心、肺和肾功能障碍，这些是脓毒症病理的特征。从我们以前的临床研究中收集的数据显示，我们的IVD测试可以在出现生理症状之前24-48小时预测病情恶化为脓毒症。这个项目专注于收集获得FDA批准所需的临床数据，通过de Novo 510(K)应用程序进行一种新的临床诊断测试，该测试基于我们发现的一种血浆蛋白-血浆诱导型一氧化氮合酶(INOS)，这是区分创伤SIRS和SIRS的早期和特异性生物标记物，SIRS将发展为败血症病理及其相关的器官损伤和功能障碍。