Mechanisms of organ dysfunction and recovery in the Acetaminophen and Ascorbate Trial in Sepsis

对乙酰氨基酚和抗坏血酸脓毒症试验中器官功能障碍和恢复的机制

基本信息

批准号：
10644023
负责人：
Lorraine B Ware
金额：
$ 42.68万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644023
关键词：
Acetaminophen Acute Acute Renal Failure with Renal Papillary Necrosis Acute Respiratory Distress Syndrome Affect Alveolar Angiopoietin-2 Antibiotics Ascorbic Acid Bicarbonates Biological Biological Markers Blood capillaries COVID-19 Cardiovascular system Cells Cessation of life Classification Clinical Clinical Trials Data Distal Double-Blind Method Endothelium Epithelium F2-Isoprostanes Functional disorder Funding Future Health Expenditures Hemeproteins Hemodialysis Hemoglobin Hemoglobin concentration result Heterogeneity Human IL18 gene IL8 gene In Vitro Incidence Infection Inflammation Inflammatory Injury Injury to Kidney Interleukin-1 beta Interleukin-10 Interleukin-6 Intravenous LCN2 gene Life Lipid Peroxidation Liquid substance Lung Measures Mechanical Ventilators Mechanical ventilation Methods Modeling Morbidity - disease rate National Heart, Lung, and Blood Institute Organ Outcome Oxidants Patients Permeability Phase Phase III Clinical Trials Phenotype Placebos Plasma Plasma Cells Predictive Value Protein C Proteins Pulmonary Inflammation Randomized Recovery Reducing Agents Regional Perfusion Research Rest Sampling Sepsis Site Subgroup Supportive care Testing Therapeutic Effect Tubular formation Urine Vascular Endothelium Vasoconstrictor Agents antimicrobial ascorbate clinical efficacy cytokine design improved kidney dysfunction mortality novel oxidation oxidative damage phase 3 study phase III trial precision medicine prospective response septic patients severe injury targeted treatment treatment comparison treatment effect treatment group urinary ventilation

项目摘要

Sepsis with acute organ dysfunction is a common condition with high morbidity and mortality and no specific therapies other than antimicrobials. The NHLBI PETAL Network Phase 2B Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery (ASTER trial) is a randomized double blind platform trial that will test the effect of two potential therapies, acetaminophen or vitamin C versus a common placebo to improve lung, cardiovascular and kidney dysfunction in 900 patients with sepsis and pulmonary or cardiovascular dysfunction including patients with sepsis due to COVID-19. The rationale for this clinical trial rests, in part, on novel findings from our group and others that (1) circulating cell-free hemoglobin (CFH) is elevated in patients with sepsis, including those with COVID-19; (2) higher plasma CFH in sepsis is associated with death and organ dysfunction including ARDS and acute kidney injury; (3) both acetaminophen and vitamin C are hemoprotein reductants that reduce the capacity of CFH to cause lipid peroxidation and other oxidant injury and (4) acetaminophen and vitamin C can reduce the injurious effects of CFH on the microvascular endothelium both in vitro and in the isolated perfused human lung. Although ASTER is well designed to test the clinical efficacy of acetaminophen and vitamin C, key information will be needed to understand trial results and plan for potential phase 3 studies. The proposed studies in this R01 will define the mechanisms by which acetaminophen and vitamin C affect organ dysfunction in sepsis (Aim 1) and determine whether there are subgroups that can be identified within the trial for whom a differential treatment effect exists (Aim 2). Specific Aim 1 will determine the mechanisms by which acetaminophen and vitamin C improve lung and kidney dysfunction in sepsis by testing the hypothesis that acetaminophen and vitamin C reduce levels of oxidized ferryl (4+) hemoglobin resulting in decreased oxidative injury, inflammation, and endothelial injury as measured by plasma, distal airspace fluid, and urinary biomarkers of hemoglobin oxidation (ferryl hemoglobin) lipid peroxidation (F2-Isoprostanes, Isofurans), inflammation and endothelial injury. Distal airspace fluid will be sampled at ten participating PETAL Network sites by collecting fluid that condenses on heat moisture exchanger filters placed in the mechanical ventilator circuit, a method that has been developed and validated by Dr. Ware's research group. Specific Aim 2 will identify whether previously described and validated hyperinflammatory or hypoinflammatory subgroups of sepsis patients benefit more from treatment with acetaminophen or vitamin C. A finding of heterogeneity of treatment effect in Aim 2 would be of great value for predictive enrichment in a future phase 3 clinical trial. In summary, the proposed studies will greatly enhance the value of the ASTER clinical trial by determining the biologic mechanisms of the therapeutic effects of acetaminophen and Vitamin C and assessing for heterogeneity of treatment effect in this NHLBI-funded Phase 2B clinical trial.

脓毒症伴急性器官功能障碍是一种发病率和死亡率较高的常见疾病，目前尚无特异性抗菌药物以外的治疗。 NHLBI PETAL 网络 2B 期对乙酰氨基酚和抗坏血酸脓毒症：靶向治疗促进康复（ASTER 试验）是一项随机双盲平台试验，将测试两种潜在疗法（对乙酰氨基酚或维生素 C）与常见安慰剂的效果，以改善症状 900 例脓毒症患者的肺、心血管和肾功能障碍以及肺或心血管疾病功能障碍，包括因 COVID-19 导致败血症的患者。这项临床试验的理由部分取决于我们小组和其他人的新发现是：(1) 患者循环游离血红蛋白 (CFH) 升高患有败血症，包括患有 COVID-19 的患者； (2) 败血症时较高的血浆 CFH 与死亡相关器官功能障碍，包括ARDS和急性肾损伤； (3)对乙酰氨基酚和维生素C都是血红素蛋白还原剂，可降低 CFH 引起脂质过氧化和其他氧化损伤的能力 (4)对乙酰氨基酚和维生素C可减轻CFH对微血管的损伤作用。体外和分离的灌注人肺中的内皮细胞。尽管 ASTER 的设计初衷是为了测试对乙酰氨基酚和维生素 C 的临床疗效，需要关键信息来了解试验结果并计划潜在的第三阶段研究。本 R01 中拟议的研究将定义以下机制：对乙酰氨基酚和维生素 C 会影响脓毒症的器官功能障碍（目标 1），并确定是否存在试验中可以确定存在差异治疗效果的亚组（目标 2）。具体的目标 1 将确定对乙酰氨基酚和维生素 C 改善肺和肾的机制通过测试对乙酰氨基酚和维生素 C 降低氧化水平的假设来研究败血症的功能障碍经测量，ferryl (4+) 血红蛋白可减少氧化损伤、炎症和内皮损伤通过血浆、远端空腔液体和尿血红蛋白氧化（铁基血红蛋白）脂质生物标志物过氧化（F2-异前列腺素、异呋喃）、炎症和内皮损伤。远端空域液体将是通过收集受热湿气凝结的液体，在 10 个参与 PETAL Network 的站点进行采样将交换器过滤器放置在机械呼吸机回路中，这是一种已经开发和验证的方法由 Ware 博士的研究小组开发。具体目标 2 将确定先前是否已描述和验证脓毒症患者的高炎症或低炎症亚组从治疗中获益更多对乙酰氨基酚或维生素 C。发现目标 2 中治疗效果的异质性对于未来三期临床试验中的预测丰富。总之，拟议的研究将极大地提高通过确定治疗效果的生物学机制，ASTER 临床试验的价值对乙酰氨基酚和维生素 C 并评估 NHLBI 资助阶段治疗效果的异质性 2B临床试验。