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

• 批准号: 10502613
• 负责人: Lorraine B Ware
• 金额: $ 44.51万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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/10502613
• 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; Clinical; Clinical Trials; Data; Distal; Double-Blind Method; Endothelium; Epithelial; F2-Isoprostanes; Functional disorder; Funding; Future; Health Expenditures; Hemeproteins; Hemodialysis; Hemoglobin; Hemoglobin concentration result; Heterogeneity; Human; IL8 gene; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Injury; Injury to Kidney; Interleukin-1 beta; Interleukin-10; Interleukin-18; 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; Oxides; Patients; Permeability; Phase; Phase III Clinical Trials; Placebos; Plasma; Plasma Cells; Predictive Value; Protein C; Pulmonary Inflammation; Randomized; Recovery; Reducing Agents; Research; Rest; Sampling; Sepsis; Site; Subgroup; Supportive care; Testing; Therapeutic Effect; Tubular formation; Urine; 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; protein biomarkers; response; septic patients; severe injury; targeted treatment; treatment comparison; treatment effect; treatment group; urinary

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.

具有急性器官功能障碍的败血症是一种常见的疾病，具有高发病率和死亡率，没有特定的 抗菌素以外的其他疗法。 NHLBI Petal网络阶段2B对乙酰氨基酚和抗坏血酸 败血症：针对增强恢复的有针对性疗法（ASTER试验）是一项随机的双盲平台试验， 将测试两种潜在疗法，即对乙酰氨基酚或维生素C与普通安慰剂的影响 900例败血症和肺部或心血管的肺，心血管和肾功能障碍 功能障碍，包括19.19导致的败血症患者。该临床试验的基本原理部分基于 我们小组和其他人的新发现表明（1）患者循环无细胞血红蛋白（CFH）升高 与败血症，包括19日的败血症； （2）败血症中较高的血浆CFH与死亡和 器官功能障碍，包括ARDS和急性肾脏损伤； （3）对乙酰氨基酚和维生素C均为 降低CFH导致脂质过氧化和其他氧化剂损伤的能力的血蛋白还原剂 （4）对乙酰氨基酚和维生素C可以减少CFH对微血管的有害作用 体外和孤立的灌注人肺的内皮。虽然Aster的设计良好用于测试 对乙酰氨基酚和维生素C的临床功效，需要关键信息以了解试验结果 并计划潜在的3阶段研究。此R01中提出的研究将定义 对乙酰氨基酚和维生素C会影响败血症的器官功能障碍（AIM 1），并确定是否存在 可以在存在差异治疗效果的试验中可以识别的亚组（AIM 2）。具体的 AIM 1将确定对乙酰氨基酚和维生素C改善肺和肾脏的机制 通过测试对乙酰氨基酚和维生素C降低氧化水平的假说，败血症的功能障碍。 渡轮（4+）血红蛋白，导致氧化损伤，炎症和内皮损伤减少 通过血浆，远端空域流体和血红蛋白氧化（Ferryl血红蛋白）脂质的尿生物标志物 过氧化（F2-异前列腺，异呋喃），炎症和内皮损伤。远端空域流体将是 通过收集凝结在热水分的液体中，在十个参与的花瓣网络站点进行采样 放置在机械呼吸机电路中的交换器过滤器，该方法已被开发和验证 由Ware博士的研究小组。特定目标2将确定是否先前描述和验证 败血症患者的高炎或低炎性亚组受益于治疗 对乙酰氨基酚或维生素C. AIM 2中治疗效应异质性的发现对 在未来的3阶段临床试验中预测富集。总而言之，拟议的研究将大大增强 通过确定Aster临床试验的价值通过确定治疗作用的生物学机制 对乙酰氨基酚和维生素C，并评估该NHLBI资助的期治疗效应的异质性 2B临床试验。