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: 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
• 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

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.

脓毒症合并急性器官功能障碍是一种常见病，发病率和死亡率高， 除抗菌药物外的其他治疗方法。NHLBI PETAL网络2B期对乙酰氨基酚和抗坏血酸 脓毒症：靶向治疗以促进恢复（ASTER试验）是一项随机双盲平台试验， 将测试两种潜在疗法的效果，对乙酰氨基酚或维生素C与普通安慰剂，以改善 900例脓毒症和肺或心血管疾病患者的肺、心血管和肾功能障碍 包括因COVID-19导致败血症的患者。这项临床试验的基本原理部分取决于 我们小组和其他人的一项新发现是：（1）患者的循环无细胞血红蛋白（CFH）升高， 脓毒症患者，包括COVID-19患者;（2）脓毒症患者血浆CFH升高与死亡相关， 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 降低CFH引起脂质过氧化和其它氧化损伤能力的血红素蛋白还原剂 对乙酰氨基酚和维生素C可减轻CFH对微血管的损伤作用 内皮细胞在体外和在分离的灌注人肺。虽然ASTER的设计是为了测试 对乙酰氨基酚和维生素C的临床疗效，关键信息将需要了解试验结果 并计划潜在的3期研究。本R 01中拟定的研究将定义以下机制： 对乙酰氨基酚和维生素C影响脓毒症的器官功能障碍（目的1），并确定是否有 在试验中可以确定的存在差异治疗效应的亚组（目标2）。具体 目的1将确定对乙酰氨基酚和维生素C改善肺和肾功能的机制 通过检验对乙酰氨基酚和维生素C降低氧化应激水平的假设， 铁（4+）血红蛋白导致氧化损伤、炎症和内皮损伤减少， 通过血浆、远端气腔液体和血红蛋白氧化（铁血红蛋白）脂质的尿生物标志物 过氧化（F2-异前列腺素，异呋喃），炎症和内皮损伤。远端空气腔液体将 在10个参与PETAL网络的站点通过收集在热湿下冷凝的流体进行采样 在机械呼吸机回路中放置交换器过滤器，这是一种已经开发和验证的方法 威尔博士的研究小组具体目标2将确定先前描述和确认的 脓毒症患者的高炎症或低炎症亚组从以下治疗中获益更多： 醋氨酚或维生素C在目标2中发现治疗效果的异质性将具有重要价值， 在未来的3期临床试验中预测富集。总之，拟议的研究将大大提高 ASTER临床试验的价值，通过确定治疗效果的生物学机制， 对乙酰氨基酚和维生素C，并评估该NHLBI资助阶段的治疗效果异质性 2B临床试验。