A Phase 1b Study of Inhaled CO for the Treatment of Sepsis-Induced ARDS

吸入 CO 治疗脓毒症引起的 ARDS 的 1b 期研究

• 批准号: 10274795
• 负责人: Rebecca M Baron
• 金额: $ 164.52万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274795
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Adverse event; Affect; Algorithms; Anabolism; Animal Model; Attenuated; Award; Biogenesis; Biological; Biological Markers; Bronchoalveolar Lavage Fluid; Carbon Monoxide; Carboxyhemoglobin; Cell Culture Techniques; Cell Death; Chronic lung disease; Clinical; Critical Care; Critical Illness; Data; Development; Dose; Double-Blind Method; Ensure; Enzymes; Equation; Experimental Models; Functional disorder; Gases; Goals; Immune response; Impairment; Incidence; Individual; Infection; Inflammasome; Inflammation; Inhalation; Interleukin-18; Lead; Life; Measures; Mechanical ventilation; Mediator of activation protein; Mitochondria; Mitochondrial DNA; Organ; Organ failure; Outcome; Papio; Participant; Pathogenesis; Pathway interactions; Patients; Persons; Phase; Phase I/II Trial; Phase Ia Trial; Phase Ib Clinical Trial; Phase Ib Trial; Placebo Control; Placebos; Plasma; Play; Positioning Attribute; RIPK3 gene; Randomized; Resolution; Respiratory Failure; Risk Factors; Safety; Sepsis; Severities; Specific qualifier value; Syndrome; System; Testing; Time; Ventilator; air treatment; base; cytokine; dose individualization; efficacy evaluation; efficacy trial; heme oxygenase-1; indexing; individual patient; inflammatory lung disease; innovation; lung injury; mitochondrial dysfunction; mortality; nonhuman primate; novel; novel therapeutics; personalized medicine; pneumonia model; precision medicine; primary endpoint; secondary endpoint; sepsis induced ARDS; uptake

PROJECT SUMMARY/ABSTRACT: Mortality from sepsis and the acute respiratory distress syndrome (ARDS) remain unacceptably high despite advances in critical care. Carbon monoxide (CO) is a novel therapeutic for ARDS supported by compelling data from experimental models of sepsis and acute lung injury (ALI). We have demonstrated that low dose CO confers protection in cell culture and animal models of sepsis and ALI. We have shown that CO suppresses mitochondrial dysfunction and inflammasome activation, activates mitochondrial biogenesis, and accelerates resolution of inflammation via biosynthesis of specialized pro-resolving mediators (SPM), making CO a highly promising therapy for treatment of sepsis and ARDS. We have developed and tested a ventilator-compatible CO Delivery System and a CO dosing strategy in a non-human primate model of pneumonia-induced ALI. We demonstrated that low dose inhaled CO (iCO) can be safely administered to mechanically ventilated baboons with sepsis and ALI, and that the rise in carboxyhemoglobin (COHb) can be accurately predicted using the Coburn-Forster-Kane (CFK) equation. We recently completed a fixed dose Phase Ia trial of iCO in patients with sepsis-induced ARDS, which showed that precise delivery of low dose iCO is feasible and safe in mechanically ventilated ARDS patients. We showed that the CFK equation is highly accurate at predicting COHb levels, suggesting that the CFK equation can be used to individually titrate iCO dosing to ensure consistent and safe systemic uptake in ARDS patients with varying degrees of impaired gas exchange. We now propose a Phase Ib trial to evaluate a personalized medicine approach to iCO dosing and to examine functional biological signatures underlying the beneficial effects of iCO in sepsis-induced ARDS. In Aim 1, we will conduct a randomized, double-blind, placebo-controlled Phase Ib trial to evaluate the safety and accuracy of a CFK equation-based personalized iCO dosing algorithm in mechanically ventilated patients with sepsis-induced ARDS. For our primary endpoint, we will evaluate safety and the accuracy of our precision medicine approach to achieve a target COHb level of 6-8%. In Aim 2, we will examine the impact of personalized iCO therapy on biological signatures of mitochondrial dysfunction, inflammasome activation, necroptosis, and resolution of inflammation in patients with sepsis-induced ARDS. We will measure levels of mitochondrial DNA, inflammasome-regulated cytokine IL-18, necroptosis regulator RIPK3, and SPMs in plasma and bronchoalveolar lavage fluid in iCO- and placebo-treated subjects to determine whether CO modulates these pathways. We will examine whether modulation of these novel pathways correlates with plasma COHb levels and clinical outcomes in the Phase Ib trial. At the completion of this study, we will be well-poised to conduct a Phase IIb trial to evaluate the efficacy of precision-based low dose iCO therapy in patients with sepsis-induced ARDS.

项目摘要/摘要： 尽管 重症监护的进步。一氧化碳（CO）是一种新型的治疗方法，可通过引人注目 来自败血症和急性肺损伤（ALI）实验模型的数据。我们已经证明了低剂量CO 赋予败血症和Ali动物模型的细胞培养保护。我们已经表明CO抑制 线粒体功能障碍和炎性体激活，激活线粒体生物发生并加速 通过专门的促介质介体（SPM）的生物合成解决炎症，使CO成为高度 有前途的败血症治疗疗法。我们已经开发并测试了呼吸机兼容 在非人类灵长类动物模型的肺炎引起的ALI中，CO递送系统和CO剂量策略。我们 证明低剂量吸入CO（ICO）可以安全地施用机械通气狒狒 使用败血症和Ali，可以使用羧基血红蛋白（COHB）的上升来准确预测 Coburn-Forster-Kane（CFK）方程。我们最近完成了ICO的固定剂量IA期试验 败血症引起的ARD，这表明低剂量ICO的精确递送在机械上是可行且安全的 通风的ARDS患者。我们表明，CFK方程在预测COHB水平方面非常准确， 建议CFK方程可用于单独滴定ICO剂量以确保一致且安全 气体交换受损程度不同的ARDS患者的全身摄取。我们现在提出一个阶段 IB试验评估一种个性化药物的ICO给药并检查功能生物学的方法 ICO在败血症诱导的ARD中产生有益作用的签名。在AIM 1中，我们将进行 随机，双盲，安慰剂控制期IB试验，以评估CFK的安全性和准确性 基于方程式的个性化ICO剂量算法在机械通风的患者中 ARDS。对于我们的主要终点，我们将评估精确医学方法的安全性和准确性 达到目标COHB水平为6-8％。在AIM 2中，我们将研究个性化ICO疗法对 线粒体功能障碍，炎性体激活，坏死和分辨率的生物学特征 败血症诱导的ARDS患者的炎症。我们将测量线粒体DNA的水平， 血浆和血浆中的细胞因子IL-18，坏死调节剂RIPK3和SPMS的炎性细胞因子IL-18和 ICO和安慰剂处理的受试者中的支气管肺泡灌洗液确定CO是否调节这些 途径。我们将检查这些新途径的调节是否与血浆COHB水平相关 和IB期试验中的临床结果。这项研究完成后，我们将被付诸实践，以进行 IIB期试验评估基于精确的低剂量ICO治疗在败血症患者中的疗效 ARDS。