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

基本信息

批准号：
10698000
负责人：
Rebecca M Baron
金额：
$ 160.42万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
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/10698000
关键词：
Acceleration 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 Cell Death Inhibition Chronic lung disease Clinical Critical Care Critical Illness Cytoprotection Data Development Dose Double-Blind Method Eligibility Determination Ensure Enzymes Equation Experimental Models Functional disorder Gases Goals IL18 gene Immune response Impairment Incidence Individual Infection Inflammasome Inflammation Inhalation Life Measures Mechanical ventilation Mediator 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 Titrations Ventilator air treatment cytokine dose individualization efficacy evaluation efficacy trial heme oxygenase-1 indexing 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

项目摘要

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.

项目概要/摘要：尽管脓毒症和急性呼吸窘迫综合征（ARDS）的死亡率仍然高得令人无法接受重症监护方面的进步。一氧化碳 (CO) 是一种治疗 ARDS 的新型疗法，受到令人信服的支持来自脓毒症和急性肺损伤（ALI）实验模型的数据。我们已经证明低剂量的CO 在脓毒症和急性肺损伤的细胞培养和动物模型中提供保护。我们已经证明 CO 可以抑制线粒体功能障碍和炎症小体激活，激活线粒体生物合成，并加速通过生物合成专门的促消退介质 (SPM) 来解决炎症，使 CO 成为一种高度脓毒症和急性呼吸窘迫综合征 (ARDS) 的治疗有希望的疗法。我们开发并测试了与呼吸机兼容的 CO 输送系统和非人灵长类肺炎诱导 ALI 模型中的 CO 给药策略。我们证明低剂量吸入二氧化碳 (iCO) 可以安全地给予机械通气狒狒脓毒症和急性肺损伤 (ALI)，并且可以使用以下方法准确预测碳氧血红蛋白 (COHb) 的升高科伯恩-福斯特-凯恩 (CFK) 方程。我们最近在患有以下疾病的患者中完成了 iCO 的固定剂量 Ia 期试验脓毒症诱发的 ARDS，这表明低剂量 iCO 的精确输送在机械上是可行且安全的通气 ARDS 患者。我们证明 CFK 方程在预测 COHb 水平方面非常准确，表明 CFK 方程可用于单独滴定 iCO 剂量，以确保一致和安全具有不同程度气体交换受损的 ARDS 患者的全身摄取。我们现在提出一个阶段 Ib 试验评估 iCO 剂量的个性化医疗方法并检查功能性生物学 iCO 对脓毒症引起的 ARDS 有益作用的特征。在目标 1 中，我们将开展评估 CFK 安全性和准确性的随机、双盲、安慰剂对照 Ib 期试验脓毒症机械通气患者基于方程的个性化 iCO 剂量算法 ARDS。对于我们的主要终点，我们将评估精准医疗方法的安全性和准确性达到 6-8% 的目标 COHb 水平。在目标 2 中，我们将研究个性化 iCO 疗法对线粒体功能障碍、炎性小体激活、坏死性凋亡和消退的生物学特征脓毒症引起的 ARDS 患者的炎症。我们将测量线粒体 DNA 的水平，血浆和血浆中炎症小体调节的细胞因子 IL-18、坏死性凋亡调节因子 RIPK3 和 SPM 对 iCO 和安慰剂治疗的受试者进行支气管肺泡灌洗液以确定 CO 是否调节这些途径。我们将研究这些新途径的调节是否与血浆 COHb 水平相关以及 Ib 期试验的临床结果。完成这项研究后，我们将做好准备进行 IIb 期试验评估基于精准的低剂量 iCO 治疗对脓毒症患者的疗效 ARDS。