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

项目总结/摘要： 败血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， 重症监护的进步一氧化碳（CO）是一种新的治疗ARDS的支持， 数据来自脓毒症和急性肺损伤（ALI）的实验模型。我们已经证明，低剂量CO 在细胞培养物和脓毒症和ALI的动物模型中提供保护。我们已经证明，CO抑制 线粒体功能障碍和炎性小体激活，激活线粒体生物合成， 通过专门的促消退介质（SPM）的生物合成来缓解炎症，使CO成为一种高度 治疗败血症和ARDS的有前景的疗法。我们已经开发并测试了一种呼吸机兼容 在肺炎诱导的ALI的非人灵长类动物模型中的CO输送系统和CO给药策略。我们 证明低剂量吸入CO（iCO）可以安全地给予机械通气狒狒 脓毒症和ALI，碳氧血红蛋白（COHb）的上升可以准确预测使用 Coburn-Forster-Kane（CFK）方程。我们最近完成了一项在以下患者中进行的iCO固定剂量Ia期试验 脓毒症诱导的ARDS，这表明精确输送低剂量iCO在机械上是可行和安全的。 呼吸机辅助的ARDS患者。我们发现，CFK方程在预测COHb水平方面非常准确， 这表明CFK方程可用于单独滴定iCO剂量，以确保一致和安全 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试验旨在评价iCO给药的个性化药物方法并检查功能生物学 iCO在脓毒症诱导的ARDS中的有益作用的潜在特征。在目标1中，我们将进行 一项随机、双盲、安慰剂对照的Ib期试验，旨在评价CFK的安全性和准确性 基于方程式的个性化iCO给药算法在脓毒症诱导的机械通气患者中的应用 ARDS。对于我们的主要终点，我们将评估我们精准医学方法的安全性和准确性 以达到6- 8%的目标COHb水平。在目标2中，我们将研究个性化iCO治疗对 线粒体功能障碍、炎性小体激活、坏死性凋亡和 脓毒症诱导的ARDS患者的炎症。我们将测量线粒体DNA的水平， 血浆中炎性小体调节的细胞因子IL-18、坏死性凋亡调节因子RIPK 3和SPM， iCO和安慰剂治疗受试者的支气管肺泡灌洗液，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。在这项研究完成后，我们将作好准备， 评价基于精确度的低剂量iCO治疗在脓毒症诱导的患者中的疗效的IIb期试验 ARDS。

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.