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

项目摘要/摘要： 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，尽管 重症监护的进展。一氧化碳(CO)是一种新的治疗ARDS的药物 来自脓毒症和急性肺损伤(ALI)实验模型的数据。我们已经证明了低剂量的一氧化碳 在细胞培养和脓毒症和ALI的动物模型中提供保护。我们已经证明，一氧化碳能抑制 线粒体功能障碍和炎性小体激活，激活线粒体生物发生，加速 通过生物合成特殊的促分解介质(SPM)来化解炎症，使CO成为高度 脓毒症和ARDS的治疗前景看好。我们已经开发并测试了一种与呼吸机兼容的 肺炎所致ALI非人类灵长类动物模型中的一氧化碳输送系统和一氧化碳给药策略。我们 证明小剂量吸入一氧化碳(ICO)可以安全地应用于机械通气的狒狒 与脓毒症和ALI有关，并且可以使用 Coburn-Forster-Kane(CFK)方程。我们最近完成了固定剂量的ICO患者的Ia期试验 脓毒症所致的ARDS，说明小剂量ICO精确输注在机械上是可行和安全的 使用呼吸机的ARDS患者。我们证明了CFK方程在预测COHb水平方面是高度准确的， 建议使用CFK方程单独滴定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 评价ICO个体化给药方法和检查功能生物学的IB试验 ICO在脓毒症诱导的ARDS中的有益作用的特征。在目标1中，我们将进行 评价CFK安全性和准确性的随机、双盲、安慰剂对照的Ib期试验 基于方程的个体化ICO给药算法在脓毒症患者中的应用 阿兹。对于我们的主要终点，我们将评估我们的精准医疗方法的安全性和准确性 以达到6-8%的COHb目标水平。在目标2中，我们将检查个性化ICO治疗对 线粒体功能障碍、炎性小体激活、坏死性下垂的生物学特征及其解决 脓毒症引起的ARDS患者的炎症反应。我们将测量线粒体DNA的水平， 炎症组调节的细胞因子IL-18，坏死下垂调节因子RIPK3，以及血浆和 ICO和安慰剂治疗受试者的支气管肺泡灌洗液以确定一氧化碳是否调节这些 小路。我们将研究这些新通路的调制是否与血浆COHb水平相关 和Ib期试验的临床结果。在这项研究完成后，我们将可进行一项 IIb期试验评估基于精确的小剂量ICO治疗脓毒症患者的疗效 阿兹。

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.