Multi-center, randomized, controlled trial of the feasibility and safety of inhaled hydrogen gas during ECPR

项目总结/摘要 背景这项研究的目的是测试吸入氢气的可行性和安全性 (H2)在需要体外心肺复苏的心脏骤停期间作为抢救治疗给药 复苏（ECPR）。在接受ECPR的先天性心脏病（CHD）患者中， 患有严重的神经损伤双原子氢（H2）化学还原有毒氧介质， 直接损害细胞结构，并已被证明可以改善神经和肾功能，在一些 临床前缺血性损伤模型。最近，我们已经证明，吸入2.4%的H2， 在健康的成年人中是安全的。然而，H2从未应用于ECPR群体。 研究设计.我们提出了一个早期阶段，两个网站，随机试验H2在ECPR患者，题为 氢快速试验（氢作为治疗剂的可行性和安全性）。关键入选标准为 (1)CHD患者（广义定义，包括心肌炎、通道病、移植排斥），（2） 经历心脏骤停>5分钟并接受持续的CPR，以及（3）做出复苏的决定 使用ECPR。该试验将由MPI John Kheir，MD和林恩睡眠者，ScD领导，他们有很强的 在这一领域的合作历史和互补的专业知识，在重症监护，转化研究和临床 审判此外，试验设计也得到了FDA的积极反馈。 在R61阶段：（1）将获得监管机构（IRB和FDA）批准，包括例外情况 知情同意（EFIC）要求。这是必要的，因为ECPR的紧急性质和时间- H2敏感性排除了传统的知情同意。相反，非选择退出的患者将被随机分组， 紧急入组，随后获得传统知情同意。(2)试验药物（IP） 将建立生产，储存和行政后勤。(3)终点裁定过程 将建立DSMB基础设施。(4)将完成研究展开和临床工作人员教育， 随后是3名患者的先锋期（0期）试验。 在R33阶段，53例CHD患者将以3：2（32/21）的比例随机分配至常规治疗组 在ECPR后72小时加2.4%H2气体或从两个地点进行常规护理。主要终点包括 可行性和安全性指标（治疗相关严重不良事件的发生率，由 对治疗组设盲的独立委员会）。次要终点将包括功能状态、大脑 使用新的即时MRI设备获得的生物标志物和颅骨图像。 冲击本试验的经验丰富的团队和基础设施将确保成功完成 R31和R466里程碑。如果H2疗法被证明是可行的和安全的，这项工作将为 重症监护环境中的H2给药，以及随后在心脏骤停、中风、心肌梗死中的测试 梗塞和其中缺血-再灌注损伤起作用的其它病症。

Project Summary/Abstract Background. The purpose of the proposed research is to test the feasibility and safety of inhaled hydrogen gas (H2) administration as a rescue therapy during cardiac arrest requiring extracorporeal cardiopulmonary resuscitation (ECPR). Among patients with congenital heart disease (CHD) receiving ECPR, 52% either die or suffer severe neurologic impairment. Diatomic hydrogen (H2) chemically reduces toxic oxygen mediators that directly damage cellular structures, and has been shown to improve neurologic and renal function in a number of preclinical ischemic injury models. Recently, we have demonstrated that inhalation of 2.4% H2 for up to 72 hours is safe in healthy adults. However, H2 has never been applied to the ECPR population. Study design. We propose an early-phase, two-site, randomized trial of H2 in ECPR patients entitled the ‘Hydrogen FAST Trial’ (Hydrogen’s Feasibility And Safety as a Therapeutic agent). Key Inclusion criteria are (1) patients with CHD (broadly defined, including myocarditis, channelopathies, transplant rejection), (2) experiencing a cardiac arrest >5 minutes and receiving ongoing CPR, and (3) a decision made to resuscitate using ECPR. The trial will be led by MPIs John Kheir, MD and Lynn Sleeper, ScD, who have a strong collaborative history in this area and complementary expertise in critical care, translational research, and clinical trials. Furthermore, the trial design has received favorable feedback from the FDA. During the R61 Phase: (1) Regulatory (IRB and FDA) approvals will be obtained, including exception from informed consent (EFIC) requirements. This is necessary because the emergent nature of ECPR and time- sensitivity of H2 preclude traditional informed consent. Instead, non-opt-out patients will be randomized and enrolled emergently, with subsequent traditional informed consent. (2) Investigational product (IP) manufacturing, storage, and administration logistics will be established. (3) Endpoint adjudication processes and DSMB infrastructure will be established. (4) Study roll-out and clinical staff education will be completed, followed by a 3-patient vanguard phase (Phase 0) trial. During the R33 Phase, 53 patients with CHD will be randomly assigned in a 3:2 (32/21) ratio to either usual care plus 2.4% H2 gas following ECPR for 72 hours or to usual care from two sites. Primary endpoints include measures of feasibility and safety (rate of treatment-associated severe adverse events, adjudicated by an independent committee blinded to treatment group). Secondary endpoints will include functional status, brain biomarkers and cranial images obtained using a new point-of-care MRI device. Impact. The experienced team and infrastructure in place for this trial will ensure the successful completion of R31 and R466 milestones. If H2 therapy is shown to be feasible and safe, this work will provide a foundation for H2 administration in the critical care environment, and subsequent testing in cardiac arrest, stroke, myocardial infarction, and other disorders in which ischemia-reperfusion injury plays a role.