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

项目摘要/摘要 背景资料。拟议研究的目的是测试吸入氢气的可行性和安全性。 (H2)在需要体外循环的心脏骤停期间，给予药物作为抢救疗法 复苏(ECPR)。在接受ECPR的先天性心脏病(CHD)患者中，52%的患者死亡或 遭受严重的神经损伤。双原子氢(H2)化学上减少了有毒的氧介体 直接损害细胞结构，并已被证明在许多方面改善了神经和肾功能 临床前脑缺血损伤模型。最近，我们已经证明吸入2.4%的氢气可以持续72分钟 对于健康的成年人来说，工作时间是安全的。然而，H2从未被应用于ECPR种群。 研究设计。我们建议在ECPR患者中进行一项H2的早期、两点、随机试验，名为 氢气快速试验(氢气作为治疗剂的可行性和安全性)。主要的纳入标准是 (1)冠心病患者(广义，包括心肌炎、渠道疾病、移植排斥反应)，(2) 经历心脏骤停5分钟并接受持续心肺复苏术，以及(3)作出复苏决定 使用ECPR。审判将由国会议员John Kheir，MD和Lynn Sleeper，ScD领导，他们拥有强大的 在这一领域的合作历史和在重症监护、转化性研究和临床方面的互补专业知识 审判。此外，该试验设计也得到了FDA的好评。 在R61阶段：(1)将获得监管(IRB和FDA)批准，包括以下例外 知情同意(EFIC)要求。这是必要的，因为ECPR和时间的紧急性质- H2的敏感性排除了传统的知情同意。取而代之的是，非选择退出患者将被随机和 紧急登记，随后获得传统的知情同意。(2)调查产品(IP) 建立制造、仓储和行政物流。(3)终结点裁决程序 并将建立DSMB基础设施。(4)将完成研究推广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名冠心病患者将按3：2(32/21)的比例随机分配到两种常规护理中的一种 外加2.4%的氢气，在ECPR 72小时后或从两个部位进行常规护理。主要终端包括 可行性和安全性措施(与治疗相关的严重不良事件发生率，由 独立委员会对治疗组盲目观察)。次要终端将包括功能状态、大脑 使用新的医疗点核磁共振设备获得的生物标志物和头颅图像。 冲击力。为这次试验准备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。如果氢气疗法被证明是可行和安全的，这项工作将为 在重症监护环境中给药，以及随后心脏骤停、中风、心肌梗死的检测 脑梗塞等在脑缺血再灌注损伤中起作用的疾病。

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.