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

ECPR期间吸入氢气可行性和安全性的多中心、随机、对照试验

• 批准号: 10700219
• 负责人: John Nagi Kheir
• 金额: $ 79.57万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700219
• 关键词: Multi; center; randomized; controlled; trial

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.

项目概要/摘要 背景 本研究的目的是测试吸入氢气的可行性和安全性。 (H2) 在需要体外心肺的心脏骤停期间作为抢救治疗的给药 在接受 ECPR 的先天性心脏病 (CHD) 患者中，52% 死亡或死亡。 遭受严重的神经损伤。双原子氢 (H2) 可以化学还原有毒的氧介质。 直接损害细胞结构，并已被证明可以改善许多神经系统和肾功能 最近，我们已经证明吸入 2.4% H2 最多可治疗 72 例。 小时对于健康成年人来说是安全的，但是 H2 从未应用于 ECPR 人群。 研究设计。我们提出了一项针对 ECPR 患者的 H2 早期、两中心、随机试验，名为“ “Hydrogen FAST 试验”（氢作为治疗剂的可行性和安全性）的关键纳入标准是。 (1) 冠心病患者（广义，包括心肌炎、离子通道病、移植排斥），(2) 经历超过 5 分钟的心脏骤停并接受持续的心肺复苏，以及 (3) 做出复苏决定 该试验将由 MPI John Kheir（医学博士）和 Lynn Sleeper（理学博士）领导，他们拥有强大的研究能力。 该领域的合作历史以及重症监护、转化研究和临床方面的互补专业知识 此外，试验设计得到了 FDA 的好评。 在 R61 阶段：(1) 将获得监管机构（IRB 和 FDA）批准，包括例外情况 这是必要的，因为 ECPR 的紧急性质和时间。 H2 的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​​并进行治疗。 (2) 研究产品（IP） (3) 端点裁决流程 (4) 研究推广和临床人员教育将完成， 随后进行 3 名患者的先锋阶段（第 0 阶段）试验。 在 R33 阶段，53 名 CHD 患者将按 3:2 (32/21) 的比例随机分配至常规护理组 ECPR 72 小时后加 2.4% 氢气或从两个地点进行常规护理主要终点包括。 可行性和安全性的衡量（与治疗相关的严重不良事件的发生率，由 次要终点包括功能状态、大脑 使用新的护理点 MRI 设备获得的生物标志物和颅骨图像。 影响力 本次试验的经验丰富的团队和基础设施将确保试验的成功完成。 R31 和 R466 里程碑如果 H2 疗法被证明是可行和安全的，这项工作将为 重症监护环境中的 H2 给药，以及心脏骤停、中风、心肌梗塞的后续测试 梗塞以及缺血再灌注损伤起作用的其他疾病。