Hydrogen's Feasibility and Safety as a Therapy in ECPR (HydrogenFAST)

Hydrogen's Feasibility and Safety as a Therapy in Extracorporeal Cardiopulmonary Resuscitation

The purpose of this project 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, i.e. mechanical circulatory support). Under exemption from informed consent, patients undergoing refractory cardiac arrest in the cardiac ICU at a participating center will be randomized to standard therapy with or without the administration of 2% hydrogen in gases administered via the ventilator and ECMO membrane for 72 hours.

Study Overview

• Status: Recruiting
• Conditions: Extracorporeal Membrane Oxygenation; Reperfusion Injury; Cardiac Arrest
• Intervention / Treatment: Drug: Hydrogen; Other: Usual care

Detailed Description

The purpose of this project 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, i.e. mechanical circulatory support). Each year, 500,000 patients in the US suffer a cardiac arrest and a growing number of them are resuscitated using ECPR. However, neurologic and renal injury remain important resulting comorbidities. The pathophysiology of these often-devastating injuries is ischemia (inadequacy of blood flow, at times compounded by hypoxemia) followed by an abrupt reperfusion (ECMO flow initiation). Among patients with congenital heart disease (CHD) receiving ECPR, 52% either die prior to discharge or suffer severe neurologic impairment. Diatomic hydrogen (H2) administration during and following ECPR may chemically reduce the toxic mediators that directly damage cellular structures and improve neurologically intact survival.

Preclinical data. Several groups have described that H2 inhalation decreases injury when administered following ischemic stroke, myocardial infarction, and cardiac arrest in rodents. Our group demonstrated that inhalation of 2.4% H2 for 24 hours following an experimental swine ischemia-reperfusion injury (as occurs in ECPR) improved neurologic scores, decreased seizures, diminished T2 white matter injury volume by 65%, and improved serum creatinine. Safety study in healthy participants. Under an investigator-initiated IND, we exposed 8 healthy adult participants to up to 72 hours of 2.4% H2 inhalation via high flow nasal cannula, finding no adverse effects on markers of hepatic, renal, cardiac or pulmonary function and no clinically significant symptoms reported. Having received a favorable pre-IND review from the FDA, we propose a two-center early phase study of H2 administration in patients with CHD receiving ECPR.

Study overview. We propose an early-phase randomized trial entitled the 'Hydrogen FAST Trial' (Hydrogen's Feasibility And Safety as a Therapeutic agent). The trial will have a 3-patient vanguard phase and 53 patients with CHD experiencing ECPR randomly assigned in a 3:2 (32/21) ratio to either usual care plus 2% H2 gas for 72 hours or to usual care. Patients will be recruited from two sites, Boston Children's Hospital and Texas Children's Hospital. We will primarily examine feasibility and safety (severe adverse events, independently adjudicated), as well as some indicators of efficacy.

Hypotheses. Feasibility endpoint: We hypothesize that H2 gas will be administered for >90% of the first 72 post-arrest hours in patients so-assigned and will be environmentally safe. Safety endpoint: We hypothesize that compared with patients receiving usual post-arrest care, patients receiving H2 will not exceed the treatment-related SAE rate of the usual care group by >12.5% in the 30 days following randomization.

• Study Type: Interventional
• Enrollment (Estimated): 53
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: John N Kheir, MD; Phone Number: 8576368890; Email: john.kheir@childrens.harvard.edu
• Study Contact Backup: Name: Julia Mancebo, MD

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: John Kheir, MD; Phone Number: 857-636-8890; Email: john.kheir@childrens.harvard.edu
      • Principal Investigator: John Kheir, MD
      • Sub-Investigator: Victoria Habet, DO

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Patients admitted to a cardiac intensive care unit at Boston Children's Hospital or Texas Children's Hospital with cardiac comorbidity, including congenital heart disease, myocarditis, cardiac arrhythmia, or rejection of a transplanted heart.
2. Patients are anticipated to be between birth to 18 years of age, although occasionally a patient over the age of 18 may be enrolled.
3. Patient experiencing a refractory cardiac arrest >5 minutes and receiving ongoing CPR in the ICU.
4. The decision made by the clinical team to resuscitate from ongoing, refractory cardiac arrest using ECPR due to a lack of other available options.

EXCLUSION CRITERIA

Meeting any of the following criterion renders the patient ineligible for the trial:

1. Enrollment in the opt-out program.
2. Patients known to be pregnant.
3. Patients who are prisoners.
4. Prior ECPR episode during admission (whether or not they were enrolled in the trial).
5. Enrollment does not occur within 2 hours of the decision to resuscitate using ECPR.

Note that ECMO cannulation without preceding CPR does not qualify as ECPR and such patients will not be included.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Usual care + H2 therapy; Hydrogen administered via mechanical ventilator and sweep gas into ECMO membrane for 72 hours	Drug: Hydrogen; Hydrogen gas (2%) in air or oxygen administered for 72 hours via ventilator and ECMO membrane. Oxygen concentration titrated per clinical team.; Other Names: H2 gas; Other: Usual care; Usual care post-ECPR event, including targeted temperature management.; Other Names: Standard of care
Active Comparator: Usual care; The current standard of care.	Other: Usual care; Usual care post-ECPR event, including targeted temperature management.; Other Names: Standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of hydrogen administration	Percentage of the first 72 post-randomization hours (starting at the time of randomization) in which H2 gas was administered via all of the applicable pathways (e.g. mechanical ventilator and ECMO membrane).	72 hours
Safety of hydrogen administration	Incidence rate of SAEs of interest per day during the first 30 days post-randomization that have been classified as treatment-related or possibly treatment-related.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival to hospital discharge	Survival to hospital discharge	From date of randomization until the date of hospital discharge or date of death from any cause, whichever came first, assessed up to 12 months
ICU length of stay	Duration of ICU stay until first transfer out of ICU	From date of randomization until the date of first ICU discharge or date of death from any cause, whichever came first, assessed up to 12 months
Hospital length of stay	Duration of hospital stay until first hospital discharge	From date of randomization until the date of hospital discharge or date of death from any cause, whichever came first, assessed up to 12 months
Functional status score	Functional status score computed based on a detailed review of neurology notes, primary team notes, nursing notes and physical exam documentation by two independent investigators.	Calculated on admission to the hospital, at 24 h before cardiac arrest, at hospital discharge, and at 6 months post-randomization

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: Baylor College of Medicine
• Investigators: Principal Investigator: John N Kheir, MD, Associate Professor of Pediatrics, Harvard Medical School

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2024
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): August 31, 2027

Study Registration Dates

• First Submitted: October 5, 2022
• First Submitted That Met QC Criteria: October 6, 2022
• First Posted (Actual): October 10, 2022

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Reperfusion Injury
• Other Study ID Numbers: IRB-P00043374

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No