Inhaled Nitric Oxide for Cardiac Arrest in Pediatrics and Adults (iNOCAPA)

Phase 2

Recruiting

• Conditions: Cardiac Arrest
• Interventions: Drug: inhaled nitric oxide (iNO); Drug: Sham

• Registration Number: NCT05868109
• Lead Sponsor: The Hospital for Sick Children

Brief Summary

This study is a multi-center, double blind, randomized controlled trial of inhaled nitric oxide (iNO) in children and adults with cardiac arrest (CA). The purpose of this pilot study is to test the feasibility of rapidly randomizing patients to iNO or sham treatment during cardiopulmonary resuscitation (CPR) or shortly after return of circulation (ROC) and evaluate blood biomarkers associated with iNO compared to sham. Return of circulation may refer to return of spontaneous circulation (ROSC) or ROC through extracorporeal cardiopulmonary resuscitation (E-CPR).

Detailed Description

Background: Sudden cardiac arrest is a leading cause of death and neurological handicaps but there is no neuroprotective drug which improves outcome. Recently we discovered a blood biomarker of response to a neuroprotective therapy in our pre-clinical model of cerebral ischemia-reperfusion injury. Biomarkers will likely be used, in the future, to assess response to specific neuroprotective drugs and to help titrate drug dose and duration in individual patients.

Inhaled nitric oxide (iNO) has recently been shown to improve return of spontaneous circulation, survival, and neurological outcome in animal models of cardiac arrest. We have therefore started a pilot randomized controlled trial (RCT) and translational biology study of iNO in children and adults with cardiac arrest. This study will help us design future fully powered RCTs of iNO. We will use methods, from our pre-clinical model, to discover blood biomarkers of response to therapy.

Objectives: In patients with cardiac arrest: (1) Test the safety and feasibility of rapidly randomizing patients to iNO or sham during chest compressions, or shortly after return of circulation (ROC), either spontaneous or by extracorporeal life support. (2) Maintain blinding and measure study outcomes for 6 months post-arrest. (3) Use immunoassays, mass spectrometry and fluorometric assays to determine the differences in serum protein, nitrite, and nitrate biomarker concentrations between the two intervention groups and discover blood biomarkers of therapeutic response to iNO.

Patient population and sample size: Pediatric and adult (total N=40) patients with cardiac arrest admitted to 8 intensive care units (ICUs) at 4 hospitals: SickKids, University Health Network - Toronto General Hospital (TGH) and Toronto Western Hospital (TWH) and Unity Health - St. Michael's Hospital (SMH).

Methods: All patients meeting eligibility criteria will be enrolled, during chest compressions or within 6 hours of ROC, using deferred consent. Patients will be randomized to iNO or sham procedures, using a Redcap screening and randomization tool. Registered respiratory therapists will rapidly start the study gas using our blinded study apparatus. Inhaled NO will be started at a dose of 80 ppm via the endotracheal or tracheostomy tube during chest compressions and reduced to, or started at, 20 ppm after ROC. The iNO or sham procedures will be continued for 72 hours, and weaned off over 12 hours, or stopped earlier if the patient is extubated or dies. Using the Utstein data template for cardiac arrest research, we will collect data into an electronic case report form and Oracle database. Survival, cerebral performance category scores and quality of life scores will be assessed at 1 and 6 months following cardiac arrest. Data and documentation will be reviewed intermittently to ensure that we are compliant with Health Canada guidelines for drug trials.

Serum is being collected and banked at 4 time points following cardiac arrest. The concentrations of biomarkers will be measured and compared between the 2 intervention groups.

Progress: This study is funded by the Heart and Stroke Foundation of Canada.

Study Timeline

• Study Start: 2022-08-31
• Study First Submitted: 2022-12-01
• Study First Submitted QC: 2023-05-11
• Study First Posted: 2023-05-22
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-27
• Last Update Posted: 2023-11-30
• Primary Completion: 2025-01-31
• Study Completion: 2026-01-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

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

1. Aged 1 day* to 80 years on the day the study intervention is started
2. In-hospital or out-of-hospital CA with CPR > 5 minutes
3. It is possible to randomize and start the iNO or sham during CPR or within 5 hours of ROC**
4. Mechanically ventilated in a study site ICU

Note: *Age 1 day is defined as 24 hours and a minimum corrected gestational age ≥ 38 weeks.

Note: **ROC refers to either ROSC or ROC via extracorporeal cardiopulmonary resuscitation (E-CPR).

Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Unwitnessed cardiac arrest
2. Cardiac arrest due to birth asphyxia
3. Pre-arrest poor neurologic function*
4. Already receiving iNO at the time of CA
5. Any condition or diagnosis, in the opinion of the PI, Co-Investigators, or MRPs, in which iNO would have adverse effects on physiology or where the cardiac anatomy and physiology has not yet been adequately assessed
6. Any condition or diagnosis, in the opinion of the PI, Co-Investigators, or MRPs, in which iNO would be indicated as therapy post-arrest
7. CPR duration > 45 minutes; if less than 18 years old, in-hospital CPR duration > 60 minutes**
8. Known pregnancy***
9. Terminal illness ʈ

Note: * Poor neurologic function is defined as CPC ≥ 4 or PCPC ≥ 4.

Note: **CPR duration is defined as total cumulative duration of CPR (i.e., if a patient has multiple arrests with CPR, the duration of these will be added); patients who undergo E-CPR will not be excluded, to maximize recruitment for this feasibility trial.

Note: ***B-HCG screening is not required for enrollment in women of reproductive age, but testing will occur as soon as possible (within 6 hours of enrollment).

Patients who are cannulated to ECMO for cardiorespiratory support will NOT be excluded a priori.

ʈ The MRP knew that the patient was dying pre-arrest

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Participants with Nitric Oxide	inhaled nitric oxide (iNO)	The mechanical ventilator circuit of the study participants are attached to the inhaled nitric oxide delivery device and nitric oxide is delivered.
Participants with Sham (no nitric oxide)	Sham	The mechanical ventilator circuit of the study participants are attached to the inhaled nitric oxide delivery device but nitric oxide is not delivered.

Primary Outcome Measures

Name	Time	Method
Drug Procedural Feasibility	We will monitor compliance to the study intervention during the 72 hours of drug/sham delivery and 12 hours of weaning and stopping the study intervention on each enrolled patient over the 2 years of study enrolment.	Number of successful continuations of iNO or sham for 72 hours followed by weaning and stopping the study intervention over the next 12 hours. Using real time monitoring of the study intervention we will optimize compliance to the full duration of the study intervention and improve upon any deviations to the study intervention over the full 72 + 12 hours of the study protocol.

Secondary Outcome Measures

Name	Time	Method
Monitor time to randomization of eligible patients	At study enrollment during the 2 years of study recruitment.	Timing of randomization. The time of randomization following onset of cardiac arrest will be recorded. We will attempt to speed up this time using simulations with study and clinical personnel and by debriefing each enrolled patient with the teams involved. We will attempt to enrol some patients who have a cardiac arrest in the ICU during chest compressions and for those patients enrolled following return of circulation, the timeframe is a maximum of 5 hours.
Monitor recruitment rate	For study duration, approximately 2 years.	Recruitment rate is the rate of enrolment/randomization/consent divided by the number of eligible patients which meet all inclusion criteria and have no exclusion criteria.
Monitor masking and unmasking events	During the 2 year study duration and data analysis.	Number of unblinding instances. The study apparatus (inhaled nitric oxide gas delivery device) has a secure cover that only the Respiratory Therapists are trained to open. The RTs will record any unblinding events which may include breaking/cutting of the cover ties and opening of the apparatus cover by clinical personnel other than RTs. The RTs will record and sign 'unblinding yes/no' into their masked RT study case report form on each RT clinical shift and study Research Coordinators will enter this data into the study electronic database. We will monitor unblinding events in real time and attempt to prevent these from happening.
Study follow-up rates	For study follow-up, approximately 2.5 years.	We will measure outcomes at 1 and 6 months following cardiac arrest as outlined in more detail below. Number of completed study outcomes at 6 months following cardiac arrest will be followed in real time and we will attempt to maximize follow-up rates.

Trial Locations

Locations (4)

St. Michael's Hospital; 🇨🇦 Toronto, Ontario, Canada

Toronto General Hospital; 🇨🇦 Toronto, Ontario, Canada

Toronto Western Hospital; 🇨🇦 Toronto, Ontario, Canada

The Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada