Inhaled Nitric Oxide After Out-of-Hospital Cardiac Arrest

NCT03079102 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: PRO16100408
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 5

Brief Summary

Phase II double blind (participants and investigator) placebo controlled randomized (1:1) clinical trial of inhaled nitric oxide (iNO) 20 ppm administered over 12h beginning as soon as possible but within 4 h of return of spontaneous circulation (ROSC) from out-of-hospital cardiac arrest (OHCA). Planned enrollment is 180 subjects over 48 months at University of Pittsburgh Medical Center (UPMC) Hospitals with randomization stratified in blocks of 8. Recruitment will be performed under exception from informed consent (EFIC) to facilitate early enrollment and treatment. The study will have a pre-specified safety analysis at the mid-point (after 1 year or 60 patients whichever occurs first). Subjects will be screened by members of the University of Pittsburgh post-cardiac arrest service (PCAS), all of whom will serve as the study co-investigators, and the Research Coordinators. Notification of inclusion under EFIC will be performed as soon as possible by a member of the study team generally to a surrogate as the subjects will be comatose after OHCA.

Conditions

Heart Arrest, Out-Of-Hospital

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Death or Significant Neurological or Cardiac Impairment

  Composite of in-hospital death; OR unfavorable discharge location defined as a skilled nursing facility (SNF), long term acute care (LTAC) or hospice; OR New York Heart Association (NYHA) class III/IV heart failure at the time of discharge.\* \*In the setting of pre-existing heart failure there must be at least a 1 class decrement (eg III -\> IV). If patient was previously housed in a "unfavorable" destination there must be a 1 point decrement (eg from SNF to LTAC or LTAC to hospice). Subjects with pre-existing NYHA IV symptoms or living in hospice are excluded from meeting the respective outcome.

  Hospital discharge (+/- 3 days)

Secondary Outcomes (20)

• Number of Subjects Dead

  Hospital discharge (+/- 3 days)

• Number of Subjects Dead

  30 days after cardiac arrest (+/- 3 days)

• Number of Subjects Dead

  90 days after cardiac arrest (+/- 3 days)

• Number of Subjects With a Favorable Cerebral Performance Category (CPC)

  Hospital discharge (+/- 3 days)

• Number of Subjects With a Favorable Cerebral Performance Category (CPC)

  30 days after cardiac arrest (+/- 3 days)

Study Arms (2)

inhaled nitric oxide (iNO)

EXPERIMENTAL

20 ppm iNO delivered via mechanical ventilator connected to the iNO ventilator delivery system (iNOvent). Drug will be started as soon as possible after return of spontaneous circulation (ROSC) but no later than 4h after ROSC. Study drug will be dosed for 12h then tapered off over 1h.

Drug: Nitric Oxide

Placebo

PLACEBO COMPARATOR

Nitrogen carrier gas delivered by identical system with similar dose/taper.

Drug: Nitrogen

Interventions

Nitric Oxide DRUG

An endogenous gaseous signaling molecule which stimulates soluble guanylate cyclase and may act via S-nitrosation, nitrite/nitrate or nitrated fatty acid formation.

Also known as: inhaled nitric oxide, iNO, iNOMax

inhaled nitric oxide (iNO)

Nitrogen DRUG

Nitrogen is the carrier gas (vehicle) for iNO. Subjects receiving placebo will receive equivalent doses of nitrogen.

Also known as: Placebo

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Intubated and comatose adult (\>18 yo) resuscitated from out-of-hospital cardiac arrest (OHCA)\*
• \*Cardiac arrest within an emergency department or outpatient medical center will be included). OHCA includes Emergency Medical Service (EMS) witnessed cardiac arrest.
• Return of spontaneous circulation (ROSC) within 40 min of CPR initiation
• Full Outline of Unresponsiveness (FOUR) Brainstem score ≥ 2 (i.e. patient must have pupil OR corneal reflex at the time of ED presentation or within 1h if sedation/neuromuscular blockade clouds the picture)

You may not qualify if:

• Traumatic etiology of OHCA
• Prisoner
• Known pregnancy (beta-human chorionic gonadotropin screening is NOT REQUIRED for enrollment in women of appropriate age)
• Hemodynamic instability defined as \>1 recurrent arrest prior to enrollment OR inability to maintain mean arterial blood pressure (MAP) \> 65 using vasopressors and inotropes (ie actively up titrating medications or giving fluid bolus)
• Head CT grey-white ratio \< 1.2; Head CT is NOT REQUIRED prior to enrollment
• Fixed and dilated pupils without another explanation
• Known intracranial hemorrhage or acute cerebral infarction; Head CT is NOT REQUIRED prior to enrollment
• Malignant EEG upon presentation defined as: myoclonic status epilepticus, non-convulsive status epilepticus, generalized periodic epileptiform discharges. EEG screening is NOT REQUIRED prior to enrollment
• Alert and interactive patient with minimal evidence of neurologic injury
• Plan to extubate within 12 hours
• Post-cardiac arrest service (PCAS) physician opinion that patient will die with \>95% likelihood. This may be based on:
• Multiple medical comorbidities
• Late discovery of don not resuscitate (DNR) or advanced directive
• Terminal diagnosis (other than OHCA; may have caused OHCA)
• Clinical judgement based on current exam and data

Sponsors & Collaborators

• Cameron Dezfulian: lead
• Mallinckrodt: collaborator

Study Sites (5)

UPMC McKeesport

McKeesport, Pennsylvania, 15132, United States

Location

UPMC East

Monroeville, Pennsylvania, 15219, United States

Location

UPMC Presbyterian Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

UPMC Mercy Hospital

Pittsburgh, Pennsylvania, 15219, United States

Location

UPMC Shadyside

Pittsburgh, Pennsylvania, 15232, United States

Location

Related Publications (1)

• Magliocca A, Fries M. Inhaled gases as novel neuroprotective therapies in the postcardiac arrest period. Curr Opin Crit Care. 2021 Jun 1;27(3):255-260. doi: 10.1097/MCC.0000000000000820.

  PMID: 33769417 DERIVED

MeSH Terms

Conditions

Out-of-Hospital Cardiac Arrest

Interventions

Nitric Oxide; Inosine; Endothelium-Dependent Relaxing Factors; Nitrogen

Condition Hierarchy (Ancestors)

Heart Arrest; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Reactive Nitrogen Species; Free Radicals; Inorganic Chemicals; Nitrogen Oxides; Nitrogen Compounds; Oxides; Oxygen Compounds; Organic Chemicals; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Vasodilator Agents; Cardiovascular Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Elements; Gases

Limitations and Caveats

Planned Echocardiogram data was not able to be collected due to technical and feasibility constraints. Laser speckle contrast imaging data still requires validation and is therefore not reported. CPC-extended data was incomplete across many domains and therefore is not reported.

Results Point of Contact

• Title: Cameron Dezfulian
• Organization: Baylor College of Medicine

cameron.dezfulian@bcm.edu

832-826-6210

Study Officials

• Cameron Dezfulian, MD

  Assistant Professor of Critical Care Medicine and Clinical and Translational Science

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Gas canisters will be marked with a bar code which will be recorded by the study coordinator and available to the study team. Only the respiratory therapy directors will be aware of the canister content (placebo vs. active drug). Treatment assignment will be revealed upon opening a sealed opaque envelope after enrollment has been confirmed.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Model Details: Subjects will be randomized 1:1 to either placebo or active study drug (iNO). This will be stratified within blocks of 8 subjects at each center.

Study Record Dates

• First Submitted: January 5, 2017
• First Posted: March 14, 2017
• Study Start: August 26, 2017
• Primary Completion: May 22, 2020
• Study Completion: June 2, 2020
• Last Updated: April 25, 2022
• Results First Posted: April 25, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)