Inhaled Nitric Oxide After Out-of-Hospital Cardiac Arrest (iNOOHCA)

• Sponsor: Cameron Dezfulian
• Collaborator: Mallinckrodt
• Information provided by (Responsible Party): Cameron Dezfulian, University of Pittsburgh

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Heart Arrest, Out-Of-Hospital	Drug: Nitric Oxide; Drug: Nitrogen	Phase 2

  Show Detailed Description

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 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.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: 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.
• Primary Purpose: Treatment
• Official Title: Inhaled Nitric Oxide After Out-of-Hospital Cardiac Arrest
• Actual Study Start Date: August 21, 2017
• Estimated Primary Completion Date: June 30, 2021
• Estimated Study Completion Date: December 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: inhaled nitric oxide (iNO); 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; An endogenous gaseous signaling molecule which stimulates soluble guanylate cyclase and may act via S-nitrosation, nitrite/nitrate or nitrated fatty acid formation.
Placebo Comparator: Placebo; Nitrogen carrier gas delivered by identical system with similar dose/taper.	Drug: Nitrogen; Nitrogen is the carrier gas (vehicle) for iNO. Subjects receiving placebo will receive equivalent doses of nitrogen.; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Death or significant neurological or cardiac impairment [ Time Frame: Hospital discharge (+/- 3 days) ]

   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.

Secondary Outcome Measures :

1. Death [ Time Frame: Hospital discharge (+/- 3 days) ]
   Patient declared dead at designated time point
2. Death [ Time Frame: 30 days after cardiac arrest (+/- 3 days) ]
   Patient declared dead at designated time point
3. Death [ Time Frame: 90 days after cardiac arrest (+/- 3 days) ]
   Patient declared dead at designated time point
4. Cerebral performance category (CPC) [ Time Frame: Hospital discharge (+/- 3 days) ]
   CPC is a standardized scale from 1-5 describing neurological and functional outcome. CPC will be dichotomized as favorable (1, 2) or unfavorable (3-5) at designated time
5. Cerebral performance category - extended (CPC-E) [ Time Frame: Hospital discharge (+/- 3 days) ]
   CPC-E as a continuous measure (1-5) across each of 6 categories within 48h of discharge
6. Cerebral performance category - extended (CPC-E) [ Time Frame: 30 days after cardiac arrest (+/- 3 days) ]
   CPC-E as a continuous measure (1-5) across each of 4 categories at designated time assuming patient is discharged from hospital (if subject is hospitalized the 6 category scale designated above will be used)
7. Cerebral performance category - extended (CPC-E) [ Time Frame: 90 days after cardiac arrest (+/- 3 days) ]
   CPC-E as a continuous measure (1-5) across each of 4 categories at designated time assuming patient is discharged from hospital (if subject is hospitalized the 6 category scale designated above will be used)
8. Cerebral performance category (CPC) [ Time Frame: 30 days after cardiac arrest (+/- 3 days) ]
   CPC dichotomized as favorable (1, 2) or unfavorable (3-5) at designated time
9. Cerebral performance category (CPC) [ Time Frame: 90 days after cardiac arrest (+/- 3 days) ]
   CPC dichotomized as favorable (1, 2) or unfavorable (3-5) at designated time
10. Modified Rankin Score (mRS) [ Time Frame: Hospital discharge (+/- 3 days) ]
    mRS dichotomized as favorable (0-3) or unfavorable (4-6) at hospital discharge
11. Modified Rankin Score (mRS) [ Time Frame: 30 days after cardiac arrest (+/- 3 days) ]
    mRS dichotomized as favorable (0-3) or unfavorable (4-6) at 30 days post-cardiac arrest
12. Modified Rankin Score (mRS) [ Time Frame: 90 days after cardiac arrest (+/- 3 days) ]
    mRS dichotomized as favorable (0-3) or unfavorable (4-6) at 90 days post-cardiac arrest
13. Discharge destination [ Time Frame: Hospital discharge (+/- 3 days) ]
    Location to which patient will be discharged dichotomized as favorable (home or inpatient rehabilitation) or unfavorable (skilled nursing facility, long term acute care, hospice or morgue)
14. Barthel Index (activities of daily living) [ Time Frame: Hospital discharge (+/- 3 days) ]
    Barthel Index of Independence in Activities of Daily Living scored as a continuous 0-100 at designated time
15. Barthel Index (activities of daily living) [ Time Frame: 30 days after cardiac arrest (+/- 3 days) ]
    Barthel Index of Independence in Activities of Daily Living scored as a continuous 0-100 at designated time
16. Barthel Index (activities of daily living) [ Time Frame: 90 days after cardiac arrest (+/- 3 days) ]
    Barthel Index of Independence in Activities of Daily Living scored as a continuous 0-100 at designated time
17. Time to awakening [ Time Frame: Within 4 days of cardiac arrest ]
    Time in hours until subject is noted to follow commands. Subjects exceeding 96 hours of coma and those that die without awakening will be designated as 100.
18. Methemoglobin level [ Time Frame: Prior to study drug ]
    Methemoglobin content as proportion (%) of total hemoglobin
19. Methemoglobin level [ Time Frame: 6 hours after study drug initiated ]
    Methemoglobin content as proportion (%) of total hemoglobin
20. Methemoglobin level [ Time Frame: 12 hours after study drug initiated ]
    Methemoglobin content as proportion (%) of total hemoglobin
21. ECHOcardiogram [ Time Frame: Prior to study drug ]
    Measurement of left ventricular ejection fraction, tricuspid regurgitant velocity and trans-anular pulmonic valve excursion.
22. ECHOcardiogram [ Time Frame: 12 hours after study drug initiated ]
    Measurement of left ventricular ejection fraction, tricuspid regurgitant velocity and trans-anular pulmonic valve excursion.
23. Reactive hyperemia [ Time Frame: Prior to study drug ]
    Reactive hyperemia (increase in blood flow from baseline) measured by laser speckle contrast imaging before and after a 1 and 5 min blood pressure cuff occlusion (20 mm Hg above systolic blood pressure)
24. Reactive hyperemia [ Time Frame: 12 hours after study drug ]
    Reactive hyperemia (increase in blood flow from baseline) measured by laser speckle contrast imaging before and after a 1 and 5 min blood pressure cuff occlusion (20 mm Hg above systolic blood pressure)
25. Systolic blood pressure [ Time Frame: Hourly from 0 - 12 hours of study drug ]
    Measured by arterial line
26. Diastolic blood pressure [ Time Frame: Hourly from 0 - 12 hours of study drug ]
    Measured by arterial line
27. Heart rate [ Time Frame: Hourly from 0 - 12 hours of study drug ]
    Calculated from continuous telemetry by monitor

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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)

Exclusion Criteria:

• 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
• ROSC >3h from time of ED arrival (treatment allocation must be within 4h so anything that will prevent this is reason for exclusion)
• 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
• Patient is known to be taking phosphodiesterase type 5 (PDE5) inhibitors, soluble guanylyl cyclase (sGC) stimulator, or has a known diagnosis of Chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension (PAH), or erectile dysfunction
• Known enrollment in another acute interventional study.

Contacts and Locations

Contacts

Contact: Sara DiFiore, BA; 412-864-2284; difioresm@upmc.edu

Contact: Nicholas Krehel, BS; 570-561-3132; NMK54@pitt.edu

Locations

United States, Pennsylvania

UPMC McKeesport; Recruiting

McKeesport, Pennsylvania, United States, 15132

Contact: Sara DiFiore 412-864-2284 difioresm@upmc.edu

Contact: Nick Krehel, BS nmk41@pitt.edu

Principal Investigator: Cameron Dezfulian, MD

Sub-Investigator: Jonathan Elmer, MD

Sub-Investigator: Ankur Doshi, MD

Sub-Investigator: Alexandra Weissman, MD

Sub-Investigator: Frank Guyette, MD

Sub-Investigator: Clif Callaway, MD

Sub-Investigator: Meaghan Fitzpatrick, MD

Sub-Investigator: Nick Krehel, BS

Sub-Investigator: Dylan Burbee, BS

UPMC East; Recruiting

Monroeville, Pennsylvania, United States, 15219

Contact: Sara DiFiore 412-864-2284 difioresm@upmc.edu

Contact: Nick Krehel, BS nmk41@pitt.edu

Principal Investigator: Cameron Dezfulian, MD

Sub-Investigator: Clifton W Callaway, MD

Sub-Investigator: Jonathan Elmer, MD

Sub-Investigator: Frank Guyette, MD

Sub-Investigator: Alexandra Weissman, MD

Sub-Investigator: Jon Rittenberger, MD

Sub-Investigator: Ankur Doshi, MD

Sub-Investigator: Meaghan Fitzpatrick, MD

Sub-Investigator: Nick Krehel, BS

Sub-Investigator: Dylan Burbee, BS

UPMC Presbyterian Hospital; Recruiting

Pittsburgh, Pennsylvania, United States, 15213

Contact: Sara DiFiore, BA 412-864-2284 difioresm@upmc.edu

Principal Investigator: Cameron Dezfulian, MD

Sub-Investigator: Jon Rittenberger, MD, MSc

Sub-Investigator: Clifton Callaway, MD, PhD

Sub-Investigator: Jonathan Elmer, MD, Msc

Sub-Investigator: Frank X Guyette, MD

Sub-Investigator: Adam Frisch, MD

Sub-Investigator: Ankur Doshi, MD

Sub-Investigator: Bradley Molyneaux, MD

Sub-Investigator: Alexandra Weissman, MD

Sub-Investigator: Masashi Okubo, MD

Sub-Investigator: Nick M Krehel, BS

Sub-Investigator: Dylan Burbee, BS

UPMC Mercy Hospital; Recruiting

Pittsburgh, Pennsylvania, United States, 15219

Contact: Sara Difiore, BA 412-864-2284 difioresm@upmc.edu

Principal Investigator: Cameron Dezfulian, MD

Sub-Investigator: Ankur Doshi, MD

Sub-Investigator: Jon Rittenberger, MD

Sub-Investigator: Clifton Callaway, MD

Sub-Investigator: Jonathan Elmer, MD

Sub-Investigator: Francis Guyette, MD

Sub-Investigator: Alexandra Weissman, MD

Sub-Investigator: Adam Frisch, MD

Sub-Investigator: Masashi Okubo, MD

Sub-Investigator: Nick M Krehel, BS

Sub-Investigator: Dylan Burbee, BS

UPMC Shadyside; Recruiting

Pittsburgh, Pennsylvania, United States, 15232

Contact: Sara M DiFiore 412-864-2284 difioresm@upmc.edu

Contact: Nick Krehel, BS nmk41@pitt.edu

Principal Investigator: Cameron Dezfulian, MD

Sub-Investigator: Alexandra Weissman, MD

Sub-Investigator: Jennifer McComb, MD

Sub-Investigator: Clif Callaway, MD

Sub-Investigator: Jonathan Elmer, MD

Sub-Investigator: Ankur Doshi, MD

Sub-Investigator: Frank Guyette, MD

Sub-Investigator: Nick Krehel, BS

Sub-Investigator: Dylan Burbee, BS

Sponsors and Collaborators

Cameron Dezfulian

Mallinckrodt

Investigators

• Principal Investigator: Cameron Dezfulian, MD; Assistant Professor of Critical Care Medicine and Clinical and Translational Science

More Information

• Responsible Party: Cameron Dezfulian, Assistant Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT03079102 History of Changes
• Other Study ID Numbers: PRO16100408
• First Posted: March 14, 2017
• Last Update Posted: May 29, 2019
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Heart Arrest; Out-of-Hospital Cardiac Arrest; Heart Diseases; Cardiovascular Diseases; Nitric Oxide; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Free Radical Scavengers; Antioxidants; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Endothelium-Dependent Relaxing Factors; Vasodilator Agents; Gasotransmitters; Protective Agents