Inhaled Nitric Oxide After Out-of-Hospital Cardiac Arrest (iNOOHCA)
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ClinicalTrials.gov Identifier: NCT03079102 |
Recruitment Status :
Terminated
(Slow enrollment and planned change of institution by PI)
First Posted : March 14, 2017
Results First Posted : April 25, 2022
Last Update Posted : April 25, 2022
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Condition or disease | Intervention/treatment | Phase |
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Heart Arrest, Out-Of-Hospital | Drug: Nitric Oxide Drug: Nitrogen | Phase 2 |

Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 57 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 26, 2017 |
Actual Primary Completion Date : | May 22, 2020 |
Actual Study Completion Date : | June 2, 2020 |

Arm | Intervention/treatment |
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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.
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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.
Other Name: inhaled nitric oxide, iNO, iNOMax |
Placebo Comparator: Placebo
Nitrogen carrier gas delivered by identical system with similar dose/taper.
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Drug: Nitrogen
Nitrogen is the carrier gas (vehicle) for iNO. Subjects receiving placebo will receive equivalent doses of nitrogen.
Other Name: Placebo |
- Number of Participants With 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.
- Number of Subjects Dead [ Time Frame: Hospital discharge (+/- 3 days) ]Patient declared dead at designated time point
- Number of Subjects Dead [ Time Frame: 30 days after cardiac arrest (+/- 3 days) ]Patient declared dead at designated time point
- Number of Subjects Dead [ Time Frame: 90 days after cardiac arrest (+/- 3 days) ]Patient declared dead at designated time point
- Number of Subjects With a Favorable Cerebral Performance Category (CPC) [ Time Frame: Hospital discharge (+/- 3 days) ]The cerebral performance category (CPC) is a standardized scale from 1-5 describing neurological and functional outcome with a long history of use in cardiac arrest trials (N Engl J Med 1986; 314:397-403). Lower scores indicate better neurological performance as follows: (1) conscious and alert with normal function or only slight disability, (2) conscious and alert with moderate disability, (3) conscious with severe disability, (4) comatose or in a persistent vegetative state, or (5) dead. CPC will be dichotomized as favorable (1, 2) or unfavorable (3-5) at designated time.
- Number of Subjects With a Favorable Cerebral Performance Category (CPC) [ Time Frame: 30 days after cardiac arrest (+/- 3 days) ]The cerebral performance category (CPC) is a standardized scale from 1-5 describing neurological and functional outcome with a long history of use in cardiac arrest trials (N Engl J Med 1986; 314:397-403). Lower scores indicate better neurological performance as follows: (1) conscious and alert with normal function or only slight disability, (2) conscious and alert with moderate disability, (3) conscious with severe disability, (4) comatose or in a persistent vegetative state, or (5) dead. CPC will be dichotomized as favorable (1, 2) or unfavorable (3-5) at designated time.
- Number of Subjects With a Favorable Cerebral Performance Category (CPC) [ Time Frame: 90 days after cardiac arrest (+/- 3 days) ]The cerebral performance category (CPC) is a standardized scale from 1-5 describing neurological and functional outcome with a long history of use in cardiac arrest trials (N Engl J Med 1986; 314:397-403). Lower scores indicate better neurological performance as follows: (1) conscious and alert with normal function or only slight disability, (2) conscious and alert with moderate disability, (3) conscious with severe disability, (4) comatose or in a persistent vegetative state, or (5) dead. CPC will be dichotomized as favorable (1, 2) or unfavorable (3-5) at designated time.
- Number of Subjects With a Favorable Modified Rankin Score (mRS) [ Time Frame: Hospital discharge (+/- 3 days) ]The modified Rankin Score (mRS) is now recommended by consensus as the best measure of neurologic outcome in cardiac arrest studies (Circulation. 2018;137:e783-e801). The mRS runs from 0-6, where higher numbers are consistent with more severe neurologic impairment up to death (6). The scores correspond to: (0) No symptoms; (1) No significant disability. Able to carry out all usual activities, despite some symptoms.;(2) Slight disability; (3) Moderate disability; (4) Moderately severe disability; (5) Severe disability; (6) Dead. This score was dichotomized as favorable (0-3) or unfavorable (4-6) at the appointed time.
- Number of Subjects With a Favorable Modified Rankin Score (mRS) [ Time Frame: 30 days after cardiac arrest (+/- 3 days) ]The modified Rankin Score (mRS) is now recommended by consensus as the best measure of neurologic outcome in cardiac arrest studies (Circulation. 2018;137:e783-e801). The mRS runs from 0-6, where higher numbers are consistent with more severe neurologic impairment up to death (6). The scores correspond to: (0) No symptoms; (1) No significant disability. Able to carry out all usual activities, despite some symptoms.;(2) Slight disability; (3) Moderate disability; (4) Moderately severe disability; (5) Severe disability; (6) Dead. This score was dichotomized as favorable (0-3) or unfavorable (4-6) at the appointed time.
- Number of Subjects With a Favorable Modified Rankin Score (mRS) [ Time Frame: 90 days after cardiac arrest (+/- 3 days) ]The modified Rankin Score (mRS) is now recommended by consensus as the best measure of neurologic outcome in cardiac arrest studies (Circulation. 2018;137:e783-e801). The mRS runs from 0-6, where higher numbers are consistent with more severe neurologic impairment up to death (6). The scores correspond to: (0) No symptoms; (1) No significant disability. Able to carry out all usual activities, despite some symptoms.;(2) Slight disability; (3) Moderate disability; (4) Moderately severe disability; (5) Severe disability; (6) Dead. This score was dichotomized as favorable (0-3) or unfavorable (4-6) at the appointed time.
- Number of Subjects Discharged to a Favorable Destination [ Time Frame: Hospital discharge (+/- 3 days) ]Favorable discharge destination was defined as discharge from the hospital to home or inpatient rehabilitation. Unfavorable discharge destination was defined as discharge to a skilled nursing facility, long term acute care facility, hospice or death.
- 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. A higher score indicates improved ability to independently perform the activities of daily living.
- 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. A higher score indicates improved ability to independently perform the activities of daily living.
- 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. A higher score indicates improved ability to independently perform the activities of daily living.
- 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.
- Methemoglobin Level [ Time Frame: Prior to study drug ]Methemoglobin content as proportion (%) of total hemoglobin
- Methemoglobin Level [ Time Frame: 6 hours after study drug initiated ]Methemoglobin content as proportion (%) of total hemoglobin
- Methemoglobin Level [ Time Frame: 12 hours after study drug initiated ]Methemoglobin content as proportion (%) of total hemoglobin
- Diastolic Blood Pressure [ Time Frame: Hourly from 0 - 12 hours of study drug ]Measured by arterial line
- Systolic Blood Pressure [ Time Frame: Hourly from 0 - 12 hours of study drug ]Measured by arterial line
- Heart Rate [ Time Frame: Hourly from 0 - 12 hours of study drug ]Calculated from continuous telemetry by monitor

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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03079102
United States, Pennsylvania | |
UPMC McKeesport | |
McKeesport, Pennsylvania, United States, 15132 | |
UPMC East | |
Monroeville, Pennsylvania, United States, 15219 | |
UPMC Presbyterian Hospital | |
Pittsburgh, Pennsylvania, United States, 15213 | |
UPMC Mercy Hospital | |
Pittsburgh, Pennsylvania, United States, 15219 | |
UPMC Shadyside | |
Pittsburgh, Pennsylvania, United States, 15232 |
Principal Investigator: | Cameron Dezfulian, MD | Assistant Professor of Critical Care Medicine and Clinical and Translational Science |
Documents provided by Cameron Dezfulian, University of Pittsburgh:
Responsible Party: | Cameron Dezfulian, Assistant Professor, University of Pittsburgh |
ClinicalTrials.gov Identifier: | NCT03079102 |
Other Study ID Numbers: |
PRO16100408 |
First Posted: | March 14, 2017 Key Record Dates |
Results First Posted: | April 25, 2022 |
Last Update Posted: | April 25, 2022 |
Last Verified: | March 2022 |
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 |
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 |