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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
Last Update Posted : May 25, 2021
Sponsor:
Collaborator:
Mallinckrodt
Information provided by (Responsible Party):
Cameron Dezfulian, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE January 5, 2017
First Posted Date  ICMJE March 14, 2017
Last Update Posted Date May 25, 2021
Actual Study Start Date  ICMJE August 21, 2017
Actual Primary Completion Date May 22, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 7, 2017)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2017)
  • Death [ Time Frame: Hospital discharge (+/- 3 days) ]
    Patient declared dead at designated time point
  • Death [ Time Frame: 30 days after cardiac arrest (+/- 3 days) ]
    Patient declared dead at designated time point
  • Death [ Time Frame: 90 days after cardiac arrest (+/- 3 days) ]
    Patient declared dead at designated time point
  • 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
  • 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
  • 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)
  • 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)
  • 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
  • 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
  • Modified Rankin Score (mRS) [ Time Frame: Hospital discharge (+/- 3 days) ]
    mRS dichotomized as favorable (0-3) or unfavorable (4-6) at hospital discharge
  • 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
  • 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
  • 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)
  • 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
  • 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
  • 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
  • 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
  • ECHOcardiogram [ Time Frame: Prior to study drug ]
    Measurement of left ventricular ejection fraction, tricuspid regurgitant velocity and trans-anular pulmonic valve excursion.
  • ECHOcardiogram [ Time Frame: 12 hours after study drug initiated ]
    Measurement of left ventricular ejection fraction, tricuspid regurgitant velocity and trans-anular pulmonic valve excursion.
  • 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)
  • 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)
  • Systolic blood pressure [ Time Frame: Hourly from 0 - 12 hours of study drug ]
    Measured by arterial line
  • Diastolic 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
Original Secondary Outcome Measures  ICMJE
 (submitted: March 7, 2017)
  • Death [ Time Frame: Hospital discharge (+/- 3 days) ]
    Patient declared dead at designated time point
  • Death [ Time Frame: 30 days after cardiac arrest (+/- 3 days) ]
    Patient declared dead at designated time point
  • Death [ Time Frame: 90 days after cardiac arrest (+/- 3 days) ]
    Patient declared dead at designated time point
  • 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
  • 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
  • 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)
  • 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)
  • 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
  • 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
  • Modified Rankin Score (mRS) [ Time Frame: Hospital discharge (+/- 3 days) ]
    mRS dichotomized as favorable (0-3) or unfavorable (4-6) at hospital discharge
  • 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
  • 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
  • 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)
  • 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
  • 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
  • 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
  • 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: 3 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
  • ECHOcardiogram [ Time Frame: Prior to study drug ]
    Measurement of left ventricular ejection fraction, tricuspid regurgitant velocity and trans-anular pulmonic valve excursion.
  • ECHOcardiogram [ Time Frame: 12 hours after study drug initiated ]
    Measurement of left ventricular ejection fraction, tricuspid regurgitant velocity and trans-anular pulmonic valve excursion.
  • 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)
  • 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)
  • Systolic blood pressure [ Time Frame: Hourly from 0 - 12 hours of study drug ]
    Measured by arterial line
  • Diastolic 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Inhaled Nitric Oxide After Out-of-Hospital Cardiac Arrest
Official Title  ICMJE Inhaled Nitric Oxide After Out-of-Hospital Cardiac Arrest
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.
Detailed Description

Subjects will be identified upon emergency department (ED) arrival or upon transfer from an outside facility and screened for enrollment by a PCAS physician as soon as possible. Eligible patients will have receive any required resuscitation (including central venous and arterial line placement, endotracheal intubation and hemodynamic resuscitation as needed) prior ot having baseline labs and studies performed. Subjects will then be started on study drug delivered via the mechanical ventilator with a concealed canister (subject, providers and outcome assessors blind to treatment assignment). Randomization will be performed 1:1 in blocks of 8 using a random number generator. A randomization list will be prepared in advance by the director of respiratory therapy (RT) at each site and verified by a company representative. These individuals (who are not part of the study team) will be unblinded and assure that allocation to placebo and intervention is accurate. The allocation list will assign study drug canisters (by barcode) to each subject in order of study ID. Treatment assignment will be revealed after opening a sealed opaque envelope once enrollment is confirmed by a physician investigator. Study drug will then be administered by RT based on allocation. During study drug administration hourly vital signs will be obtained and methemoglobin levels for safety. Study drug will be weaned off after 12h over the course of 1h (10, 5, 4, 3, 2, 1 ppm each for 10 min) prior to discontinuation. Subjects will then receive standard post-resuscitation care with outcomes assessed by a blinded study team member (see below for outcomes).

Additional clinical variables to be collected Demographics and baseline function. Age, sex, race, maximum education level, employment status, marital status, Barthel activities of daily living (ADL) index prior to OHCA.

Arrest data. Location of OHCA, witnessed, bystander cardiopulmonary resuscitation (CPR), estimated no flow and low flow times, presenting rhythm, doses of epinephrine administered, shocks administered, recurrent arrest, date and time of ROSC.

Medical comorbidities. Diabetes, hypertension, active smoking, hyperlipidemia, chronic obstructive pulmonary disease (COPD), hypertension, drug abuse, prior myocardial infarction, prior coronary artery bypass grafting (CABG), prior coronary angiography with angioplasty or stent, congestive heart failure (EF on last echocardiogram [ECHO] prior to OHCA), obstructive sleep apnea, pulmonary hypertension, calculated Charlson comorbidity index (CCI).

Home medications. Statins, nitrates, anticoagulation, antiplatelet agents Hospital Interventions. Coronary angiography, percutaneous coronary intervention, CABG, mechanical ventilation hours and fraction of inspired oxygen (FiO2) from 0-24h after therapy start In-hospital medications. Alteplase, anti-epileptic medication use (valproate, phenytoin, lacosamide, leveteracetam), neurostimulants (methylphenidate, bromocriptine, modafinil, amantadine), cumulative dose of fentanyl, propofol, midazolam, cis-atracurium and vecuronium in at 24 (+/- 12 hours), 48 (+/- 12 hours), and 72 (+/- 12 hours) hours after therapy initiation

Data Storage Subjects will be assigned a study identifier (ID) upon entry and all data/samples stored using that ID. Linkage to patient identifiers will be maintained in a secure spreadsheet and will include name, date of birth and medical record number. Clinical data will be entered on case report forms (source documentation) which will be stored in a locked filing cabinet within a locked office assigned to the study team. Deidentified clinical and lab data will all be subsequently entered from the case report forms into a web based database (REDCap) to be maintained by Dr. Dezfulian's research assistant who has prior experience from other studies.

Statistical Analysis Plan Continuous data will be compared using t-tests and repeated measures ANOVA to compare between iNO and placebo groups at multiple times. Dichotomous outcomes including the primary endpoint will be compared by chi squared test. Time to awakening and 90d survival will be compared by log rank test of Kaplan-Meier survival plots. All tests will be two tailed with unadjusted p<0.05 considered significant. In the event of a differential distribution of baseline variables strongly associated with outcome (univariate OR >2), dichotomous outcomes will be adjusted for these baseline variables.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE Heart Arrest, Out-Of-Hospital
Intervention  ICMJE
  • 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.
  • Drug: Nitrogen
    Nitrogen is the carrier gas (vehicle) for iNO. Subjects receiving placebo will receive equivalent doses of nitrogen.
    Other Name: Placebo
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Nitric Oxide
  • Placebo Comparator: Placebo
    Nitrogen carrier gas delivered by identical system with similar dose/taper.
    Intervention: Drug: Nitrogen
Publications * 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. Review.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: June 9, 2020)
57
Original Estimated Enrollment  ICMJE
 (submitted: March 7, 2017)
130
Actual Study Completion Date  ICMJE June 2, 2020
Actual Primary Completion Date May 22, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03079102
Other Study ID Numbers  ICMJE PRO16100408
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Cameron Dezfulian, University of Pittsburgh
Study Sponsor  ICMJE Cameron Dezfulian
Collaborators  ICMJE Mallinckrodt
Investigators  ICMJE
Principal Investigator: Cameron Dezfulian, MD Assistant Professor of Critical Care Medicine and Clinical and Translational Science
PRS Account University of Pittsburgh
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP