Inhaled Nitric Oxide After Out-of-Hospital Cardiac Arrest

Heart Arrest, Out-Of-Hospital Clinical Trial

— iNOOHCA  

Official title:

Inhaled Nitric Oxide After Out-of-Hospital Cardiac Arrest

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03079102
• Other study ID #: PRO16100408
• Status: Terminated
• Phase: Phase 2
• Start date: August 26, 2017
• Est. completion date: June 2, 2020

Study information

• Verified date: March 2022
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 to 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, levetiracetam), 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 57
• Est. completion date: June 2, 2020
• Est. primary completion date: May 22, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Heart Arrest
• Heart Arrest, Out-Of-Hospital
• Out-of-Hospital Cardiac Arrest

Intervention

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

Locations

Country	Name	City	State
United States	UPMC McKeesport	McKeesport	Pennsylvania
United States	UPMC East	Monroeville	Pennsylvania
United States	UPMC Mercy Hospital	Pittsburgh	Pennsylvania
United States	UPMC Presbyterian Hospital	Pittsburgh	Pennsylvania
United States	UPMC Shadyside	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Cameron Dezfulian	Mallinckrodt

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Number of Subjects Dead	Patient declared dead at designated time point	Hospital discharge (+/- 3 days)
Secondary	Number of Subjects Dead	Patient declared dead at designated time point	30 days after cardiac arrest (+/- 3 days)
Secondary	Number of Subjects Dead	Patient declared dead at designated time point	90 days after cardiac arrest (+/- 3 days)
Secondary	Number of Subjects With a Favorable Cerebral Performance Category (CPC)	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.	Hospital discharge (+/- 3 days)
Secondary	Number of Subjects With a Favorable Cerebral Performance Category (CPC)	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.	30 days after cardiac arrest (+/- 3 days)
Secondary	Number of Subjects With a Favorable Cerebral Performance Category (CPC)	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.	90 days after cardiac arrest (+/- 3 days)
Secondary	Number of Subjects With a Favorable Modified Rankin Score (mRS)	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.	Hospital discharge (+/- 3 days)
Secondary	Number of Subjects With a Favorable Modified Rankin Score (mRS)	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.	30 days after cardiac arrest (+/- 3 days)
Secondary	Number of Subjects With a Favorable Modified Rankin Score (mRS)	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.	90 days after cardiac arrest (+/- 3 days)
Secondary	Number of Subjects Discharged to a Favorable Destination	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.	Hospital discharge (+/- 3 days)
Secondary	Barthel Index (Activities of Daily Living)	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.	Hospital discharge (+/- 3 days)
Secondary	Barthel Index (Activities of Daily Living)	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.	30 days after cardiac arrest (+/- 3 days)
Secondary	Barthel Index (Activities of Daily Living)	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.	90 days after cardiac arrest (+/- 3 days)
Secondary	Time to Awakening	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.	Within 4 days of cardiac arrest
Secondary	Methemoglobin Level	Methemoglobin content as proportion (%) of total hemoglobin	Prior to study drug
Secondary	Methemoglobin Level	Methemoglobin content as proportion (%) of total hemoglobin	6 hours after study drug initiated
Secondary	Methemoglobin Level	Methemoglobin content as proportion (%) of total hemoglobin	12 hours after study drug initiated
Secondary	Diastolic Blood Pressure	Measured by arterial line	Hourly from 0 - 12 hours of study drug
Secondary	Systolic Blood Pressure	Measured by arterial line	Hourly from 0 - 12 hours of study drug
Secondary	Heart Rate	Calculated from continuous telemetry by monitor	Hourly from 0 - 12 hours of study drug