CardioPulmonary Resuscitation With Argon (CPAr) Trial

Study Overview
=================
Brief Summary
-----------------
Preclinical studies suggest that argon (Ar) might diminish the neurological and myocardial damage after any hypoxic-ischemic insult. Indeed, Ar has been tested in different models of ischemic insult, at concentrations ranging from 20% up to 80%. Overall, Ar emerged as a protective agent on cells, tissues and organs, showing less cell death, reduced infarct size and faster functional recovery. More specifically, encouraging data has been reported in animal studies on cardiac arrest (CA) in which a better and faster neurological recovery was achieved when Ar was used in the post-resuscitation ventilation. More importantly, these benefits have been replicated in different studies, enrolling both small and large animals. Finally, ventilation with Ar in O2 has been demonstrated to be safe both in animals and humans. Based on this evidence, a clinical translation is advocated. Thus, the CardioPulmonary resuscitation with Argon - CPAr trial has been conceived. The aim of the CPAr trial is to evaluate feasibility and safety of Ar/O2 ventilation in patients resuscitated from CA. Activity endpoints will be also evaluated to assess effects of Ar.

Detailed Description
-----------------
The trial is a multicenter, randomized, controlled, single blinded, phase I and pre marketing study in patients resuscitated from Out-of-hospital cardiac arrest (OHCA). The adoption of a randomized design in a phase I trial aiming at a safety assessment of a new ventilation mixture in a very critical population is justified and necessary in the absence of reliably comparable populations on which to base estimates of a potential excess of adverse events/side effects. All eligible patients will be treated in full and documented compliance with the European ResuscitationCouncil (ERC)/European Society of Intensive Care Medicine (international guidelines and local post resuscitation protocols). Since a reliable estimate of the incidence and characteristics of the clinical events assumed as endpoints is not available in the literature, a randomized assignment is the only way to ensure a strict comparability for both the periods of data collection of safety end points (to be assessed blindly by the events Committee), the four hours of duration of study treatment, and the longer period of possibly related clinical events during the 1 month follow up.

Official Title
-----------------
CardioPulmonary Resuscitation With Argon (CPAr) Trial

Conditions
-----------------
Cardiac Arrest, Out-Of-Hospital, Cardiac Arrest With Successful Resuscitation

Intervention / Treatment
-----------------
* Other: Noble gas Argon


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ICU admission after resuscitation from witnessed non-traumatic out-of-hospital cardiac arrest (OHCA) of presumably cardiac etiology with a presenting shockable rhythm; age ≥ 18 years; unconsciousness after return of spontaneous circulation (ROSC); duration of CPR ≤ 30 mins; initiation of study intervention ≤ 3 hrs from ROSC; stable SaO2 ≥ 94% with a FiO2 of 30%. Exclusion Criteria: Non-witnessed CA; CA of traumatic origin or from a non-presumably cardiac cause; CA with a non-shockable presenting rhythm (pulseless electrical activity and asystole); female of childbearing potential defined as younger of 50 years; pregnancy; known terminal illness; pre-CA cerebral performance category (CPC) ≥ 3; initiation of the study intervention > 3 hrs from ROSC: participation to another clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The intervention (Ar/O2 or standard ventilation) is assigned to the patient using a centrally generated randomization plan, balanced by centre.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Patients will be ventilated with a mixture of Ar 70%/O2 30% for 4 hours | Other: Noble gas Argon<br>* Ventilation with Ar 70%/O2 30% in comatose patients resuscitated from OHCA with the use of an experimental mechanical ventilator.<br>|
| No Intervention: Control-standard<br>Ventilation with a FiO2 of 30% in room air is continued for 4 hours. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | The incidence, the timing, and the duration of the need to stop Ar 70% treatment in order to maintain the SPO2> 90%. The incidence of potentially Ar-attributable hemodynamic adverse events (i.e. arterial hypotension not responsive to fluids and/or vasoactive/inotropic drugs). | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial preservation | Ar effect on myocardial protection is assessed through measure of hs-cTnT release | 96 hours | 
| Neuronal preservation | Ar effect on neuronal preservation is assessed through evaluation of NSE preservation and ultimately on survival (CPC score) will be evaluated. | 96 hours | 
| Brain injury | Ar effect on brain injury is assessed through MRI (imaging) | 96 hours | 
| Survival | effect of argon on survival after cardiac arrest (days) | 1 month | 
| Neurological recovery | Neurological functional recovery iassessed with the CPC score | 1 month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cardiac arrest; Cardiopulmonary resuscitation; Argon.