CardioPulmonary Resuscitation With Argon (CPAr) Trial (CPAr)

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.

Study Overview

• Status: Recruiting
• Conditions: Cardiac Arrest With Successful Resuscitation; Cardiac Arrest, Out-Of-Hospital
• Intervention / Treatment: Other: Noble gas Argon

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 6 months follow up.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lidia Staszewsky, MD; Phone Number: 4508 02390141; Email: lidia.staszewsky@marionegri.it
• Study Contact Backup: Name: Antonella Vasamì; Phone Number: 4450 02390141; Email: antonella.vasami@marionegri.it

Study Locations

• Italy
  • AN
    • Ancona, AN, Italy, 60126
      • Not yet recruiting
      • Azienda Ospedaliera Universitaria delle Marche
      • Contact: Abele Donati, MD; Phone Number: 0715963858; Email: a.donati@univpm.it
  • MI
    • Milano, MI, Italy, 20122
      • Recruiting
      • Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
      • Contact: Giuseppe Ristagno, MD,PhD; Email: giuseppe.ristagno@unimi.it
  • Milano
    • Monza, Milano, Italy, 20900
      • Recruiting
      • Ospedale San Gerado
      • Contact: Giuseppe Foti, MD; Email: g.foti@asst-monza.it
  • RM
    • Roma, RM, Italy, 00168
      • Not yet recruiting
      • Fondazione Policlinico Universitario Agostino Gemelli Irccs
      • Contact: Claudio Sandroni, MD; Email: claudio.sandroni@policlinicogemelli.it

Participation Criteria

Eligibility Criteria

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

Description

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 ≤ 40 mins;
• initiation of study intervention ≤ 4 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 > 4 hrs from ROSC;
• participation to another clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; Patients will be ventilated with a mixture of Ar 70%/O2 30% for 4 hours	Other: Noble gas Argon; Ventilation with Ar 70%/O2 30% in comatose patients resuscitated from OHCA with the use of an experimental mechanical ventilator.
No Intervention: Control-standard; 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) if patient remains comatose	96 hours
Survival	effect of argon on survival after cardiac arrest (days)	6 months
Neurological recovery	Neurological functional recovery is assessed with the CPC score	6 months
Multiorgan function	Multiorgan function is assessed through the evaluation of sequential organ failure assessment score (SOFA). The score sequentially assesses the presence and severity of dysfunctions in six organ systems: respiratory, cardiovascular, coagulation, hepatic, neurological and renal scoring 0 to 4 points per each one of the following: PaO2-fiO2 ratio; Mean arterial pressure (mmHg) or vasoactive treatment; Creatinine (mg/dL) or 24-h diuresis (ml/24h); Platelet count (x103/mm3); Serum bilirubin (mg/dL); Glasgow coma scale The following markers are also assessed: transaminases (UI/L) Pancreatic amilase, lipase (UI/L)	96 hours

Collaborators and Investigators

• Sponsor: Mario Negri Institute for Pharmacological Research
• Investigators: Principal Investigator: Giuseppe Ristagno, MD, PhD, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2022
• Primary Completion (Estimated): March 30, 2025
• Study Completion (Estimated): September 16, 2025

Study Registration Dates

• First Submitted: July 26, 2022
• First Submitted That Met QC Criteria: July 28, 2022
• First Posted (Actual): August 1, 2022

Study Record Updates

• Last Update Posted (Estimated): January 15, 2024
• Last Update Submitted That Met QC Criteria: January 12, 2024
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Cardiac arrest; Cardiopulmonary resuscitation; Argon.
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Arrest; Out-of-Hospital Cardiac Arrest
• Other Study ID Numbers: IRFMN-7557

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No