Comparison of Isoprenaline Hydrochloride and Epinephrine in Out-of-Hospital Cardiac Arrest with Non-Shockable Rhythm

The primary objective of this study is to determine whether the use of **isoprenaline** increases the chance of sustained return of spontaneous circulation during out-of-hospital cardiac arrest with non-shockable rhythm compared with **epinephrine**. This is clinically relevant as achieving sustained return of spontaneous circulation is a critical factor in improving survival rates and outcomes in patients experiencing cardiac arrest.

Secondary objectives include: - Evaluating whether the use of isoprenaline can increase the rate of conversions from non-shockable to a shockable heart rhythm in patients with out-of-hospital cardiac arrest compared with epinephrine. - Assessing whether isoprenaline improves the chance of a good neurological outcome at discharge in these patients compared with epinephrine. - Determining if isoprenaline can increase the chance of achieving sustained return of spontaneous circulation and improving 30-day survival after out-of-hospital cardiac arrest compared with epinephrine. - Evaluating how isoprenaline affects neurological outcomes 90 days after the out-of-hospital cardiac arrest compared with epinephrine.

The clinical trial focuses on individuals experiencing **cardiac arrest** with a specific interest in those with non-shockable rhythms, such as pulseless electrical activity (PEA) or asystole. The study population includes both men and women aged 18 years and older. Participants are those who have experienced an out-of-hospital cardiac arrest witnessed by bystanders or emergency medical service personnel, with advanced life support initiated or continued by EMS personnel. The trial includes a vulnerable population, but the total number of participants is not provided as the sponsor has not disclosed this information. The selection criteria emphasize the inclusion of individuals who have experienced a witnessed cardiac arrest, ensuring that the study population is relevant to the trial's objective of assessing the efficacy of isoprenaline compared to epinephrine in achieving sustained return of spontaneous circulation. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **isoprenaline hydrochloride** compared to **epinephrine** in patients experiencing out-of-hospital **cardiac arrest** with a non-shockable rhythm. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment is being administered, thereby minimizing bias. The trial is expected to commence recruitment on June 1, 2025, and conclude by December 31, 2028. Participants will be involved in the study for a maximum treatment period of one day, with the primary endpoint being the sustained return of spontaneous circulation for at least 20 minutes.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), witnessed cardiac arrest, and non-shockable initial rhythm. Advanced life support must be initiated or continued by emergency medical services personnel. Follow-up visits will be conducted to monitor the conversion from non-shockable to shockable rhythm, assess neurological outcomes at hospital discharge, and evaluate return of spontaneous circulation at hospital arrival. The end-of-study visit will occur at the conclusion of the treatment period or upon achieving the primary endpoint.

Participants are expected to remain in the study for the duration of the treatment period unless conditions arise that necessitate early termination, such as withdrawal of consent or adverse events. The trial aims to provide valuable insights into the potential benefits of isoprenaline in improving outcomes for patients with cardiac arrest, contributing to the optimization of emergency medical interventions.

The clinical trial involves the administration of **Isoprenaline hydrochloride**, marketed as "Isoprenaline hydrochloride 'Macure'", which is a **solution for infusion**. This experimental medication is provided in the form of a concentrate for infusion solution. The active substance, isoprenaline hydrochloride, is of chemical origin. The medication is administered via **intravenous bolus use**. The maximum daily dose is 2.4 mg, with a total maximum dose of 2.4 mg over a treatment period of one day. The pharmaceutical product is not a pediatric formulation and is manufactured by Macure Pharma APS. Participant compliance with the dosing schedule will be monitored throughout the trial.

The comparator treatment in this study is **Epinephrine**, marketed as "Adrenalin 'DAK'", which is a **solution for injection**. This non-experimental treatment is also of chemical origin and is administered via intravenous bolus use. The maximum daily dose for epinephrine is 4 mg, with a total maximum dose of 4 mg over a treatment period of one day. This product is not formulated for pediatric use and is produced by Orifarm Healthcare A/S. The administration and dosing of epinephrine will be closely monitored to ensure adherence to the study protocol.

The efficacy of the clinical trial titled "Epinephrine versus Isoprenaline During Out-of-Hospital Cardiac Arrest with Non-Shockable Rhythm (EPISO)" will be assessed using both primary and secondary endpoints. The primary endpoint is the **sustained return of spontaneous circulation** (ROSC) for at least 20 minutes. This endpoint is critical in determining the immediate effectiveness of the intervention in restoring circulation during cardiac arrest.

Secondary endpoints include the conversion from non-shockable to shockable rhythm, favorable neurological outcome at hospital discharge, ROSC at hospital arrival, and thirty-day survival. These endpoints provide a comprehensive evaluation of the intervention's impact on both short-term and long-term outcomes following cardiac arrest.

The trial aims to compare the efficacy of **isoprenaline** with **epinephrine** in increasing the chance of sustained ROSC during out-of-hospital cardiac arrest with a non-shockable rhythm. The assessment of these endpoints will be conducted at various stages, including hospital discharge and thirty days post-intervention, to ensure a thorough analysis of the treatment's effectiveness.