Efficacy of Dexamethasone and Olanzapine in Patients Resuscitated from Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial

The primary objectives of the **Danish Out-of-Hospital Cardiac Arrest study (DANOHCA)** are to evaluate the efficacy of four interventions in patients resuscitated from out-of-hospital cardiac arrest. These interventions include:

• Determining the efficacy of the glucocorticoid **dexamethasone** compared with placebo, with the primary endpoint being all-cause mortality at 90 days.
• Assessing the efficacy of an elevated backrest (30-45 degrees) compared with a reclined backrest (5-15 degrees), with the primary endpoint being all-cause mortality at 90 days.
• Evaluating the efficacy of early wake-up and extubation within 6 hours after admission compared with wake-up and extubation at 28-36 hours, with the primary endpoint being days alive outside the hospital within 30 days.
• Investigating the efficacy of the antipsychotic drug **olanzapine** compared with placebo, with the primary endpoint being days alive outside the hospital within 30 days.

The secondary objectives of the trial are to explore the effects of the interventions on various clinical parameters, including inhibition of inflammation, cardiac protection, neuroprotection, renal protection, endothelial protection, and clinical endpoints such as survival and neurological outcomes, as well as safety. Additional secondary objectives include:

• Advanced hemodynamics study involving the use of a pulmonary artery catheter for routine hemodynamic monitoring.
• Retrograde venous catheter and jugular vein blood and microdialysis for lactate/pyruvate analysis.
• Early mobilization of patients, involving positioning in a chair or more aggressive mobilization depending on the patient's condition.
• CNS evaluation and prognostication through automated pupillometry, sonography of the optic nerve sheath diameter, and transcranial Doppler sonography.
• Assessment of coagulation and inflammatory markers using ROTEM, Multiplate, and Calibrated Automated Thrombogenesis (CAT).

The clinical trial involves a study population of **patients resuscitated from out-of-hospital cardiac arrest**. The trial includes both male and female participants, aged 18 years and older, who have experienced an out-of-hospital cardiac arrest of presumed cardiac cause. Participants must have achieved sustained return of spontaneous circulation (ROSC), defined as not requiring chest compressions or mechanical circulatory support for 20 consecutive minutes with persistent signs of circulation. Additionally, participants are required to be unconscious, with a Glasgow Coma Scale (GCS) score of less than 9, indicating an inability to obey verbal commands at the time of randomization. The trial population is considered vulnerable, and the sponsor has not provided the total number of participants. The selection criteria ensure that the study focuses on individuals who meet specific medical and physiological conditions relevant to the trial's objectives.

The clinical trial is designed to evaluate the efficacy of various interventions in patients resuscitated from **out-of-hospital cardiac arrest**. This study employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The trial is expected to run from March 2023 to February 2027, with participant involvement lasting up to 90 days. The primary interventions being tested include the administration of **dexamethasone disodium phosphate** and **olanzapine**, each compared against a placebo, as well as non-pharmacological interventions such as elevated backrest positioning and early wake-up and extubation protocols.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), sustained return of spontaneous circulation (ROSC), and unconsciousness post-ROSC. Following randomization, participants will receive their assigned intervention. Follow-up visits will be conducted to monitor primary endpoints, including all-cause mortality at 90 days and days alive outside the hospital within 30 days. Secondary endpoints will assess various biomarkers, organ damage, and quality of life metrics.

The end-of-study visit will occur at the 90-day mark, where final assessments will be made. Participants may be withdrawn from the study early if they experience significant adverse effects or if they withdraw consent. The trial's rigorous methodology and comprehensive follow-up schedule are designed to provide robust data on the interventions' protective effects in this critical patient population.

The clinical trial involves the administration of **ZYPREXA VELOTAB**, which contains the active substance **olanzapine**. This medication is provided in the form of orodispersible tablets, each containing 10 mg of olanzapine. The tablets are designed for **gastroenteral use**, allowing for rapid disintegration in the mouth. The maximum daily dose is 10 mg, with a total maximum dose of 30 mg over a treatment period of up to 3 days. The medication is of chemical origin and is not a paediatric formulation. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

In addition to the experimental medication, a **placebo** is used as a comparator in the study. The placebo is available in two forms: a solution for injection and a tablet. The injectable placebo is administered via **intravenous use**, with a maximum daily dose of 20 mg and a total maximum dose of 20 mg over a 3-day period. The tablet form of the placebo is administered orally, with a maximum daily dose of 10 mg and a total maximum dose of 30 mg over the same treatment period. Both forms of the placebo are of chemical origin and are used to evaluate the efficacy of the experimental treatments by providing a baseline for comparison.

Another experimental treatment in the trial is **Dexavit**, which contains **dexamethasone disodium phosphate** as the active substance. This medication is provided as a solution for injection and is administered intravenously. The maximum daily dose is 20 mg, with a total maximum dose of 60 mg over a treatment period of up to 3 days. Dexavit is of chemical origin and is used to assess its efficacy compared to the placebo in the context of the study's objectives. Compliance with the dosing schedule is monitored to ensure accurate evaluation of the treatment's effects.

The efficacy of the interventions in the clinical trial titled "DANOHCA: The Danish Out-of-Hospital Cardiac Arrest study" will be assessed using specific primary and secondary endpoints. The primary endpoints include all-cause mortality at 90 days for the interventions involving **dexamethasone** and elevated backrest, and days alive outside the hospital within 30 days for the interventions involving early wake-up and extubation, as well as the antipsychotic drug **olanzapine**. These endpoints are designed to evaluate the protective effects of the interventions following cardiac arrest.

Secondary endpoints will provide additional insights into the efficacy of the interventions. These include all-cause mortality at 90 days in study strata where it is not a primary endpoint, serum Neuron Specific Enolase and Light Chain Neurofilament levels at 48 hours, and markers of organ damage such as TNT or TNI, CKMB, and proBNP during the initial 72 hours. Other secondary endpoints include inflammatory markers like CRP, proCT, ferritin, IL-6, and IL-10 during the first 72 hours, incidence of culture-positive pneumonia, and various measures of patient recovery and health status, such as ICU and hospital length of stay, cognitive function assessments, and quality of life evaluations at 90 days.

The collection and analysis of these efficacy parameters will be conducted at specified time points, including 48 hours, 72 hours, and 90 days post-intervention, using validated laboratory tests and patient-reported outcomes. The trial aims to provide comprehensive data on the efficacy of the interventions in improving outcomes for patients experiencing out-of-hospital cardiac arrest.