The Danish Out-of-Hospital Cardiac Arrest Study

NCT05895838 | Recruiting Phase 3 DMC

• 2 other identifiers: H-210774612021-005876-21
• Study Type: interventional
• Target: 1,000
• Locations: 1 country
• Sites: 5

Brief Summary

After resuscitation from Out-of-Hospital Cardiac Arrest (OHCA) patients experience Post Cardiac Arrest Syndrome due to ischemia and reperfusion injury. It consists of systemic inflammation, cerebral and myocardial dysfunction, and the condition that led to the arrest. Most OHCA patients will receive critical care intubated in an Intensive Care Unit (ICU). Despite this \~50% die; mainly due to brain injury. Several targets can be considered for improving outcomes. To dampen systemic inflammation and optimize cerebral perfusion seem important. Deep sedation has been required for targeted temperature management (TTM) but may also be brain protective. After end of sedation, many patients have some cerebral dysfunction that may facilitate delirium. The aim of this trial is therefore to improve treatment of comatose OHCA patients by evaluating 4 interventions in a factorial design addressing each of these targets in a randomized clinical trial:

1. 1.Systemic inflammation: Anti-inflammatory treatment with high dose steroids (dexamethasone) or placebo.
2. 2.Cerebral perfusion: Backrest elevation during sedation at 5 or 35 degrees.
3. 3.Duration of sedation: Early wakeup call and potential extubation at ≤6 hours after admission or later as current standard practice at 28-36 hours.
4. 4.Delirium: Prophylactic treatment with anti-psychotic medication (olanzapine) or placebo.

Conditions

Out-Of-Hospital Cardiac Arrest; Post-Cardiac Arrest Syndrome

Keywords

Out-Of-Hospital Cardiac Arrest; Post-Cardiac Arrest Syndrome; Systemic Inflammatory Response Syndrome; Inflammation; Cerebral perfusion; Sedation; Delirium

Outcome Measures

Primary Outcomes (4)

• Steroid intervention primary endpoint: All-cause mortality

  Number of patients dying from all causes

  90 days

• Back rest position intervention primary endpoint: All-cause mortality

  Number of patients dying from all causes

  90 days

• Early wakeup and extubation intervention primary endpoint: Days alive outside hospital

  Counted as days alive outside of hospital after discharge

  30 days

• Olanzapine intervention primary endpoint: Days alive outside hospital

  Counted as days alive outside of hospital after discharge

  30 days

Secondary Outcomes (14)

• Number of patients dying from all causes

  90 days

• Neuron Specific Enolase and Neurofilament Light Chain levels

  48 hours

• Troponin I, Troponin T, and Creatine Kinase Myocardial Band

  0-72 hours

• Plasma Creatinine and use of dialysis

  Creatinine: initial 72 hours; Dialysis: initial 30 days

• Vasopressors and inotropic drugs

  Initial ICU stay, during the first 36 hours

Study Arms (8)

Dexamethasone intervention, active

EXPERIMENTAL

As soon as possible after hospital admittance 20 mg of dexamethasonephosphate (Dexavit, Vital Pharma Nordic ApS, Denmark) will be given intravenously (i.v.) over 15 minutes - followed by 20 mg dexamethasonephosphate (or placebo) i.v. administered daily at 0600 (or at least 8 hours after initial dose) for two days, for a total of 3 doses. For this arm the dexamethasonephosphate solution is provided in the "DANOHCA trial kit" in the form of Dexavit at a concentration of 4mg/mL stored in glass vials of 5mL; three vials are provided in total.

Drug: Dexamethasone

Dexamethasone intervention, placebo

PLACEBO COMPARATOR

As soon as possible after hospital admittance placebo (isotonic saline) will be given intravenously (i.v.) over 15 minutes - followed by placebo solution administered i.v. daily at 0600 (or at least 8 hours after initial dose) for two days, for a total of 3 doses. For this arm the placebo solution is provided in the "DANOHCA trial kit" in the form of isotonic sodium chloride stored in glass vials of 5mL; three vials are provided in total.

Drug: Dexamethasone

Backrest elevation intervention, elevation to 35 degrees

EXPERIMENTAL

As soon as possible after hospital admittance the patients will have their headrest positioned at 35 degrees straight elevation of backrest in Semi-Fowler's position (elevated lower limp position). This position will be maintained during the initial 72 hours or until extubated. Adherence to assigned stratum will be checked every 8 hours and cuff pressure will be assessed and corrected if needed at the same time during the intervention period. The backrest position intervention may be temporarily canceled by the treating physician if needed for procedures or mobilization but will return to the assigned position if invasive ventilator treatment with orotracheal intubation is continued. The intervention will be terminated if the patient is extubated, or a tracheostomy is performed, during the intervention period of 72 hours.

Procedure: Backrest elevation

Backrest elevation intervention, elevation to 5 degrees

ACTIVE COMPARATOR

As soon as possible after hospital admittance the patients will have their headrest positioned at 5 degrees straight elevation of backrest in Semi-Fowler's position. This position will be maintained during the initial 72 hours or until extubated. Adherence to assigned stratum will be checked every 8 hours and cuff pressure will be assessed and corrected if needed at the same time during the intervention period. The backrest position intervention may be temporarily canceled by the treating physician if needed for procedures or mobilization but will return to the assigned position if invasive ventilator treatment with orotracheal intubation is continued. The intervention will be terminated if the patient is extubated, or a tracheostomy is performed, during the intervention period of 72 hours.

Procedure: Backrest elevation

Early wake-up intervention, wake-up ≤6 hours after ICU admission

EXPERIMENTAL

Patients will be subjected to a wakeup call and potential extubation after ≤6 hours after admission to the ICU. Definition for "ready for extubation" will be: GCS≥12, RASS 0- -1, able to raise arm or voluntary hand shake on command, spontaneous breathing trial and low ventilator settings (pressure support≤14, PEEP≤8 (10 if obese), and FiO2≤40%). A wakeup call may be aborted for the following reasons: seizures, respiratory distress, shock, or "other cause" with specification. Sedation prior to the scheduled wakeup calls is permitted in this early wakeup call group as needed for clinical care, while it is mandatory for the late wakeup call group. For both groups sedation as needed for clinical care will be permitted after the scheduled wakeup calls. For this arm, information on the assigned time for wakeup call is provided in the "DANOHCA trial kit". The assigned time for wakeup will be noted in the electronic patient file.

Procedure: Early wakeup call

Early wake-up intervention, wake-up 28-36 hours after ICU admission

ACTIVE COMPARATOR

Patients will be subjected to a wakeup call and potential extubation after 28-36 hours after admission to the ICU. Definition for "ready for extubation" will be: GCS≥12, RASS 0- -1, able to raise arm or voluntary hand shake on command, spontaneous breathing trial and low ventilator settings (pressure support≤14, PEEP≤8 (10 if obese), and FiO2≤40%). A wakeup call may be aborted for the following reasons: seizures, respiratory distress, shock, or "other cause" with specification. Sedation prior to the scheduled wakeup calls is mandatory for this late wakeup call group. For both groups sedation as needed for clinical care will be permitted after the scheduled wakeup calls. For this arm, information on the assigned time for wakeup call is provided in the "DANOHCA trial kit". The assigned time for wakeup will be noted in the electronic patient file.

Procedure: Early wakeup call

Olanzapine intervention, active

EXPERIMENTAL

As soon as possible after arriving at the ICU olanzapine 10mg (dissolved tablet) is administered by feeding tube. Thereafter 10 mg olanzapine is administered by feeding tube (or orally in awake patients) the following two evenings at 1800 (with a minimum of 12 hours between the initial doses) for a total of 3 doses. Due to the potential QT-prolonging effect, and concern for arrythmia, patients will be excluded prior to randomization if Long QT Syndrome (LQTS) is suspected, and telemetry of heart rhythm is mandatory for 96 hours or until life sustaining therapies are withdrawn. In case of delirium patients are treated according to standard care most often including dexmedetomidine, haloperidol or midazolam. For this arm the olanzapine tablets are provided in the "DANOHCA trial kit" in the form of olanzapin 10mg tablets (Accord Healthcare B.V., The Netherlands); three tablets are provided in total. Prior to administration by feeding tube the tablets are dissolved in water.

Drug: Olanzapine

Olanzapine intervention, placebo

PLACEBO COMPARATOR

As soon as possible after arriving at the ICU a placebo tablet (dissolved) is administered by feeding tube. Thereafter placebo will be administered by feeding tube (or orally in awake patients) the following two evenings at 1800 (with a minimum of 12 hours between the initial doses) for a total of 3 doses. Due to the potential QT-prolonging effect of olanzapine, and accompanying concern for arrythmia, patients will be excluded prior to randomization if LQTS is suspected, and telemetry of heart rhythm is mandatory for 96 hours or until life sustaining therapies are withdrawn. In case of delirium patients are treated according to standard care most often including dexmedetomidine, haloperidol or midazolam. For this arm the placebo tablets are provided in the "DANOHCA trial kit" in the form of placebo tablets manufactured by the Pharmacy of the Capital Region; three tablets are provided in total. Prior to administration by feeding tube the tablets are dissolved in water.

Drug: Olanzapine

Interventions

Dexamethasone DRUG

Patients will be allocated to intravenous administration of dexamethasonephosphate 20mg (Dexavit, Vital Pharma Nordic ApS, Denmark) or placebo at admission and again the following two mornings until discharge from ICU or a maximum of 3 doses.

Also known as: Dexavit

Dexamethasone intervention, active; Dexamethasone intervention, placebo

Backrest elevation PROCEDURE

Patients will be allocated to have their headrest positioned at 35 degrees backrest vs 5 degrees straight elevation of backrest for 72 hours (or until extubation if occuring prior to 72 hours).

Backrest elevation intervention, elevation to 35 degrees; Backrest elevation intervention, elevation to 5 degrees

Early wakeup call PROCEDURE

Patients will be allocated to early wakeup call and potential extubation after ≤6 hours or late wakeup call and extubation between 28-36 hours after admission to the ICU.

Early wake-up intervention, wake-up 28-36 hours after ICU admission; Early wake-up intervention, wake-up ≤6 hours after ICU admission

Olanzapine DRUG

Patients will be allocated to olanzapine 10 mg (Olanzapin, Accord Healthcare B.V., The Netherlands) administered by feeding tube (or orally in awake patients) or matching placebo at admission and again the following two evenings until discharge from ICU or a maximum of 3 doses.

Olanzapine intervention, active; Olanzapine intervention, placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years
• OHCA of presumed cardiac cause
• Sustained ROSC, defined as persistent signs of circulation and no need for chest compressions or mechanical circulatory support for 20 minutes
• Unconsciousness (GCS \<9) (patients not able to obey verbal commands) after sustained ROSC at the time of randomization

You may not qualify if:

• Known bleeding diathesis (medically induced coagulopathy (e.g. warfarin, NOAC, clopidogrel) does not exclude the patient)
• Suspected or confirmed acute intracranial bleeding
• Suspected or confirmed acute stroke
• Unwitnessed asystole
• Known limitations in therapy and Do Not Resuscitate-order
• Known disease making 180 days survival unlikely
• Known pre-arrest CPC 3 or 4 functional status
• \>3 hours (180 minutes) from ROSC to screening
• Temperature on admission \<30°C
• Known allergy for dexamethasone or olanzapine
• Ongoing (within 48 h) treatment with olanzapine or dexamethasone
• Known back or hip condition that precluded the patients from being positioned with backrest from 0 to 45-degree angle
• Known or suspected Long QT Syndrome (LQTS)
• Estimated body weight \<45kg

Sponsors & Collaborators

• Christian Hassager: lead

Study Sites (5)

Dept. of Cardiology, The Heart Centre, Copenhagen University Hospital Rigshospitalet

Copenhagen, Capital Region of Denmark, DK-2100, Denmark

RECRUITING

The Department of Intensive Care, Aalborg University Hospital

Aalborg, DK-9000, Denmark

RECRUITING

The Department of Intensive Care, Aarhus University Hospital

Aarhus, DK-8200, Denmark

RECRUITING

Department of Anaesthesiology and Intensive Care Medicine, Zealand University Hospital

Køge, DK-4600, Denmark

RECRUITING

The Department of Cardiothoracic Anaesthesiology, Odense University Hospital

Odense, DK-5000, Denmark

RECRUITING

MeSH Terms

Conditions

Out-of-Hospital Cardiac Arrest; Post-Cardiac Arrest Syndrome; Systemic Inflammatory Response Syndrome; Inflammation; Delirium

Interventions

Dexamethasone; Olanzapine

Condition Hierarchy (Ancestors)

Heart Arrest; Heart Diseases; Cardiovascular Diseases; Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Reperfusion Injury; Vascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Christian Hassager, MD DMSc

  Dept. of Cardiology, Rigshospitalet

  STUDY CHAIR

• Jesper Kjaergaard, MD PhD DMSc

  Dept. of Cardiology, Rigshospitalet

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Christian Hassager, MD DMSc

CONTACT

+4535450572; christian.hassager@regionh.dk

Jesper Kjaergaard, MD PhD DMSc

CONTACT

+4535450969; jesper.kjaergaard.05@regionh.dk

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The pharmacological interventions will be placebo controlled, and participants, care providers, investigators, and outcome assessors are blinded. The physiological interventions of early wakeup and extubation as well as the back-rest position are open label.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, MD, DMSc, FESC

Model Details: Patients will be randomized in a 1:1 fashion to receive either the experimental intervention or placebo/control intervention for each of the four interventions with an assumption of no interaction.

Study Record Dates

• First Submitted: May 10, 2023
• First Posted: June 9, 2023
• Study Start: June 16, 2023
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: January 24, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

DK (5)