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    Summary
    EudraCT Number:2021-005876-21
    Sponsor's Protocol Code Number:DANOHCA-001
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-12-20
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2021-005876-21
    A.3Full title of the trial
    The Danish Out-of-Hospital Cardiac Arrest study (DANOHCA)
    Det danske studie af hjertestop uden for hospital (DANOHCA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The Danish Out-of-Hospital Cardiac Arrest study (DANOHCA)
    Det danske studie af hjertestop uden for hospital (DANOHCA)
    A.3.2Name or abbreviated title of the trial where available
    The DANOHCA study
    DANOHCA studiet
    A.4.1Sponsor's protocol code numberDANOHCA-001
    A.5.4Other Identifiers
    Name:The DANOHCA studyNumber:Acronym
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDepartment of Cardiology, Copenhagen University Hospital, Rigshospitalet
    B.1.3.4CountryDenmark
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCopenhagen University Hospital, Rigshospitalet
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCopenhagen University Hospital, Rigshospitalet
    B.5.2Functional name of contact pointDepartment of Cardiology
    B.5.3 Address:
    B.5.3.1Street AddressBlegdamsvej 9
    B.5.3.2Town/ cityCopenhagen OE
    B.5.3.3Post code2100
    B.5.3.4CountryDenmark
    B.5.4Telephone number4535450572
    B.5.6E-mailchristian.hassager@regionh.dk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Dexavit
    D.2.1.1.2Name of the Marketing Authorisation holderVital Pharma Nordic ApS
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDexavit
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDexamethasone
    D.3.9.1CAS number 55203-24-2
    D.3.9.3Other descriptive nameDEXAMETHASONE DISODIUM PHOSPHATE
    D.3.9.4EV Substance CodeSUB122698
    D.3.10 Strength
    D.3.10.1Concentration unit MBq/mg megabecquerel(s)/milligram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Zyprexa
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameZyprexa
    D.3.4Pharmaceutical form Orodispersible tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPGastroenteral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOlanzapine
    D.3.9.1CAS number 132539-06-1
    D.3.9.4EV Substance CodeSUB09426MIG
    D.3.10 Strength
    D.3.10.1Concentration unit MBq/mg megabecquerel(s)/milligram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInfusion
    D.8.4Route of administration of the placeboIntravenous bolus use (Noncurrent)
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOrodispersible tablet
    D.8.4Route of administration of the placeboGastroenteral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    We will investigate the efficacy of four interventions (two pharmaceutical) for reducing mortality and organ damage in patients resuscitated after out-of-hospital cardiac arrest.
    E.1.1.1Medical condition in easily understood language
    Patients resuscitated from out-of-hospital cardiac arrest have a high mortality due to organ damage. We will investigate interventions to treat this and hereby improve outcome.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10003109
    E.1.2Term Arrest cardiac
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The coprimary objectives of the trial for the four interventions:

    1. Determine the efficacy of the glucocorticoid "dexamethasone" (Dexamethasone) compared with placebo. The primary endpoint is all-cause mortality at 90 days
    2. Determine the efficacy of elevated backrest (30-45 degrees) compared with reclined (5-15 degrees) backrest. The primary endpoint is all-cause mortality at 90 days
    3. Determine the efficacy of early wake up and extubation ≤6 hours after admission compared with wake up and extubation at 28-36 hours. The primary endpoint is days alive outside hospital within 30 days
    4. Determine the efficacy of the antipsychotic drug "olanzapine" (Zyprexa) compared with placebo. The primary endpoint is days alive outside hospital within 30 days
    E.2.2Secondary objectives of the trial
    The secondary objectives of the trial are to investigate the effects of the interventions on inhibition of inflammation, cardiac protection, neuroprotection, renal protection, endothelial protection, clinical endpoints including survival and neurological outcome, as well as safety.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Several pre-defined substudies are planned from the beginning of the study:

    1. Advanced hemodynamics study
    The Rigshospitalet site (and potential other sites participating in this substudy) will per routine insert a pulmonary artery catheter in the patient. The PAC is part of the routine hemodynamic monitoring in cardiac arrest patients and as such, the patients will not be exposed to excess risk.
    The study assesses effects of the trial intervention on advanced hemodynamics, in particular the steroid and the backrest position intervention.

    2. Retrograde venous catheter and jugular vein blood and micro dialyses
    Lactate/pyruvate from jugular bulb micro dialysis and blood sampling (headed by Odense University Hospital). Ultrasound guided procedure with minimal risk (bleeding) in experienced centers.

    3. Early mobilization of the patients
    At the Rigshospitalet site, patients will be allocated to early mobilization (positioning in a chair or more aggressive depending on the patient’s condition) after 72 hours and then twice daily by ICU nurses on top of usual care, or usual care (mobilization when awakening and training by physiotherapist once daily) until ICU discharge.

    4. CNS evaluation and prognostication
    At the Aarhus University Hospital site, the following additional procedures will be performed:
    • Automated pupillometry will be performed three times a day during ICU stay
    • Sonography of the optic nerve sheath diameter
    • Transcranial Doppler Sonography will be performed by ultrasound twice a day during ICU stay

    5. Coagulation and inflammatory markers
    At the Aalborg University Hospital site ROTEM, Multiplate and Calibrated Automated Thrombingeneration (CAT) will be performed 0-24 and 48-72 hours after inclusion (day 1 and 3).
    E.3Principal inclusion criteria
    1. Age ≥18 years
    2. OHCA of presumed cardiac cause
    3. Sustained ROSC#
    4. Unconsciousness (GCS <9) (patients not able to obey verbal commands) after sustained ROSC at the time of randomization

    # Sustained ROSC: Sustained ROSC is when chest compressions or mechanical circulatory support have been not required for 20 consecutive minutes and signs of circulation persist.
    E.4Principal exclusion criteria
    1. Females of childbearing potential (unless a negative HCG test can rule out pregnancy within the inclusion window)
    2. Known bleeding diathesis (medically induced coagulopathy (e.g. warfarin, NOAC, clopidogrel) does not exclude the patient)
    3. Suspected or confirmed acute intracranial bleeding
    4. Suspected or confirmed acute stroke
    5. Unwitnessed asystole
    6. Known limitations in therapy and Do Not Resuscitate-order
    7. Known disease making 180 days survival unlikely
    8. Known pre-arrest CPC 3 or 4 functional status
    9. >3 hours (180 minutes) from ROSC to screening
    10. Systolic blood pressure <80 mm Hg despite fluid loading/vasopressor and/or inotropic medication#
    11. Use of intra-aortic balloon pump/axial flow device/ECMO†
    12. Temperature on admission <30°C

    Further exclusion criteria specific to the trial interventions:
    13. Known allergy from dexamethasone or olanzapine
    14. Ongoing (within 48 h) treatment with dexamethasone or olanzapine
    15. Known back or hip condition that precluded the patients from being positioned with backrest from 0 to 45-degree angle
    16. Known or suspected Long QT Syndrome (LQTS)
    17. Known active fungal disease. Localized skin lesions do not exclude patients from inclusion
    18. Estimated body weight <45kg

    # If the systolic blood pressure (SBP) is recovering during the inclusion window (180 minutes) the patient may be included
    † If the patient is weaned and the device is removed during the inclusion window (180 minutes) the patient may be included
    E.5 End points
    E.5.1Primary end point(s)
    1. The protective effect of dexamethasone decided by all-cause mortality at 90 days following cardiac arrest
    2. The protective effect of elevated backrest (30-45 degrees) decided by all-cause mortality at 90 days following cardiac arrest
    3. The protective effect of early wake up and extubation ≤6 hours after admission decided by days alive outside hospital within 30 days
    4. The protective effect of olanzapine decided by days alive outside hospital within 30 days
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. At 90 days following cardiac arrest (Dexamethasone)
    2. At 90 days following cardiac arrest (Elevated backrest)
    3. Days alive outside hospital within 30 days (Early wake up)
    4. Days alive outside hospital within 30 days (Olanzapine)
    E.5.2Secondary end point(s)
    1. All-cause mortality at 90 days (in study strata where it is not a primary endpoint)
    2. Serum Neuron Specific Enolase and Light Chain Neurofilament levels at 48h
    3. Markers of organ damage other that CNS:
    o TNT or TNI and CKMB (cardiac) and proBNP during initial 72h
    o Creatinine during initial 72h and the use of dialysis during the first 30 days post OHCA (renal)
    4. Inflammatory markers:
    o CRP, proCT, ferritin, IL-6 and IL-10 during the first 72 hours
    5. Positive blood cultures taken on clinical indication
    6. Incidence of culture positive pneumonia in the two strata (mandatory tracheal culture after 36 hours)
    7. Need for vasopressor during ICU stay. (cumulative doses during the first 36 hours and total doses)
    8. Need for insulin and glucose during ICU stay
    9. Mixed blood venous saturation after 12, 24 and 36 hours and the daily during ICU stay
    10. Mean daily FiO2 during the first 72 hours
    11. Mean daily PEEP during the first 72 hours
    12. Duration of intubation (oral and tracheostomy combined)
    13. Number of unconscious patients at 96 hours
    14. Number of CAM-ICU positive patients 24 hours after extubation
    15. Number of CAM-ICU negative days
    16. Number of days without pharmacological treatment for delirium (other than study drug during the intervention period)
    17. ICU length of stay
    18. Hospital length of stay (including in-patient rehabilitation and transfer to referral hospital)
    19. Number of recorded decubitus ulcers in the two strata
    20. Assessment of cognitive function (RBANS and MOCA point) at 90 days
    21. Assessment of quality of life (EQ-5D-5L) and anxiety/depression (HADS) at 90 days
    22. CPC and mRS at ICU discharge, at hospital discharge and at 90 days
    23. Changes in LVEF from admission until discharge (or last recorded LVEF during initial hospital stay)


    Common tertiary endpoints to all four interventions:
    These tertiary endpoints are expected to form the basis for sub studies and the randomization code will possibly have been broken and main results published prior to their collection.

    1. All-cause mortality at 180 days
    2. Assessment of cognitive function (RBANS and MOCA point) at 180 days
    3. Assessment of quality of life (EQ-5D-5L) and anxiety/depression (HADS) at 180 days
    4. CPC and mRS at ICU discharge, at hospital discharge and at 180 days
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluation of paraclinical secondary endpoints (markers of organ dysfunction) up to 72 hours after admission.
    Evaluation of clinical secondary endpoints (survival and neurological outcome) up to 90 days after admission.
    Evaluation of clinical tertiary endpoints (neurological outcome) 180 days after admission.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.3.1Comparator description
    We are investigating two mechanical interventions, aside from the two pharmaceutical interventions
    E.8.2.4Number of treatment arms in the trial16
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 700
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2021-12-20. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients included in the study will be unconscious following resuscitation from out-of-hospital cardiac arrest.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1000
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There are no plans of trial-specific treatment or care after participation has ended. Following inclusion in the study patients will undergo clinical follow-up as usual.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-02-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-08
    P. End of Trial
    P.End of Trial StatusOngoing
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