Clinical Trials Register

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:	Trial now transitioned
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

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2021-005876-21

A.3

Full title of the trial

The Danish Out-of-Hospital Cardiac Arrest study (DANOHCA)

Det danske studie af hjertestop uden for hospital (DANOHCA)

A.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

The DANOHCA study

DANOHCA studiet

A.4.1

Sponsor's protocol code number

DANOHCA-001

A.5.4

Other Identifiers

Name:

The DANOHCA study

Number:

Acronym

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Department of Cardiology, Copenhagen University Hospital, Rigshospitalet
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Copenhagen University Hospital, Rigshospitalet
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Copenhagen University Hospital, Rigshospitalet
B.5.2	Functional name of contact point	Department of Cardiology
B.5.3	Address:
B.5.3.1	Street Address	Blegdamsvej 9
B.5.3.2	Town/ city	Copenhagen OE
B.5.3.3	Post code	2100
B.5.3.4	Country	Denmark
B.5.4	Telephone number	4535450572
B.5.6	E-mail	christian.hassager@regionh.dk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Dexavit
D.2.1.1.2	Name of the Marketing Authorisation holder	Vital Pharma Nordic ApS
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Dexamethasone phosphate
D.3.9.1	CAS number	312-93-6
D.3.9.4	EV Substance Code	SUB01612MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Olanzapine
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Gastroenteral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Olanzapine
D.3.9.1	CAS number	132539-06-1
D.3.9.4	EV Substance Code	SUB09426MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Infusion
D.8.4	Route of administration of the placebo	Intravenous bolus use (Noncurrent)
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Gastroenteral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical 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.1.1.1

Medical 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.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10003109
E.1.2	Term	Arrest cardiac
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main 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 (35 degrees) compared with reclined (5 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" compared with placebo. The primary endpoint is days alive outside hospital within 30 days

E.2.2

Secondary objectives of the trial

The secondary and tertiary 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.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full 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.3

Principal 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.4

Principal 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 5 to 35-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.5.1

Primary 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 (35 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.5.1.1

Timepoint(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.5.2

Secondary end point(s)

1. All-cause mortality at 90 days (in study strata where it is not a primary endpoint)
2. Serum Neuron Specific Enolase46 and Neurofilament Light Chain levels47 at 48h
3. Markers of cardiac and kidney injury: TNT or TNI and CKMB and proBNP (cardiac) during initial 72h and creatinine during initial 72h and the use of dialysis during the first 30 days post OHCA (kidney)
4. Need for vasopressor during ICU stay (cumulative doses during the first 36 hours and total doses)
5. Mixed blood venous saturation after 12, 24 and 36 hours and the daily during ICU stay
6. Duration of intubation (oral and tracheostomy combined)
7. Number of unconscious patients at 96 hours
8. Number of CAM-ICU positive patients 24 hours after extubation
9. Number of CAM-ICU negative days
10. Number of days without pharmacological treatment for delirium (other than study drug during the intervention period)
11. ICU length of stay
12. Hospital length of stay (including in-patient rehabilitation and transfer to referral hospital)
13. CPC and mRS at ICU discharge, at hospital discharge, and at 90 days (assessed at ambulatory follow-up)

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. Inflammatory and organ markers during initial 72 hours measured as part of routine biochemistry, including CRP, leukocytes, platelets, liver enzymes, and coagulation test, as well as markers measured on biobank samples which will include a panel of cytokines, additional inflammatory markers, and markers of organ injury.
3. Capture of results from standard biochemistry performed as part of standard of care for initial 7 days including CRP, leukocytes, platelets, liver enzymes, bilirubin, electrolytes, and coagulation test.
4. Positive blood cultures taken on clinical indication
5. Incidence of culture positive pneumonia in the two strata (mandatory tracheal culture after 36 hours)
6. Need for insulin and glucose during ICU stay
7. Mean daily FiO2 during the first 72 hours
8. Mean daily PEEP during the first 72 hours
9. Number of recorded decubitus ulcers in the two strata
10. Assessment of cognitive function (RBANS and MOCA point) at ambulatory follow-up
11. Assessment of quality of life (EQ-5D-5L) and anxiety/depression (HADS) at ambulatory follow-up
12. Changes in LVEF from admission until discharge (or last recorded LVEF during initial hospital stay)
13. Two simple questions and frailty assessment at 6-12 months
14. Assessment of cognitive function (RBANS and MOCA point) at 6-12 months
15. Assessment of quality of life (EQ-5D-5L) and anxiety/depression (HADS) at 6-12 months
16. CPC and mRS at ICU discharge, hospital discharge, and at 6-12 months

E.5.2.1

Timepoint(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.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.3.1

Comparator description

We are investigating two mechanical interventions, aside from the two pharmaceutical interventions

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial 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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

700

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women 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.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients included in the study will be unconscious following resuscitation from out-of-hospital cardiac arrest.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

1000

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-02-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-07-08

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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