Clinical Trials Register

Summary
EudraCT Number:	2018-002699-42
Sponsor's Protocol Code Number:	DANBLOCK
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:	2018-07-17
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

2018-002699-42

A.3

Full title of the trial

Danish trial of beta blocker treatment after myocardial infarction without reduced ejection fraction (DANBLOCK)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Danish trial of beta blocker treatment after myocardial infarction without signs of heart failure (DANBLOCK)

Et landsdækkende dansk studie af betablokker behandling efter akut myokardieinfarkt hos patienter uden hjertesvigt - DANBLOCK

A.3.2

Name or abbreviated title of the trial where available

DANBLOCK

A.4.1

Sponsor's protocol code number

DANBLOCK

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	Bispebjerg Frederiksberg Hospital
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	Danish Heart Foundation
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Novo Nordisk Foundation
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	Bispebjerg Frederiksberg Hospital
B.5.2	Functional name of contact point	Department of Cardiology
B.5.3	Address:
B.5.3.1	Street Address	Bispebjerg Bakke
B.5.3.2	Town/ city	Copenhagen
B.5.3.3	Post code	2400
B.5.3.4	Country	Denmark
B.5.4	Telephone number	45004520836010
B.5.5	Fax number	Danma004524413242
B.5.6	E-mail	akri0172@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	Bisoprolol "Orion"
D.2.1.1.2	Name of the Marketing Authorisation holder	Orion Corporation, Orionintie 1, FI-02200 Espoo, Finland
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.3.1	Product name	Bisoprolol
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	bisoprololfumarat
D.3.9.3	Other descriptive name	BISOPROLOL FUMARATE
D.3.9.4	EV Substance Code	SUB00832MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2.5 to 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.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	Carvedilol "STADA"
D.2.1.1.2	Name of the Marketing Authorisation holder	Stada Arzneimittel AG Stadastrasse 2-18 61118 Bad Vilbel Tyskland
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.3.1	Product name	Carvedilol
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Carvedilol
D.3.9.3	Other descriptive name	CARVEDILOL
D.3.9.4	EV Substance Code	SUB06153MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	3.125 to 25
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: 3
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	Metoprololsuccinat "Polpharma"
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmaceutical Works POLPHARMA SA 19 Pelplińska Str. 83-200 Starogard Gdański Polen
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.3.1	Product name	Metoprololsuccinat
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	metoprolol succinate
D.3.9.3	Other descriptive name	METOPROLOL SUCCINATE
D.3.9.4	EV Substance Code	SUB03274MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	25 to 200
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: 4
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	Nebivolol "Pliva"
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva B.V. Swensweg 5 20310 GA Haarlem Holland
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.3.1	Product name	Nebivolol
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NEBIVOLOL
D.3.9.1	CAS number	99200-09-6
D.3.9.4	EV Substance Code	SUB09175MIG
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	5
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Myocardial infarction. We wish to test whether long-term treatment with betablocker (bisoprolol, carvedilol, metoprolol or nebivolol) leads to better prognosis than no treatment in patients suffering a myocardial infarction who do not have signs of heart failure

E.1.1.1

Medical condition in easily understood language

Heart attack

Blodprop i hjertet

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	10028595
E.1.2	Term	Myocardial infarct
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine whether long-term treatment with oral betablocker therapy after myocardial infarction in patient with no heart failure reduces the composite outcome of recurrent MI, all-cause mortality, revascularization with percutaneous coronary intervention or coronary artery bypass graft,
ischemic stroke, incident heart failure, malignant ventricular arrhythmia or resuscitated cardiac arrest.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

To be eligible for this study the following inclusion criteria must be meet:
• 18 years or older
• Left ventricular ejection fraction (LVEF) > 40%
• Myocardial infarction (MI)
The diagnosis of acute MI must meet the Universal ESC definition of MI40:
Detection of a rise and/or fall of cardiac biomarker values with at least one value above the 99th percentile upper reference limit and with at least one of the followings:
• Symptoms of ischaemia.
• New or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle branch block (LBBB).
• Development of pathological Q waves in the ECG.
• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

The inclusion- and event rate in DANBLOCK have been continuously assessed since the first patient was randomized in December 2018. The inclusion and event rate have been lower than expected, in part due to COVID-19. To enhance feasibility, the decision was made by the Steering Committees to
combine the data from DANBLOCK with the data from the Norwegian BETAMI (NCT03646357) and publish main results together.
The trials have similar designs, only minor differences in study entry criteria, and were, from the very beginning, coordinated with the aim of conducting substudies on pooled data. The primary endpoint has been harmonized without knowledge of the distribution of events. BETAMI and DANBLOCK will remain separate trials until the end of follow-up, where data from the trials will be combined and main results published together.

E.4

Principal exclusion criteria

Exclusion Criteria
Patient will be excluded if they meet any of the following criteria:
• Clinical evidence of heart failure at the time of discharge
• Pregnancy or of child bearing age not using safe anticonception
• Signed informed consent and expected cooperation during follow-up
Any medical condition where BB treatment is indicated according to the treating physician, which may include:
• BB treated arrhythmias
• BB treated hypertension
• Cardiomyopathies
• Seriously limited life-expectancy
• Any condition (i.e. dementia) that could lead to increased risk for the patient when treated with BB-therapy
Any contraindication to BB treatment according to the treating physician, which may include:
• Hypotension
• Bradyarrhythmias
• Severe peripheral artery disease
• History of not able to tolerate BB-therapy
• Severe COPD
• Severe valvular heart disease
The exclusion is not limited to this list and the responsible treating physician will need consider if any other contraindication might exist for the patient. Both patients treated with a BB before their MI and patients in whom BB was initiated during the hospital admission are eligible for the trial.

E.5 End points

E.5.1

Primary end point(s)

The composite outcome of recurrent MI, all-cause mortality, revascularization with percutaneous coronary intervention or coronary artery bypass graft,
ischemic stroke, incident heart failure, malignant ventricular arrhythmia or resuscitated cardiac arrest.

E.5.1.1

Timepoint(s) of evaluation of this end point

Min 6 months after inclusion of the last patient

E.5.2

Secondary end point(s)

Key secondary endpoints to be included in the main publication:
• Each of the components of the primary endpoint, i.e.: All-cause mortality, recurrent MI, revascularisation with PCI or CABG, ischemic stroke, incident
heart failure, malignant ventricular arrhythmia, or resuscitated cardiac arrest.
• To assess clinical outcomes linked to beta-blocker therapy in the following subgroups: age, sex, BB dosage tertiles, STEMI vs. NSTEMI, and LVEF subgroups

Other secondary objectives:
• To study whether oral beta-blocker therapy reduces the risk of cardiovascular death compared to no such therapy
• To study whether oral beta-blocker therapy reduces the risk of stable and unstable angina compared to no such therapy
• To study whether oral beta-blocker therapy reduces the risk of atrial fibrillation, atrial flutter or other atrial tachyarrhythmias compared to no
such therapy
• To study whether oral beta-blocker therapy increases the risk of hospitalization for bradycardia, syncope, implantation of pacemaker
• To study whether oral beta-blocker therapy increases the risk of hospitalization for chronic obstructive pulmonary disease, asthma or
peripheral artery disease.
• To study whether oral beta-blocker therapy increases the risk of hospitalization or outpatient visit for new-onset or dysregulated diabetes
• To study whether oral beta-blocker therapy affects the following patient
related outcomes: Quality of life, angina, dyspnoea, anxiety, depression,
sexual dysfunction or sleep disorders.
• To conduct cost-utility analysis in relation to quality of life and a
health economic evaluation including drug use, health care utilization,
employment, income, and benefit take-up
• To describe beta-blocker dosage and adherence
• To assess study safety

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months - 6 years after MI
PRO-questionnaires: at baseline, 3, 12, and 24 months
Exercise capacity and blood pressure control: Before and after cardiac rehabilitation

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

No treatment or other antihypertensive treatment

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

Follow-up of patients is through individual assessment of hospital admission, registry linkage and questionnaires. The end of the trial is planned to be after min 6 months follow-up of the last subjects entered in 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:

1380

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1380

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

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

2760

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)

Normal treatment of that condition

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Danish Society of CArdiology
G.4.3.4	Network Country	Denmark

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-09-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-09-20

P. End of Trial
P.	End of Trial Status	Ongoing

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