Clinical Trials Register

Summary
EudraCT Number:	2017-002485-40
Sponsor's Protocol Code Number:	REBOOT-CNIC
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-11-27
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

Spain - AEMPS

A.2

EudraCT number

2017-002485-40

A.3

Full title of the trial

treatment with beta-blockers after myocardial infarction without reduced ejection fraction

Tratamiento con betabloqueantes tras infarto de miocardio sin fraccion de eyeccion reducida

A.3.1

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

treatment with beta-blockers after myocardial infarction without reduced ejection fraction

Tratamiento con betabloqueantes tras infarto de miocardio sin fraccion de eyeccion reducida

A.3.2

Name or abbreviated title of the trial where available

REBOOT

A.4.1

Sponsor's protocol code number

REBOOT-CNIC

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	CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (CNIC)
B.1.3.4	Country	Spain
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	CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (CNIC)
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CNIC
B.5.2	Functional name of contact point	NOEMI ESCALERA
B.5.3	Address:
B.5.3.1	Street Address	MELCHOR FERNANDEZ ALMAGRO
B.5.3.2	Town/ city	MADRID
B.5.3.3	Post code	28029
B.5.3.4	Country	Spain
B.5.4	Telephone number	00349145312005401
B.5.6	E-mail	nescalera@cnic.es

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	metoprolol tartrate
D.2.1.1.2	Name of the Marketing Authorisation holder	metoprolol oral
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	metoprolol oral
D.3.2	Product code	C07A B02
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.3.11 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	nebivolol
D.2.1.1.2	Name of the Marketing Authorisation holder	nebivolol
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.2	Product code	C07AB12
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.3.11 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	atenolol
D.2.1.1.2	Name of the Marketing Authorisation holder	atenolol
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	atenolol
D.3.2	Product code	C07AB03
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.3.11 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	bisoprolol
D.2.1.1.2	Name of the Marketing Authorisation holder	bisoprolol
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.2	Product code	C07AB07
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.3.11 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: 5
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
D.2.1.1.2	Name of the Marketing Authorisation holder	carvedilol
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.2	Product code	C07AG02
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.3.11 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

STEMI or NSTEMI patients being discharged from the index hospitalization with a LVEF>40% without previous heart failure

paciente con iam con y sin elevacion del segmento ST que son dados de alta con una FEVI de >40% sin insuficiencia cardiaca previa

E.1.1.1

Medical condition in easily understood language

Patients discharged from an acute myocardial infarction-related admission without reduced cardiac function and without heart failure

Pacientes dados de alta de un ingreso por infarto agudo de miocardio con función cardiaca no reducida y sin insuficiencia cardiaca

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

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 investigate the effects of chronic beta-blocker therapy on mortality and morbidity in post-MI without reduced ejection fraction in terms of the incidence of the composite "all cause death, reinfarction, heart failure admission"

Estudiar el efecto del tratamiento crónico con beta-bloqueantaes tras un infarto agudo de miocardio sin disfunción sistólica ventricular izquierda evaluada como la incidencia de "muerte de cualquier causa, reinfarto, ingreso por insuficiencia cardiaca"

E.2.2

Secondary objectives of the trial

To investigate the effects of chronic beta-blocker therapy on cardiac mortality in post-MI without reduced ejection fraction

To investigate the effects of chronic beta-blocker therapy on the incidence of cardiac arrhtyhmias in post-MI without reduced ejection fraction
1)incidence of individual components of the primary outcome
2)incidence of cardiac mortality
3)incidence of cardiac arrhythmias ( atrial fibrillation,
sustained ventricular tachycardia)

Estudiar el efecto del tratamiento crónico con beta-bloqueantaes en la mortalidad cardiaca tras un infarto agudo de miocardio sin disfunción sistólica ventricular izquierda
Estudiar el efecto del tratamiento crónico con beta-bloqueantaes en la incidencia de arrtimias cardiacas tras un infarto agudo de miocardio sin disfunción sistólica ventricular izquierda
1)incidencia de los componentes individuales del objetivo primario
2)incidencia de la mortalidad cardiaca
3)incidencia de arritmias (fibrilacion auricular , taquicardia ventricular sostenida)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

> 18 years old or 18 years old
STEMI or STEMI patient
LVEF >40%
INFORM CONSENT SIGNED

Mayor o igual a 18 años,
ingresado por sTEMI o NSTEMI
FEVI>40% evaludada por cualquier tecnica en cualquier momento del ingreso
haber firmado el consentimiento informado

E.4

Principal exclusion criteria

Known allergy or intolerance to beta-blockers
Absolute contraindication to beta-blocker therapy according to treating physician judge
Prior history of HF, Killip class on admission or during hospitalization ≥ II
Severe valvular heart disease (> 3+ for aortic or mitral insufficiency, aortic or mitral valve area ≤1.0 cm2).
Any condition (appart from AMI) that requires beta-blocker prescription on discharge according to treating physician judge
Any medical condition that, in the investigator´s judgment, would seriously limit life expectancy (less than one year),
Patients participating in other clinical trials.

Alergia o intolerancia conocida a beta-bloqueantes
Contraindicación absoluta para beta-bloqueantes de acuerdo con criterio de médico tratante
Historia previa de insuficiencia cardiaca o clase killip ≥ II durante el ingreso
Enfermedad valvular severa
Cualquier condición (aparte del infarto) que requiera tratamiento con beta-bloqueantes a criterio del médico tratante
Cualquier condición que limite seriamente la esperanza de vida del paciente a menos de 1 año
Estar participando en otro ensayo clínico

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint: Incidence rate of the composite of “all-cause death, reinfarction, or heart failure re-hospitalization”.

Objetivo primario: Incidencia del combinado de “muerte por cualquier causa, reinfarto o ingreso por insuficiencia cardiaca”

E.5.1.1

Timepoint(s) of evaluation of this end point

minimum follow-up 2 years, maximum follow-up 3 years.
Estimated median follow-up 2.75 years

seguimiento mínimo 2 años, seguimiento máximo 3 años.
Seguimiento mediano anticipado 2.75 años

E.5.2

Secondary end point(s)

Estudiar el efecto del tratamiento crónico con beta-bloqueantaes en la mortalidad cardiaca tras un infarto agudo de miocardio sin disfunción sistólica ventricular izquierda

Estudiar el efecto del tratamiento crónico con beta-bloqueantaes en la incidencia de arrtimias cardiacas tras un infarto agudo de miocardio sin disfunción sistólica ventricular izquierda
1)incidencia de los componentes individuales del objetivo primario
2)incidencia de la mortalidad cardiaca
3)incidencia de arritmias (fibrilacion auricular , taquicardia ventricular sostenida)

E.5.2.1

Timepoint(s) of evaluation of this end point

minimum follow-up 2 years, maximum follow-up 3 years.
Estimated median follow-up 2.75 years

seguimiento mínimo 2 años, seguimiento máximo 3 años.
Seguimiento mediano anticipado 2.75 años

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.1.7.1

Other trial design description

- Ciego para la evaluación de eventos - Diseño adaptativo (3 meses antes de finalizar el reclutamien

- Blinded for outcome evaluation. - Adpative design (3 months after end of enrolment, the incidence

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 reciben tratamiento con beta bloqueante

not receiving the beta blockers

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

146

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

A blinded examination of the study overall event rate
Patient follow up is done at 3 moments: 3, 15, and 36 months. After 36 months follow-up trial is finished.

Two years after last patient enrollment, all subjects without the last visit done will undergo this and the trial finished

Los seguimientos serán a los 3, 15 y 36 meses. Tras el seguimiento de 36 meses el paciente sale del estudio.

Dos años despues de la inclusión del último pacientes, se realziará la última visita a todos aquellos que no se hayan sometido a ésta, y el ensayo se dará por finalizado.

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

E.8.9.2

In all countries concerned by the trial years

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:

6000

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

2468

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

7000

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1468

F.4.2.2

In the whole clinical trial

8468

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)

none

ninguno

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-03-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-13

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

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