Clinical Trials Register

Summary
EudraCT Number:	2017-005077-39
Sponsor's Protocol Code Number:	BBLOQ-2017
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:	2018-05-21
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

2017-005077-39

A.3

Full title of the trial

Betablockers Withdrawal in Patients with Heart Failure with Preserved Ejection Fraction and Chronotropic Incompetence: Effect on Functional Capacity and life quality

Retirada del Tratamiento Betabloqueante en Pacientes con Insuficiencia Cardíaca con Función Sistólica Preservada y Evidencia de Incompetencia Cronotrópica: Efecto sobre la Capacidad Funcional y Calidad de Vida.

A.3.1

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

BBLOQ-2017

A.4.1

Sponsor's protocol code number

BBLOQ-2017

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	Instituto de Investigación Sanitaria INCLIVA
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	INSTITUTO DE SALUD CARLOS III
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	Instituto de Investigación Sanitaria INCLIVA
B.5.2	Functional name of contact point	Scientific Subdirector
B.5.3	Address:
B.5.3.1	Street Address	Avd. Menéndez Pelayo 4 acc
B.5.3.2	Town/ city	Valencia
B.5.3.3	Post code	46010
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034961973976
B.5.5	Fax number	0034961973540
B.5.6	E-mail	gestioncientifica@incliva.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.2.1.2	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.3.4	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	PROPRANOLOL HYDROCHLORIDE
D.3.9.1	CAS number	318-98-9
D.3.9.3	Other descriptive name	PROPRANOLOL HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB04091MIG
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heart Failure

Insuficiencia Cardíaca

E.1.1.1

Medical condition in easily understood language

Heart Failure

Insuficiencia Cardíaca

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	HLGT
E.1.2	Classification code	10019280
E.1.2	Term	Heart failures
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 evaluate the effect of betablockers withdrawal in patients with HFpEF and chronotropic incompetence assessed by the peak oxygen consumption and heart rate at 15 and 30 days after the intervention.

Evaluar el efecto de la retirada del tratamiento betabloqueante en pacientes con IC-FEP y criterios de incompetencia cronotrópica sobre: el consumo pico de oxígeno (VO2máx) y la frecuencia cardiaca a los 15 y 30 días tras la intervención.

E.2.2

Secondary objectives of the trial

Changes in:
1. Score in the quality of life questionnaire [Minnesota Living with Heart Failure Questionnaire (MLHFQ)
2. Functional class of the NYHA.
3. Echocardiographic parameters: a) diameters, volumes and systolic function of the left and right ventricle;
b) diastolic function parameters (E / e ', e' media); c) systolic pulmonary arterial pressure; and, d) left atrial volume index.
4. Distance traveled in the six minute walk test (6MWT).Changes in submaximal functional capacity.
5. Ventilatory efficiency, estimated by the slope of the exhaled volume /CO2 elimination ratio throughout the test (VE/VCO2).
6. Maximum inspiratory pressure (PIM).
7. Plasma biomarkers: amino-terminal fraction of brain pro-natriuretic peptide (NT-proBNP), carbohydrate antigen 125 (CA125), ST-2 and Galectin-3
8. Average of the daily heart rate.
9. Global cognitive function through the miniexamen of mental state (MMSE) and the Montreal Cognitive Assessment (MoCa).
10. Fried's fragility index.

Cambios en:
1. Puntuación en el cuestionario de calidad de vida [Minnesota Living with Heart Failure Questionnaire
2. Clase funcional NYHA.
3. Parámetros ecocardiográficos: a)diámetros, volúmenes y función sistólica del ventrículo izquierdo y derecho; b) parámetros de función diastólica (E/e’,e’ media); c)presión arterial pulmonar sistólica; d) índice de volumen auricular izquierdo.
4. Distancia recorrida en el test de la marcha de los seis minutos
5. Capacidad funcional submáxima.
6. Eficiencia ventilatoria, estimada mediante la pendiente de la relación volumen espirado/eliminación de CO2 durante todo el test (VE/VCO2).
7. Presión inspiratoria máxima
8. Biomarcadores plasmáticos: fracción amino-terminal del pro-péptido natriurético cerebral, antígeno carbohidrato 125, ST-2 y Galectina-3
9. media de la frecuencia cardiaca diaria
10. Función cognitiva global mediante el miniexamen del estado mental y el Montreal Cognitive Assessment.
11. Indice de fragilidad de Fried.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients with IC-FEP who meet the diagnostic criteria according to the current HF guidelines of the European Society of Cardiology:
- Typical signs and symptoms of HF.
- Systolic function of the left ventricle ≥50% with non-dilated left ventricle (end-diastolic diameter ≥60 mm, indexed end-diastolic diameter> 32 mm / m2 or indexed end-diastolic volume> 97 mL / m2)
- Echocardiographic alteration compatible with relevant structural heart disease (hypertrophy of the left ventricle or dilatation of the left atrium) and / or diastolic dysfunction.
2. Stable functional class of NYHA II-III the last month prior to inclusion.
3. Amino-terminal fraction of the brain natriuretic pro-peptide (NT-proBNP)> 125 pg / mL in the last month.
4. Chronotropic index, defined as (46):
5. In current treatment and for more than 3 months with beta-blockers.
6. Majority of age (> 18 years).
7. The participant or his legal representative is willing and able to give informed consent for participation in the study

1. Pacientes con IC-FEP que cumplan los criterios diagnósticos de acuerdo con las actuales guías de IC de la European Society of Cardiology (8):
- Signos y síntomas típicos de IC.
- Función sistólica del ventrículo izquierdo ≥50% con ventrículo izquierdo no dilatado (diámetro telediastólico ≥60 mm, diámetro telediastólico indexado >32 mm/m2 o volumen telediastólico indexado >97 mL/m2)
- Alteración ecocardiográfica compatible con cardiopatía estructural relevante (hipertrofia del ventrículo izquierdo o dilatación de la aurícula izquierda) y/o disfunción diastólica.
2. Clase funcional estable de la NYHA II-III el último mes previo a la inclusión.
3. Fracción amino-terminal del pro-péptido natriurético cerebral (NT-proBNP) >125 pg/mL en el último mes.
4. Índice cronotrópico, definido como (46):
5. En tratamiento actual y durante más de 3 meses con betabloqueantes.
6. Mayoría de edad (>18 años).
7. El participante o su representante legal está dispuesto y es capaz de dar su consentimiento informado para la participación en el estudio.

E.4

Principal exclusion criteria

1. Diagnosis of left valvulopathy of moderate / severe degree considered to be mainly responsible for the symptoms.
2. History of coronary disease or presence of effort angina.
3. Basal HR> 75 bpm.
4. Uncontrolled hypertension, with systolic blood pressure > 140mmHg and diastolic blood pressure> 90mmHg.
5. Patients undergoing cardiac transplantation or cardiac valve replacement in the last three months.
6. Primary cardiomyopathies.
7. Diagnosis of moderate-severe pulmonary disease.
8. Any accompanying extracardiac comorbidity with life expectancy of less than 1 year.
9. Signs or symptoms of myocardial ischemia during the effort test with gas consumption.
10. Patient participating in another clinical trial or who has not yet completed at least 30 days from the completion of another clinical trial, or who is receiving another investigational agent (s).
11. Inability to perform an exercise test for osteoarticular problems.
12. Patients on chronic treatment with digitalis or calciantagonistas type verapamil or diltiazem.
13. Any type of disorder that compromises the subject's ability to give written consent and / or to comply with the study procedures.
14. Pregnancy or lactation period.

1. Diagnóstico de valvulopatía izquierda de grado moderado/severo que se considere responsable principal de los síntomas.
2. Antecedentes de enfermedad coronaria o presencia de angina de esfuerzo.
3. FC basal >75 lpm.
4. Hipertensión arterial no controlada, con cifras de presión arterial sistólica >140mmHg y de presión arterial diastólica >90 mmHg.
5. Pacientes sometidos a trasplante cardiaco o sustitución de válvula cardiaca en los últimos tres meses.
6. Miocardiopatías primarias.
7. Diagnóstico de enfermedad pulmonar moderada-severa.
8. Cualquier comorbilidad extracardiaca acompañante con esperanza de vida menor a 1 año.
9. Signos o síntomas de isquemia miocárdica durante la prueba de esfuerzo con consumo de gases.
10. Paciente participante en otro ensayo clínico o que todavía no ha completado por lo menos 30 días desde la terminación de otro ensayo clínico, o que esté recibiendo otro(s) agente(s) en investigación.
11. Incapacidad de realización de test de esfuerzo por problemas osteoarticulares.
12. Pacientes en tratamiento crónico con digitálicos o calciantagonistas tipo verapamil o diltiazem.
13. Cualquier tipo de trastorno que compromete la capacidad del sujeto para dar su consentimiento por escrito y / o para cumplir con los procedimientos del estudio.
14. Embarazo o periodo de lactancia.

E.5 End points

E.5.1

Primary end point(s)

To evaluate the effect of betablockers withdrawal in patients with HFpEF and chronotropic incompetence assessed by the peak oxygen consumption and heart rate at 15 and 30 days after the intervention.

E.5.1.1

Timepoint(s) of evaluation of this end point

15 and 30 days

15 y 30 días

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

15 and 30 days

15 y 30 días

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

Yes

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

E.8.1.6

Cross over

Yes

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

Retirada de Tratamiento

Treatment withdrawal

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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

LVLS

última visita último paciente

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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)

After completing all the examinations, the results will be carefully explained and the reintroduction or definitive withdrawal of the beta-blocker treatment will be assessed individually based on a qualitative and quantitative assessment of the results of the examinations and the patient's symptoms.

Tras finalizar todas las exploraciones se explicarán detenidamente los resultados y se valorará de forma individualizada la reintroducción o la retirada definitiva del tratamiento con betabloqueantes en función de una valoración cualitativa y cuantitativa de los resultados de las exploraciones y la sintomatología del paciente.

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

2018-06-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-31

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

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