Clinical Trials Register

Summary
EudraCT Number:	2021-003889-12
Sponsor's Protocol Code Number:	3
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:	2021-12-03
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

2021-003889-12

A.3

Full title of the trial

Prospective, multicenter and open study to evaluate the efficacy of esmolol in the early identification of cardiovascular disorders induced by cirrhosis, diabetes mellitus and cardiotoxic treatments.

Estudio prospectivo, multicéntrico y abierto para evaluar la eficacia del esmolol en la identificación precoz de las alteraciones cardiovasculares inducidas por la cirrosis, la diabetes mellitus y los tratamientos cardiotóxicos.

A.3.1

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

Study to evaluate the best diagnosis for the early identification of cardiovascular disorders induced by cirrhosis, diabetes mellitus and cardiotoxic treatments.

Estudio para evaluar el mejor diagnóstico para la identificación precoz de trastornos cardiovasculares inducidos por cirrosis, diabetes mellitus y tratamientos cardiotóxicos.

A.3.2

Name or abbreviated title of the trial where available

CIBER-bB-ECHO

A.4.1

Sponsor's protocol code number

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	Consorcio Centro de Investigacion Biomedica en Red, M.P. (CIBER)
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	Consorcio Centro de Investigacion Biomedica en Red, M.P. (CIBER)
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	Consorcio Centro de Investigacion Biomedica en Red, M.P. (CIBER)
B.5.2	Functional name of contact point	Rebeca
B.5.3	Address:
B.5.3.1	Street Address	Instituto de Salud Carlos III, Avda. Monforte de Lemos, 3-5 \| Pabellon 11
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28029
B.5.3.4	Country	Spain
B.5.6	E-mail	proyectos@ciberisciii.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	Brevibloc
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter, S.L.
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	esmolol hydrochloride
D.3.2	Product code	670502
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.3.11 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

Cardiovascular disorders induced by cirrhosis, diabetes mellitus and cardiotoxic treatments.

Alteraciones cardiovasculares inducidas por la cirrosis, la diabetes mellitus y los tratamientos cardiotóxicos.

E.1.1.1

Medical condition in easily understood language

Cardiovascular disorders induced by cirrhosis, diabetes mellitus and cardiotoxic treatments.

Alteraciones cardiovasculares inducidas por la cirrosis, la diabetes mellitus y los tratamientos cardiotóxicos.

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 evaluate the efficacy of esmolol in the early identification of cardiovascular disorders induced by cirrhosis, diabetes mellitus and cardiotoxic treatments.

Evaluar la eficacia del esmolol en la identificación precoz de las alteraciones cardiovasculares inducidas por la cirrosis, la diabetes mellitus y los tratamientos cardiotóxicos.

E.2.2

Secondary objectives of the trial

1. To determine the reduction of variability in the measurement of LV systolic function that is obtained by the combination of acute adrenergic blockade. This reduction in variability will be studied with reference to two conventional indices (EF and global longitudinal strain) and an alternative index (IVPD).
2. Establish the normality patterns and physiological changes in the measurement of myocardial function during a longitudinal period in healthy patients , obtained at baseline and after the administration of esmolol.
3. Compare the diagnostic accuracy (ROC curve analysis) of esmolol echocardiography with baseline echocardiography to identify patients with myocardial damage associated with DM2 (with and without HFNEF) and advanced cirrhosis.
4. To compare the anticipation capacity of esmolol echocardiography with baseline echocardiography for the prediction of antineoplastic-induced cardiotoxicity.

1. Determinar la reducción de la variabilidad en la medida de la función sistólica del VI que se obtiene mediante la combinación del bloqueo adrenérgico agudo. Esta reducción de la variabilidad se estudiará referente a dos índices convencionales (FE y strain longitudinal global) y a un índice
alternativo (EIVPD).
2. Establecer los patrones de normalidad y cambios fisiológicos en la medida de la función miocárdica durante un periodo longitudinal en pacientes y normales, obtenidos en situación basal y tras la administración de esmolol.
3. Comparar la exactitud diagnóstica (análisis de curvas ROC) de la ecocardiografía con esmolol con la ecocardiografía basal para identificar pacientes con daño miocárdico asociado a DM2 (con y sin ICFEN) y cirrosis avanzada.
4. Comparar la capacidad de anticipación de la ecocardiografía con esmolol con la ecocardiografía basal para la predicción de cardiotoxicidad inducida por antineoplásicos.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age ≥ 18 years.
- Absence of previous heart disease, defined as the absence of relevant cardiac structural alterations such as moderate or severe hypertrophy, alteration of segmental contraction, Moderate or severe valvular disease, intraventricular obstructive gradient, or old myocardial infarction.
- Existence of an at least acceptable ultrasonic window, which allows the visualization of at least 14 of the 17 segments of the LV myocardium.
- Sinus rhythm, with a basal heart rate greater than 50 bpm.
- Diabetic patients with a diagnosis of DM2 with or without HFNEF (n = 300) will be included. Previous diagnosis of HFNEF with clinical stability at the time of inclusion (n = 200). No previous diagnosis of HFNEF (n = 100).
- 200 patients with cirrhosis stratified by the following additional criteria will be included: Child-Pugh A class (n = 25); Child-Pugh B class (n = 75); Child-Pugh C class (with and without ascites n = 50 and n = 50, respectively).
- 300 cancer patients will be included, divided into 3 therapeutic groups: 125 patients diagnosed with Lymphoma or Sarcoma receiving chemotherapy based on anthracyclines at high doses (≥ 240 mg / m2); 125 patients with HER2 positive breast cancer receiving chemotherapy regimen that includes trastuzumab without anthracyclines; 50 patients with hepatocarcinoma receiving treatment with Sorafenib.
- Expected survival> 6 months, first-diagnosis of cancer, and receiving treatment with chemotherapy that includes any of the previous schemes.
- A control group (n = 200) without heart disease and without any of the study conditions will be included: diabetes from any cause, cancer or active cancer treatment or some degree of liver disease.

- Edad ≥ 18 años.
- Ausencia de cardiopatía previa, definida como ausencia de alteraciones estructurales cardiacas relevantes como hipertrofia moderada o severa, alteración de la contracción segmentaria, valvulopatía moderada o severa, gradiente obstructivo intraventricular, o infarto de miocardio antiguo.
- Existencia de ventana ultrasónica al menos aceptable, que permita la visualización de, al menos, 14 de los 17 segmentos del miocardio del VI.
- Ritmo sinusal, con frecuencia cardiaca basal superior a los 50 lpm.
- Se incluirán pacientes diabéticos con diagnóstico de DM2 con o sin ICFEN (n = 300). Diagnóstico previo de ICFEN con estabilidad clínica en el momento de la inclusión (n = 200). Sin diagnóstico previo de ICFEN (n = 100).
- Se incluirán 200 pacientes con cirrosis estratificados por los siguientes criterios adicionales: Clase Child-Pugh A (n = 25); Clase Child-Pugh B (n = 75); Clase Child-Pugh C (con y sin ascitis n = 50 y n = 50, respectivamente).
- Se incluirán 300 pacientes oncológicos distribuidos en 3 grupos terapéuticos: 125 pacientes diagnosticados de Linfoma o Sarcoma que reciben esquema de quimioterapia fundamentado en antraciclinas a dosis altas (≥ 240 mg/m2). 125 pacientes con cáncer de mama HER2 positivo que reciben esquema de quimioterapia que incluye trastuzumab sin antraciclinas. 50 pacientes con hepatocarcinoma que reciben tratamiento con Sorafenib.
- Supervivencia esperada > 6 meses, primo-diagnóstico de cáncer, y recibir tratamiento con quimioterapia que incluya alguno de los esquemas anteriores.
- Se incluirán grupo control (n=200) sin cardiopatía y sin ninguna de las condiciones de estudio: diabetes por cualquier causa, cáncer o tratamiento activo contra el cáncer o algún grado de hepatopatía.

E.4

Principal exclusion criteria

- Contraindication for the administration of esmolol (according to technical data sheet): Hypersensitivity to esmolol hydrochloride; Severe sinus bradycardia (HR <50 bpm); 2nd or 3rd degree atrioventricular block without pacemaker; Cardiogenic shock, severe hypotension, or decompensated heart failure; Untreated pheochromocytoma; Acute asthmatic attack; Concomitant intravenous administration or within the first 48 hours after verapamil.
- Treatment with beta-blocker drugs (oral, topical or intravenous) in the last 7 days before the study.
- History of ventricular or supraventricular arrhythmias that prevent the safe withdrawal of antiarrhythmic or braking treatment before the administration of esmolol.
- History of previous high-grade AV conduction disorder in non-pacemaker patients.
- Severe asthma with bronchial hyperresponsiveness.
- Patients with acute infection.
- Participants in other clinical trials in the 30 days prior to the start of the study.
- Pregnant women, or who plan to be, and women during breastfeeding.
- Patients with limitation to follow the protocol for any reason.
- Diagnosis of DM of any type other than type 2 (type 1, LADA, MODY, NODAT, etc.).
- Patients in NYHA functional class IV or with advanced heart failure.
- Treatment with an oral beta-blocker at the time of the examination that cannot be safely temporarily suspended 72 hours before the test.
- Active evidence of HBV or HCV infection.
- Personal history of previous cancer requiring systemic treatment (excludes skin or localized cancers treated locally surgically).
- Previous exposure to systemic antitumor treatment or radiotherapy on the thoracic region.

- Contraindicación para la administración de esmolol (según ficha técnica): Hipersensibilidad al hidrocloruro de esmolol; Bradicardia sinusal grave (FC < 50 lpm); Bloqueo auriculoventricular de 2º o 3er grado sin marcapasos; Shock cardiogénico, hipotensión grave, o insuficiencia cardíaca descompensada; Feocromocitoma no tratado; Crisis asmática aguda; Administración intravenosa concomitante o en las primeras 48 horas posteriores de verapamilo.
- Tratamiento con fármacos betabloqueantes (orales, tópicos o intravenosos) en los últimos 7 días antes del estudio.
- Antecedente de arritmias ventriculares o supraventriculares que impidan la retirada segura de tratamiento antiarrítmico o frenador antes de la administración de esmolol.
- Antecedente de trastorno de la conducción AV de alto grado previo en pacientes no portadores de marcapasos.
- Asma grave con hiperreactividad bronquial.
- Pacientes con infección aguda.
- Participantes en otros ensayos clínicos en los 30 días previos al inicio del estudio.
- Mujeres embarazadas, o que planean estarlo, y mujeres durante lactancia materna.
- Pacientes con limitación para seguir el protocolo por cualquier causa.
- Diagnóstico de DM de cualquier tipo que no sea tipo 2 (tipo 1, LADA, MODY, NODAT, etc.).
- Pacientes en clase funcional IV de la NYHA o en situación de insuficiencia cardiaca avanzada.
- Tratamiento con betabloqueante oral en el momento de la realización de la exploración que no pueda ser suspendido con seguridad de forma temporal 72h antes de la prueba.
- Evidencia activa de infección VHB o VHC.
- Antecedentes personales de cáncer previo con necesidad de tratamiento sistémico (excluye cánceres cutáneos o localizados tratados de forma quirúrgica local).
- Exposición previa a tratamiento antitumoral sistémico o a radioterapia sobre la región torácica.

E.5 End points

E.5.1

Primary end point(s)

Improve one of the still unresolved aspects of cardiovascular diagnosis. By combining a simple pharmacological intervention with a safe, ultra-short-acting drug, a fundamental parameter can be obtained to guide therapeutic decision-making in patients with a large number of cardiac and extra-cardiac diseases.

Mejorar uno de los aspectos aún sin resolver del diagnóstico cardiovascular. Combinando una simple intervención farmacológica con un fármaco seguro y de acción ultracorta, se puede obtener un parámetro fundamental para orientar la toma de decisiones terapéuticas en pacientes con un gran número de enfermedades cardíacas y extracardíacas.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients with DM2 and cirrhosis: ECHO with esmolol at Day 1. ECHO without esmolol at Day 1 and month 12.
Cancer patients: ECHO with esmolol at Day 1, Month 1, Month 3, Month 6. ECHO without esmolol at Day 1, Month 1, Month 3, Month 6, Month 12, Month 24. NMR at Day 1, Month 12.
Control Group: ECHO with esmolol at Day 1, Month 3, Month 6. ECHO without esmolol at Day 1, Month 3, Month 6, Month 12.

Pacientes con DM2 y cirrosis: ECHO con esmolol el día 1. ECHO sin esmolol el día 1 y el mes 12.
Pacientes con cáncer: ECHO con esmolol el día 1, mes 1, mes 3, mes 6. ECHO sin esmolol el día 1, mes 1, mes 3, mes 6, mes 12, mes 24. RMN el día 1, mes 12.
Grupo de control: ECHO con esmolol en el día 1, mes 3, mes 6. ECHO sin esmolol en el día 1, mes 3, mes 6, mes 12.

E.5.2

Secondary end point(s)

To study the incremental value that molecular biomarkers contribute to characterization by echocardiography with esmolol and to establish diagnostic and prognostic criteria in patients with DM2, cirrhosis and cancer.
To analyze whether the degree of neurohumoral activation, inflammation and myocardial damage characterized by blood biomarkers condition the response to esmolol and the characterization of systolic function in the different groups of patients.

Estudiar el valor incremental que aportan los biomarcadores moleculares a la caracterización por ecocardiografía con esmolol y establecer criterios diagnósticos y pronósticos en pacientes con DM2, cirrosis y cáncer.
Analizar si el grado de activación neurohumoral, inflamación y daño miocárdico caracterizado por biomarcadores sanguíneos condicionan la respuesta al esmolol y la caracterización de la función sistólica en los diferentes grupos de pacientes.

E.5.2.1

Timepoint(s) of evaluation of this end point

Patients with DM2 and cirrhosis: Biomarkers at Day 1 and Month 12.
Cancer patients: Biomarkers at Day 1, Month 1, Month 3, Month 6, Month 12, Month 24.
Control Group: Biomarkers at Day 1, Month 3, Month 6, Month 12.

Pacientes con DM2 y cirrosis: biomarcadores en el día 1 y mes 12.
Pacientes con cáncer: biomarcadores en el día 1, mes 1, mes 3, mes 6, mes 12, mes 24.
Grupo de control: biomarcadores en el día 1, mes 3, mes 6, mes 12.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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)

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

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

Grupo de control: pacientes sin enfermedades descritas en la indicación del ensayo.

Control Group: patients without diseases described in the trial indication.

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

The study will end when last patient included in the trial has performed the last study visit or whatever happens before such as : Appearance of Adverse Effects unknown to date with respect to their nature, severity, and duration or unexpected incidence of known Adverse Effects; Medical or ethical reasons that affect the continued development of the study; Cancellation of the development of the medical product. However, the end of the trial can be dictated by the Health Regulatory Authorities.

El estudio finalizará cuando el último paciente incluido haya realizado la última visita del estudio o lo que ocurra antes: Aparición de efectos adversos desconocidos hasta la fecha con respecto a su naturaleza, gravedad y duración o incidencia inesperada de efectos adversos conocidos; Razones médicas o éticas que afecten el desarrollo continuo del estudio; Cancelación del desarrollo del producto médico. El final del ensayo puede ser dictado por las Autoridades Reguladoras Sanitarias.

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:

800

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

200

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

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

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)

None

Ninguno

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

2022-01-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-23

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

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