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Efficacy of Esmolol in the Identification of Cardiovascular Disorders by Cirrhosis, Diabetes Mellitus and Cardiotoxic Treatments (CIBERbBECHO)

Primary Purpose

Cirrhosis, Diabetes Mellitus, Oncologic Disorders

Status
Recruiting
Phase
Phase 3
Locations
Spain
Study Type
Interventional
Intervention
Esmolol Injection [Brevibloc]
Sponsored by
Consorcio Centro de Investigación Biomédica en Red (CIBER)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Cirrhosis focused on measuring beta blockers, echocardiography, esmolol, systolic function, cardiovascular diagnosis, biomarkers, diagnostic techniques, medical imaging

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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 Diabetes Mellitus 2 (DM2) with or without Heart Failure with Normal Ejection Fraction (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 Human Epidermal growth factor Receptor 2 (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. 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 atrioventricular (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 Diabetes Mellitus (DM) of any type other than type 2 [type 1, Latent Autoimmune Diabetes in Adults (LADA), Maturity-Onset Diabetes of the Young (MODY), New Onset Diabetes After Transplant (NODAT), etc.] Patients in New York Heart Association (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 Hepatitis B Virus (HBV) or Hepatitis B Virus (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.

Sites / Locations

  • Hospital Universitari Vall d'Hebron
  • Hospital Clínic de Barcelona
  • Hospital General Universitario Gregorio MarañónRecruiting
  • Hospital Universitario La Paz
  • Hospital Clínico Universitario de Salamanca
  • Hospital Universitari i Politècnic La Fe

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single Arm

Arm Description

1 conventional echocardiography without esmolol administration followed by 1 echocardiography with esmolol administration at Baseline and other study visits.

Outcomes

Primary Outcome Measures

Left Ventricle (LV) ejection fraction
Estimated with 3D echocardiography (Both: convectional and with esmolol administration)
Peak measurement of global LV systolic longitudinal strain
Estimated with 3D echocardiography (Both: convectional and with esmolol administration)
Ejection Intraventricular Pressure Difference (EIVPD) measure
Estimated with M-mode echocardiography (Both: convectional and with esmolol administration)

Secondary Outcome Measures

Ejection fraction
Obtained with 2D echocardiography (Simpson's biplane method)
Interleukin (IL)-1β
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
High-sensitivity IL-6 (hsIL-6)
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Soluble Suppression of Tumorigenicity 2 (ST-2)
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
N-terminal fragment of brain natriuretic peptide (NT-proBNP)
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Ultrasensitive troponin I (hsTnI)
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Procollagen type I terminal propeptide (PICP)
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
C-terminal telopeptide collagen type I (CITP)
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Matrix metalloproteinase-1 (MMP-1)
Biochemical variables in blood in relation to the alteration of the different components of the myocardium

Full Information

First Posted
February 15, 2023
Last Updated
April 27, 2023
Sponsor
Consorcio Centro de Investigación Biomédica en Red (CIBER)
Collaborators
Instituto de Salud Carlos III
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1. Study Identification

Unique Protocol Identification Number
NCT05769868
Brief Title
Efficacy of Esmolol in the Identification of Cardiovascular Disorders by Cirrhosis, Diabetes Mellitus and Cardiotoxic Treatments
Acronym
CIBERbBECHO
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 18, 2023 (Actual)
Primary Completion Date
March 2027 (Anticipated)
Study Completion Date
September 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Consorcio Centro de Investigación Biomédica en Red (CIBER)
Collaborators
Instituto de Salud Carlos III

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to assess the superiority of esmolol echocardiography over conventional echocardiography in the diagnosis of subclinical myocardial involvement associated with diabetes mellitus 2, cirrhosis and antineoplastic treatments.
Detailed Description
After being informed about the study and potential risks, all patients giving written informed consent will undergo a 10 days screening period to determine eligibility for study entry. At Baseline, patients who meet the eligibility requirements will be allocate in one of the 4 cohorts according to their medical conditions. Trial design consists in a Screening period, Baseline, and 6 additional visits until Month-36. All patients will undergo to a conventional echocardiography and echocardiography with esmolol administration at Baseline. This procedure will be performed at the following visits according their cohort. Other complementary procedures will be the collection of blood samples to determine biomarkers, as well as hematology and biochemistry, vital signs and another explorations.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis, Diabetes Mellitus, Oncologic Disorders
Keywords
beta blockers, echocardiography, esmolol, systolic function, cardiovascular diagnosis, biomarkers, diagnostic techniques, medical imaging

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 3
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
1000 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Single Arm
Arm Type
Experimental
Arm Description
1 conventional echocardiography without esmolol administration followed by 1 echocardiography with esmolol administration at Baseline and other study visits.
Intervention Type
Drug
Intervention Name(s)
Esmolol Injection [Brevibloc]
Other Intervention Name(s)
Anatomical Therapeutic Chemical (ATC) code: C07AB09, Esmolol Hydrochloride
Intervention Description
Brevibloc® will be administered intravenously by infusion pump following the administration schedule: Loading dose of 500 μg/kg for 1 minute, followed by a maintenance infusion of 50 μg/kg/minute over 5 minutes. If the target response is not obtained, the loading dose is repeated and the 50 dose is increased by 50 μg/kg/minute to a maximum of 200 μg/kg/minute. The objective response to esmolol beta-blockade is defined as a 15-20% reduction in heart rate, with lower limits of 55 bpm and a systolic blood pressure not less than 90 mmHg and diastolic blood pressure not less than 50 mmHg. The perfusion is kept active while the echocardiography image acquisition is completed (approx. 15-30 min).
Primary Outcome Measure Information:
Title
Left Ventricle (LV) ejection fraction
Description
Estimated with 3D echocardiography (Both: convectional and with esmolol administration)
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Title
Peak measurement of global LV systolic longitudinal strain
Description
Estimated with 3D echocardiography (Both: convectional and with esmolol administration)
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Title
Ejection Intraventricular Pressure Difference (EIVPD) measure
Description
Estimated with M-mode echocardiography (Both: convectional and with esmolol administration)
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Secondary Outcome Measure Information:
Title
Ejection fraction
Description
Obtained with 2D echocardiography (Simpson's biplane method)
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Title
Interleukin (IL)-1β
Description
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Title
High-sensitivity IL-6 (hsIL-6)
Description
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Title
Soluble Suppression of Tumorigenicity 2 (ST-2)
Description
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Title
N-terminal fragment of brain natriuretic peptide (NT-proBNP)
Description
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Title
Ultrasensitive troponin I (hsTnI)
Description
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Title
Procollagen type I terminal propeptide (PICP)
Description
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Title
C-terminal telopeptide collagen type I (CITP)
Description
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Time Frame
At Baseline (Day 1) until Month-24 according to cohort
Title
Matrix metalloproteinase-1 (MMP-1)
Description
Biochemical variables in blood in relation to the alteration of the different components of the myocardium
Time Frame
At Baseline (Day 1) until Month-24 according to cohort

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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 Diabetes Mellitus 2 (DM2) with or without Heart Failure with Normal Ejection Fraction (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 Human Epidermal growth factor Receptor 2 (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. 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 atrioventricular (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 Diabetes Mellitus (DM) of any type other than type 2 [type 1, Latent Autoimmune Diabetes in Adults (LADA), Maturity-Onset Diabetes of the Young (MODY), New Onset Diabetes After Transplant (NODAT), etc.] Patients in New York Heart Association (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 Hepatitis B Virus (HBV) or Hepatitis B Virus (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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Tania Luis García, BS
Phone
+34 917996034
Ext
47304
Email
tanialuisgarcia@cibercv.es
First Name & Middle Initial & Last Name or Official Title & Degree
Projects Department (CIBER)
Phone
+34 918222874
Email
proyectos@ciberisciii.es
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Javier Bermejo Thomas, MD, PhD
Organizational Affiliation
Hospital Universitario Gregorio Marañón
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Universitari Vall d'Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
José F Rodríguez Palomares, MD, PhD
Phone
+34 932746134
Email
jfrodriguezpalomares@gmail.com
Facility Name
Hospital Clínic de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marta Sitges Carreño, MD, PhD
Phone
+34 932275722
Email
msitges@clinic.cat
Facility Name
Hospital General Universitario Gregorio Marañón
City
Madrid
ZIP/Postal Code
28007
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Javier Bermejo Thomas, MD, PhD
Phone
+34 915868279
Email
javier.bermejo@salud.madrid.org
Facility Name
Hospital Universitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Esther Pérez David, MD, PhD
Phone
+34 639607988
Email
eperezdavid@gmail.com
Facility Name
Hospital Clínico Universitario de Salamanca
City
Salamanca
ZIP/Postal Code
37007
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Candelas Pérez del Villar Moro, MD
Phone
+34 620778540
Email
cperezdelvillar@gmail.com
Facility Name
Hospital Universitari i Politècnic La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jaume Agüero Ramón-Llin, MD, PhD
Phone
+34 629378483
Email
jaimeaguero30@hotmail.com

12. IPD Sharing Statement

Citations:
PubMed Identifier
24173273
Citation
Yotti R, Bermejo J, Benito Y, Sanz-Ruiz R, Ripoll C, Martinez-Legazpi P, del Villar CP, Elizaga J, Gonzalez-Mansilla A, Barrio A, Banares R, Fernandez-Aviles F. Validation of noninvasive indices of global systolic function in patients with normal and abnormal loading conditions: a simultaneous echocardiography pressure-volume catheterization study. Circ Cardiovasc Imaging. 2014 Jan;7(1):164-72. doi: 10.1161/CIRCIMAGING.113.000722. Epub 2013 Oct 30.
Results Reference
background
PubMed Identifier
16172285
Citation
Yotti R, Bermejo J, Desco MM, Antoranz JC, Rojo-Alvarez JL, Cortina C, Allue C, Rodriguez-Abella H, Moreno M, Garcia-Fernandez MA. Doppler-derived ejection intraventricular pressure gradients provide a reliable assessment of left ventricular systolic chamber function. Circulation. 2005 Sep 20;112(12):1771-9. doi: 10.1161/CIRCULATIONAHA.104.485128.
Results Reference
background
PubMed Identifier
28195341
Citation
Yotti R, Ripoll C, Benito Y, Catalina MV, Elizaga J, Rincon D, Fernandez-Aviles F, Bermejo J, Banares R. Left ventricular systolic function is associated with sympathetic nervous activity and markers of inflammation in cirrhosis. Hepatology. 2017 Jun;65(6):2019-2030. doi: 10.1002/hep.29104. Epub 2017 Apr 28.
Results Reference
background

Learn more about this trial

Efficacy of Esmolol in the Identification of Cardiovascular Disorders by Cirrhosis, Diabetes Mellitus and Cardiotoxic Treatments

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