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

Diabetes Mellitus Clinical Trial

— 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05769868
• Other study ID #: ICI20/00011
• Secondary ID: 2021-003889-12
• Status: Recruiting
• Phase: Phase 3
• Start date: April 18, 2023
• Est. completion date: September 2027

Study information

• Verified date: April 2023
• Source: Consorcio Centro de Investigación Biomédica en Red (CIBER)
• Contact: Tania Luis García, BS
• Phone: +34 917996034
• Email: tanialuisgarcia[@]cibercv.es
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1000
• Est. completion date: September 2027
• Est. primary completion date: March 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age = 18 years.

2. 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.

3. Existence of an at least acceptable ultrasonic window, which allows the visualization of at least 14 of the 17 segments of the LV myocardium.

4. Sinus rhythm, with a basal heart rate greater than 50 bpm.

5. 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).

6. 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).

7. 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.

8. Expected survival> 6 months, first-diagnosis of cancer, and receiving treatment with chemotherapy that includes any of the previous schemes.

9. 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:

1. 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.

2. Treatment with beta-blocker drugs (oral, topical or intravenous) in the last 7 days before the study.

3. History of ventricular or supraventricular arrhythmias that prevent the safe withdrawal of antiarrhythmic or braking treatment before the administration of esmolol.

4. History of previous high-grade atrioventricular (AV) conduction disorder in non-pacemaker patients.

5. Severe asthma with bronchial hyperresponsiveness.

6. Patients with acute infection.

7. Participants in other clinical trials in the 30 days prior to the start of the study.

8. Pregnant women, or who plan to be, and women during breastfeeding.

9. Patients with limitation to follow the protocol for any reason.

10. 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.]

11. Patients in New York Heart Association (NYHA) functional class IV or with advanced heart failure.

12. Treatment with an oral beta-blocker at the time of the examination that cannot be safely temporarily suspended 72 hours before the test.

13. Active evidence of Hepatitis B Virus (HBV) or Hepatitis B Virus (HCV) infection.

14. Personal history of previous cancer requiring systemic treatment (excludes skin or localized cancers treated locally surgically).

15. Previous exposure to systemic antitumor treatment or radiotherapy on the thoracic region.

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Cirrhosis
• Diabetes Mellitus
• Fibrosis
• Liver Cirrhosis
• Oncologic Disorders

Intervention

Drug:
• Esmolol Injection [Brevibloc]
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).

Locations

Country	Name	City	State
Spain	Hospital Clínic de Barcelona	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Clínico Universitario de Salamanca	Salamanca
Spain	Hospital Universitari i Politècnic La Fe	Valencia

Sponsors (2)

Lead Sponsor	Collaborator
Consorcio Centro de Investigación Biomédica en Red (CIBER)	Instituto de Salud Carlos III

Country where clinical trial is conducted

Spain, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Left Ventricle (LV) ejection fraction	Estimated with 3D echocardiography (Both: convectional and with esmolol administration)	At Baseline (Day 1) until Month-24 according to cohort
Primary	Peak measurement of global LV systolic longitudinal strain	Estimated with 3D echocardiography (Both: convectional and with esmolol administration)	At Baseline (Day 1) until Month-24 according to cohort
Primary	Ejection Intraventricular Pressure Difference (EIVPD) measure	Estimated with M-mode echocardiography (Both: convectional and with esmolol administration)	At Baseline (Day 1) until Month-24 according to cohort
Secondary	Ejection fraction	Obtained with 2D echocardiography (Simpson's biplane method)	At Baseline (Day 1) until Month-24 according to cohort
Secondary	Interleukin (IL)-1ß	Biochemical variables in blood in relation to the alteration of the different components of the myocardium	At Baseline (Day 1) until Month-24 according to cohort
Secondary	High-sensitivity IL-6 (hsIL-6)	Biochemical variables in blood in relation to the alteration of the different components of the myocardium	At Baseline (Day 1) until Month-24 according to cohort
Secondary	Soluble Suppression of Tumorigenicity 2 (ST-2)	Biochemical variables in blood in relation to the alteration of the different components of the myocardium	At Baseline (Day 1) until Month-24 according to cohort
Secondary	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	At Baseline (Day 1) until Month-24 according to cohort
Secondary	Ultrasensitive troponin I (hsTnI)	Biochemical variables in blood in relation to the alteration of the different components of the myocardium	At Baseline (Day 1) until Month-24 according to cohort
Secondary	Procollagen type I terminal propeptide (PICP)	Biochemical variables in blood in relation to the alteration of the different components of the myocardium	At Baseline (Day 1) until Month-24 according to cohort
Secondary	C-terminal telopeptide collagen type I (CITP)	Biochemical variables in blood in relation to the alteration of the different components of the myocardium	At Baseline (Day 1) until Month-24 according to cohort
Secondary	Matrix metalloproteinase-1 (MMP-1)	Biochemical variables in blood in relation to the alteration of the different components of the myocardium	At Baseline (Day 1) until Month-24 according to cohort