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

Study Overview
=================
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.

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

Conditions
-----------------
Cirrhosis, Diabetes Mellitus, Oncologic Disorders

Intervention / Treatment
-----------------
* Drug: Esmolol Injection [Brevibloc]


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>1 conventional echocardiography without esmolol administration followed by 1 echocardiography with esmolol administration at Baseline and other study visits. | Drug: Esmolol Injection [Brevibloc]<br>* 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).<br>* Other names: Esmolol Hydrochloride;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ejection fraction | Obtained with 2D echocardiography (Simpson's biplane method) | At Baseline (Day 1) until Month-24 according to cohort | 
| Interleukin (IL)-1β | 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
beta blockers, echocardiography, esmolol, systolic function, cardiovascular diagnosis, biomarkers, diagnostic techniques, medical imaging