Effects of Carvedilol on Cardiotoxicity in Cancer Patients Submitted to Anthracycline Therapy

Study Overview
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Brief Summary
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Neoplasia is the main cause of general death in the Brazilian population. In 2016, they were responsible for approximately 211,343 (16%) deaths, followed by cardiovascular diseases (12.6%). Despite the high mortality rate of neoplasia, oncological treatment have advanced substantially in recent decades improving the prognosis of patients. However, growing evidence suggest that some oncological agents may induce significant toxicity that may play a major role in the quality of life, morbidity and mortality. The cardiovascular system is often negatively affected with cancer therapy, predisposing several patients to stop appropriate treatments or to have cardiovascular events related to the cardiotoxicity. The most typical manifestation of cardiotoxicity and related consequences (heart failure) are related to the use of anthracyclines. Anthracyclines are part of the chemotherapy regimen for solid tumors and hematological neoplasms in children and adults, and are associated with an increase in life expectancy. Carvedilol is an α and β-blocker that also has antioxidant properties. Preliminary studies have shown that carvedilol and its metabolites prevent lipid peroxidation, inhibit the formation and inactivate free radicals, in addition to preventing the depletion of endogenous antioxidants, such as vitamin E. These effects would potentially prevent anthracycline injury but definitive evidence is still needed. This is a multi-center, double-blind, randomized, placebo-controlled study that aims to establish the efficacy of carvedilol for the primary prevention of left ventricular systolic dysfunction in cancer patients obtained with anthracycline chemotherapy, in different schedules and doses.

Official Title
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A Prospective Multi-Center Randomized Study to Evaluate the Effects of Carvedilol on Cardiotoxicity in Cancer Patients Submitted to Anthracycline Therapy

Conditions
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Cancer

Intervention / Treatment
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* Drug: Carvedilol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age at the time of screening Cancer patients that will receive chemotherapy with anthracyclines. Exclusion Criteria: Inability to adequate asses left ventricular function Previous history of heart failure Previous history of any cardiomyopathy (eg.: valve disease, Chagas' disease, infiltrative cardiomyopathy) LVEF < 50% Previous history of myocardial revascularization Permanent tachyarrhythmia (flutter, atrial fibrillation, atrial tachycardia) Contra-indication to the use of beta-blockers. Trastuzumab indication Pregnant or Breast-feeding females. On kidney replacement therapy ECOG >= 4 or Karnofsky <=30 Advanced hepatic failure (C score Child-Pugh and MELD > 15); Previous use of anthracycline Have any serious concomitant systemic disease, condition, or disorder that, in the opinion of the investigator, should preclude participation in this study Are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Group<br>Patients allocated to the intervention group will receive carvedilol 6.25 mg twice daily, then increased to 12.5 mg twice daily, until maximum dose of 25 mg twice daily according to the patients' tolerance; The dosis increments will occur every 5 days. If after the increment the patient develops bradycardia or hypotension, the dose will be reduced to the maximum tolerated dose. Carvedilol will ideally be maintained for up to 30 days after the end of chemotherapy. | Drug: Carvedilol<br>* Carvedilol will be dispensed in a staggered and progressive manner, initially from 6.25 mg twice daily, then increased to 12.5 mg twice daily, until maximum dose of 25 mg twice daily or development of contraindications<br>|
| Placebo Comparator: Control Group<br>Patients allocated to this group will receive placebo in a presumably staggered and progressive manner similar to the group intervention. The placebo will ideally be maintained for up to 30 days after the end of chemotherapy. | Drug: Placebo<br>* Patients will receive placebo in a presumed staggered and progressive manner similar to the intervention group. The placebo will ideally be maintained for up to 30 days after the end of chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drop in ejection fraction within 12 months of starting treatment. | Drop in ejection fraction> 10% to values less than 50% of the left ventricle | 12 months | 
| Cardiac events within 12 months of starting treatment. | Cardiac events such as death, resuscitated cardiac arrest, myocardial infarction, heart failure and cardiac arrhythmias | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drop in ejection fraction within 24 months. | Drop in ejection fraction greater than 10% and values less than 55% | 24 months | 
| Reduction in myocardial strain in 24 months from the start of treatment. | Relative reduction of more than 15% in myocardial strain | 24 months | 
| Diastolic dysfunction within 24 months | Development of diastolic dysfunction within 24 months | 24 months | 
| Elevation of biomarkers during chemotherapy and up to 24 months of follow-up | Elevation of biomarkers (NT-pro BNP and troponin) during chemotherapy and up to 24 months of follow-up | 24 months | 
| Quality of life (EuroQol-5D). | Quality of life measured by questionnaire in up to 24 months. | 24 months | 
| Cardiovascular complications in 24 months. | Cardiovascular complications (death, resuscitated cardiac arrest, myocardial infarction, heart failure and cardiac arrhythmias) in 24 months. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carvedilol, Anthracyclines, Cardiotoxicity, Chemotherapy