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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Cancer
• Intervention / Treatment: Drug: Carvedilol; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 1018
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ana Cecilia A Silva, MD, PhD; Phone Number: +551133944094; Email: ana.ceasilva@hsl.org.br
• Study Contact Backup: Name: Isabela B dos Santos da Silva, MD, PhD; Phone Number: +551133944094; Email: isabela.bsscosta@hsl.org.br

Study Locations

• Brazil
  • Sao Paulo
    • São Paulo, Sao Paulo, Brazil, 01308-050
      • Recruiting
      • Hospital Sírio Libanês
      • Sub-Investigator: Luciano Drager, MD, PhD
      • Sub-Investigator: Roberto K Filho, MD,PhD
      • Contact: Renato D Lopes, MD, PhD; Email: renato.lopes@duke.edu
      • Principal Investigator: Renato D Lopes, MD, PhD
      • Sub-Investigator: Isabela B Costa, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 symptoms (dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, and pulmonary and systemic congestion) suggestive of or a previous diagnosis 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)
• Congenital heart disease with left ventricular function impared
• Contra-indication to the use of beta-blockers.
• Pregnant or Breast-feeding females or women of childbearing age who intend to became pregnant.
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Group; 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; 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
Placebo Comparator: Control Group; 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; 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.

What is the study measuring?

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 12 months.	Drop in ejection fraction greater than 10% and values less than 55%	12 months
Reduction in myocardial strain in 12 months from the start of treatment.	Relative reduction of more than 15% in myocardial strain	12 months
Diastolic dysfunction within 12 months	Development of diastolic dysfunction within 12 months	12 months
Elevation of biomarkers during chemotherapy and up to 12 months of follow-up	Elevation of biomarkers (NT-pro BNP and troponin) during chemotherapy and up to 24 months of follow-up	12 months
Quality of life (EuroQol-5D).	Quality of life measured by questionnaire in up to 12 months.	12 months
Cardiovascular complications in 12 months.	Cardiovascular complications (death, resuscitated cardiac arrest, myocardial infarction, heart failure and cardiac arrhythmias) in 24 months.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnosis of neoplasia within 12 months.	Diagnosis of another neoplasia	12 months
Progression of oncological disease within 12 months.	Progression of oncological disease	12 months
Tumor recurrence within 12 months.	Tumor recurrence	12 months.

Collaborators and Investigators

• Sponsor: Hospital Sirio-Libanes
• Collaborators: Ministry of Health, Brazil
• Investigators: Principal Investigator: Renato H D. lopes, MD, PhD, Hospital Sírio-Libanês

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2021
• Primary Completion (Estimated): December 30, 2025
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: June 17, 2021
• First Submitted That Met QC Criteria: June 17, 2021
• First Posted (Actual): June 25, 2021

Study Record Updates

• Last Update Posted (Actual): June 28, 2024
• Last Update Submitted That Met QC Criteria: June 26, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Carvedilol; Chemotherapy; Cardiotoxicity; Anthracyclines
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Wounds and Injuries; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Cardiotoxicity; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Protective Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Carvedilol
• Other Study ID Numbers: AVAP-NG 989

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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