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

NCT ID: NCT04939883

Last Updated: 2024-06-28

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 1018 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-01
• Study Completion Date: 2025-12-30

Brief Summary

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.

Conditions

Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

Carvedilol

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Interventions

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

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ministry of Health, Brazil

OTHER_GOV

Sponsor Role: collaborator

Hospital Sirio-Libanes

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Renato H D. lopes, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hospital Sírio-Libanês

Locations

Hospital Sirio Libanes

São Paulo, São Paulo, Brazil

Site Status: RECRUITING

Countries

Brazil

Central Contacts

Ana Cecilia A Silva, MD, PhD

Role: CONTACT

ana.ceasilva@hsl.org.br

+551133944094

Isabela B dos Santos da Silva, MD, PhD

Role: CONTACT

isabela.bsscosta@hsl.org.br

+551133944094

Facility Contacts

Renato D Lopes, MD, PhD

Role: primary

renato.lopes@duke.edu

References

Costa IBSDS, Furtado RHM, Drager LF, de Barros E Silva PGM, Melo MDT, Araruna P, Bacchiega BC, Cauduro S, Walter E, Fialho GL, Silvestre O, Damiani LP, Barbosa LM, Luz MN, Silva ACA, de Mattos RR, Saretta R, Rehder MHHS, Hajjar LA, Lopes-Fernandez T, Dent S, Gibson CM, Lopes RD, Kalil Filho R; on behalf the CARDIOTOX Investigators. Effects of carvedilol on the prevention of cardiotoxicity induced by anthracyclines: Design and rationale of the CARDIOTOX trial. Am Heart J. 2025 Jul;285:1-11. doi: 10.1016/j.ahj.2025.02.014. Epub 2025 Feb 22.

Reference Type: DERIVED

PMID: 39988204 (View on PubMed)

Other Identifiers

AVAP-NG 989

Identifier Type: -

Identifier Source: org_study_id