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

NCT04939883 | Unknown Phase 4 DMC

• 1 other identifier: AVAP-NG 989
• Study Type: interventional
• Target: 1,018
• Locations: 1 country
• Sites: 1

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

Keywords

Carvedilol; Anthracyclines; Cardiotoxicity; Chemotherapy

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Drop in ejection fraction within 12 months.

  12 months

• Reduction in myocardial strain in 12 months from the start of treatment.

  12 months

• Diastolic dysfunction within 12 months

  12 months

• Elevation of biomarkers during chemotherapy and up to 12 months of follow-up

  12 months

• Quality of life (EuroQol-5D).

  12 months

Other Outcomes (3)

• Diagnosis of neoplasia within 12 months.

  12 months

• Progression of oncological disease within 12 months.

  12 months

• Tumor recurrence within 12 months.

  12 months.

Study Arms (2)

Intervention Group

EXPERIMENTAL

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

Control Group

PLACEBO COMPARATOR

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

Interventions

Carvedilol 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

Intervention Group

Placebo 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.

Control Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥18 years of age at the time of screening
• Cancer patients that will receive chemotherapy with anthracyclines.

You may not qualify if:

• 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

Sponsors & Collaborators

• Hospital Sirio-Libanes: lead
• Ministry of Health, Brazil: collaborator

Study Sites (1)

Hospital Sirio Libanes

São Paulo, São Paulo, 01308-050, Brazil

RECRUITING

Related Publications (1)

• 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.

  PMID: 39988204 DERIVED

MeSH Terms

Conditions

Neoplasms; Cardiotoxicity

Interventions

Carvedilol

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring

Study Officials

• Renato H D. lopes, MD, PhD

  Hospital Sírio-Libanês

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ana Cecilia A Silva, MD, PhD

CONTACT

+551133944094; ana.ceasilva@hsl.org.br

Isabela B dos Santos da Silva, MD, PhD

CONTACT

+551133944094; isabela.bsscosta@hsl.org.br

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Randomization will be in the proportion of 1: 1 (carvedilol x placebo). Both randomization and allocation of patients will be chosen in a veiled manner to patients and to assess. Data on randomization and allocation will be under custody of the Data analysis and safety committee.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 17, 2021
• First Posted: June 25, 2021
• Study Start: August 1, 2021
• Primary Completion: December 30, 2025
• Study Completion: December 30, 2025
• Last Updated: June 28, 2024

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)