Ivabradine to Prevent Anthracycline-induced Cardiotoxicity (IPAC)

Ivabradine to Prevent Anthracycline-induced Cardiotoxicity: a Randomized Clinical Trial

Anthracyclines are associated with cardiotoxic effects. Previous studies suggest that enalapril, and or carvedilol, protect against cardiovascular effects of these drugs.

Ivabradine selectively reduces heart rate through inhibition of the cardiac pace maker IF channel, thus prolonging the duration of spontaneous depolarization in the sinus node. Additionally, ivabradine might preserve myocardial perfusion without negative inotropic effect and probably maintain cardiac contractility despite the reduction of heart rate.

Ivabradine has been shown to improve outcome in patients with heart failure and angina. The aim of this study is to evaluate whether ivabradine might prevent anthracycline-induced cardiotoxicity.

Study Overview

• Status: Unknown
• Conditions: Heart Failure; Neoplasms; Chemotherapy Effect; Cardiotoxicity; Oncology
• Intervention / Treatment: Drug: Ivabradine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • SP
    • Sao Paulo, SP, Brazil, 01246000
      • Recruiting
      • Instituto do Cancer do Estado de Sao Paulo
      • Contact: Stephanie I Rizk, MD; Phone Number: +551138933267; Email: stephrizk@gmail.com
      • Contact: Ludhmila A Hajar, MD, PhD; Phone Number: +551138933267; Email: ludhmila@terra.com.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-year-old or older;
• Cancer diagnosis;
• Chemotherapy with anthracycline;
• Written informed consent

Exclusion Criteria:

• Chronic Kidney Disease (Creatinine clearance inferior to 30mL/min/1.73m2)
• Bradycardia (heart rate less than 60 beats per minute)
• Atrial fibrilation;
• Previous diagnosis of heart failure;
• Pregnancy;
• History of previous hypersensibility to the study drug;
• Participating in another study protocol.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ivabradine; Patients will receive ivabradine just before anthracycline chemotherapy, 5 mg per oral twice daily, until one month after the last chemotherapy session.	Drug: Ivabradine; Ivabradine capsule
Placebo Comparator: Placebo; Patients will receive placebo just before anthracycline chemotherapy, one capsule per oral twice daily, until one month after the last chemotherapy session.	Drug: Placebo; Placebo oral capsule.; Other Names: Placebo oral capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventricular function	Reduction in global longitudinal strain of at least 10% (GLS)	365 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite endpoint of mortality or major cardiovascular outcomes	Composite endpoint of mortality or major cardiovascular outcomes (defined as acute myocardial infarction, heart failure, inappropriate sinus tachycardia and arrhythmia)	365 days after randomization
Left ventricular dysfunction	Incidence of left ventricular (LV) dysfunction defined as reduction of LV ejection fraction by 10%.	365 days after randomization
Incidence of myocardial injury	Levels of NT-proBNP and high-sensitivity cardiac troponin T	90 days after randomization
Incidence of myocardial injury	Levels of NT-proBNP and high-sensitivity cardiac troponin T	180 days after randomization
Incidence of myocardial injury	Levels of NT-proBNP and high-sensitivity cardiac troponin T	365 days after randomization
Diastolic dysfunction	Assessment by echocardiography the incidence of diastolic dysfunction using the following parameters: peak E-wave velocity, peak A-wave velocity, mitral valve (MV) E/A ratio, MV deceleration time, pulsed-wave tissue doppler imaging e' velocity, Mitral E/e', left atrium maximum volume index, pulmonary vein(PV) systole(S) wave, PV diastole (D) wave, continuous wave (CW) doppler: tricuspid regurgitation, systolic jet velocity; Color M- mode.	365 days after randomization
Ventricular function	Reduction in global longitudinal strain of at least 10% (GLS)	180 days after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of myocardial injury	Levels of NT-proBNP and high-sensitivity cardiac troponin T	90 days after randomization
Incidence of myocardial injury	Levels of NT-proBNP and high-sensitivity cardiac troponin T	180 days after randomization
Composite endpoint of mortality or major cardiovascular outcomes	Composite endpoint of mortality or major cardiovascular outcomes (defined as acute myocardial infarction, heart failure, inappropriate sinus tachycardia and arrhythmia)	yearly after randomization until 5 years
Left ventricular dysfunction	Incidence of left ventricular (LV) dysfunction defined as reduction of LV	180 days after randomization
Diastolic dysfunction	Assessment by echocardiography the incidence of diastolic dysfunction using the following parameters: peak E-wave velocity, peak A-wave velocity, mitral valve (MV) E/A ratio, MV deceleration time, pulsed-wave tissue doppler imaging e' velocity, Mitral E/e', left atrium maximum volume index, pulmonary vein(PV) systole(S) wave, PV diastole (D) wave, continuous wave (CW) doppler: tricuspid regurgitation, systolic jet velocity; Color M- mode.	180 days after randomization
Adverse events	bradycardia, hypertension, atrial fibrillation, luminous phenomena, syncope, hypotension, erythema, rash, diplopia, vertigo, urticaria	180 days after randomization
Adverse events	bradycardia, hypertension, atrial fibrillation, luminous phenomena, syncope, hypotension, erythema, rash, diplopia, vertigo, urticaria	365 days after randomization
Heart rate variability	Assessment of heart variability through 24-hour holter the following parameters: mRR - ms, SDNN - ms, SDANN - ms, SDNNi - ms, rMSSD-ms, NN50, pNN50.	180 days after randomization
Oxygen consumption (VO2)	Measurement of VO2 by cardiopulmonary exercise test	180 days after randomization
Ventilatory equivalents for oxygen (VE/VO2) and for carbon dioxide (VE/VCO2)	Measurement of ventilatory equivalents for oxygen (VE/VO2) and for carbon dioxide (VE/VCO2) by cardiopulmonary exercise test	180 days after randomization
Left Ventricular Dimensions	LV diastolic diameter, LV diastolic diameter, LV diastolic diameter	yearly after randomization until 5 years
Left ventricular geometry and mass	LV mass, Septal thickness, Posterior wall thickness	yearly after randomization until 5 years
Subgroup analyses regarding the primary outcome	Type of cancer, gender, age	365 days after randomization

Collaborators and Investigators

• Sponsor: University of Sao Paulo

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2019
• Primary Completion (Anticipated): October 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: August 13, 2018
• First Submitted That Met QC Criteria: August 26, 2018
• First Posted (Actual): August 28, 2018

Study Record Updates

• Last Update Posted (Actual): April 2, 2019
• Last Update Submitted That Met QC Criteria: April 1, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• 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
• Other Study ID Numbers: 42559415520020065

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