Cardioprotective Effects of Nebivolol Versus Placebo in Patients Undergoing Chemotherapy With Anthracyclines

Breast Cancer Clinical Trial

— CONTROL  

Official title:

Cardioprotective Effects of Nebivolol Versus Placebo in Patients Undergoing Chemotherapy With Anthracyclines (CONTROL Trial)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05728632
• Other study ID #: 012018CONTROL
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: January 1, 2019
• Est. completion date: February 28, 2023

Study information

• Verified date: February 2023
• Source: Humanitas Hospital, Italy
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

As the cancer-related prognosis improves thanks to recent advances in cancer-targeted therapies, the prognostic burden of chemotherapy-related complications - including cardiotoxicity - is increasingly recognised. So far, the evidence supporting pharmacological preventive strategies in cardio-oncology has been inconsistent and conflicting, and there is a clear need for well-designed trials with novel interventions. In this study, by using cardiac magnetic resonance, the investigators want to assess if a commonly used beta-blocker with a unique pharmacological profile, i.e. nebivolol, can prevent cardiac dysfunction in patients with breast cancer or diffuse large B-cell lymphoma undergoing chemotherapy with anthracyclines.

Description:

During the last decades, major efforts have been made in the field of cancer therapy to improve prognosis and quality of life of patients treated with any sort of chemotherapy. Cardiotoxicity represents one of the most relevant adverse effects of chemotherapy, primarily in patients treated with anthracyclines. The potential protective role of cardiovascular medications in the prevention of cardiotoxicity associated with anthracyclines chemotherapy is still a matter of debate since evidence in this field are scarce and largely inconclusive. Indeed, prior studies were often limited by a non-blinded design or an echocardiography-based assessment of left ventricular ejection fraction (with a relevant inter and intra-operator variability). The primary objective of the trial is to evaluate the cardioprotective effects of the betablocker nebivolol in an individually randomized, parallel, placebo-controlled, double-blinded (patient, treating physician, investigator, outcomes assessor, statistician), superiority trial in patients with a solid tumor (i.e., breast cancer) or a hematologic malignancy (i.e., diffuse large B cell lymphoma) who have a normal cardiac function as assessed by echocardiography and will receive anthracyclines as part of their first-line chemotherapy program. Indeed, recent evidence suggests that anthracycline cardiotoxicity seems mainly due to an anthracycline-induced dysregulation of mitochondrial activity and metabolism in cardiomyocytes. Nebivolol has a distinctive profile among beta-blockers, with the unique power of increasing the nitric oxide bioavailability. Nebivolol-induced nitric oxide release has shown favourable effects in terms of antioxidant activity, cardiac neo-angiogenesis, mitochondrial and endothelial protection. On this basis, the individually randomized, parallel, placebo-controlled, double-blinded (patient, treating physician, investigator, outcomes assessor, statistician), superiority CONTROL trial will assess the cardioprotective effects of a commonly used betablocker (nebivolol) in patients with baseline normal left ventricular systolic function receiving anthracycline chemotherapy as first-line chemotherapy for breast cancer or diffuse large B-cell lymphoma. The assessment of left ventricular ejection fraction and related endpoints will be performed with cardiac magnetic resonance.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 80
• Est. completion date: February 28, 2023
• Est. primary completion date: February 28, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age =18 years

• Established histologic diagnosis of breast cancer or diffuse large B-cell lymphoma

• Planned chemotherapy with anthracyclines

• left ventricular ejection fraction =55% (assessed by echocardiography)

• Ability to provide informed consent

Exclusion Criteria:

• Known intolerance/contraindications to betablocker therapy

• History of coronary artery disease

• History of cardiomyopathy

• History of heart failure

• Ongoing treatment with betablockers for other indications

• Heart rate at baseline <60 beats per minute

• Arterial blood pressure at baseline <100/60 mmHg

• Contraindications to undergo cardiac magnetic resonance (e.g., non-compatible pacemakers or metallic prosthesis)

• Pregnancy or lactation

• Current participation to another study

Related Conditions & MeSH terms

• Breast Cancer
• Cardiotoxicity
• Chemotherapy Effect
• Left Ventricular Dysfunction
• Lymphoma, Large B-Cell, Diffuse
• Ventricular Dysfunction
• Ventricular Dysfunction, Left

Intervention

Drug:
• Nebivolol
Nebivolol, capsule, 5 mg once daily, for 12 months
• Placebo
Placebo, capsule, once daily, for 12 months

Locations

Country	Name	City	State
Italy	IRCCS Humanitas Research Hospital	Rozzano	Milan

Sponsors (2)

Lead Sponsor	Collaborator
Giulio Stefanini	Agenzia Italiana del Farmaco

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Left Ventricular Ejection Fraction reduction assessed by Cardiac Magnetic Resonance	The primary endpoint is defined as Left Ventricular Ejection Fraction (LVEF) reduction (unit of measurement: %) assessed by Cardiac Magnetic Resonance at 12 months of follow-up.; LVEF reduction is defined as the difference between LVEF at baseline and LVEF at 12 months follow-up (LVEF reduction = Baseline LVEF - 12 months LVEF).	from baseline to 12 months
Secondary	Left ventricular ejection fraction assessed by Cardiac Magnetic Resonance	Left ventricular ejection fraction (unit of measurement: %) assessed by Cardiac Magnetic Resonance at 12-month follow-up.	at 12-month follow-up
Secondary	Myocardial fibrosis assessed by Cardiac Magnetic Resonance	Myocardial fibrosis assessed by Cardiac Magnetic Resonance with T1-mapping sequences and with Late Gadolinium Enhancement images.	at 12-month follow-up
Secondary	Myocardial edema assessed by Cardiac Magnetic Resonance	Myocardial edema assessed by Cardiac Magnetic Resonance with T2 sequences.	at 12-month follow-up
Secondary	Right ventricular ejection fraction assessed by Cardiac Magnetic Resonance	Right ventricular ejection fraction (unit of measurement: %) assessed by Cardiac Magnetic Resonance	at 12-month follow-up
Secondary	Left ventricular end-diastolic volume assessed by Cardiac Magnetic Resonance	Left ventricular end-diastolic volume (unit of measurement: ml) assessed by Cardiac Magnetic Resonance	at different timepoints (1-month, 6-month, 12-months)
Secondary	Left ventricular end-systolic volume assessed by Cardiac Magnetic Resonance	Left ventricular end-systolic volume (unit of measurement: ml) assessed by Cardiac Magnetic Resonance	at different timepoints (1-month, 6-month, 12-months)
Secondary	Left ventricular mass assessed by Cardiac Magnetic Resonance	Left ventricular mass (unit of measurement: g/m²) assessed by Cardiac Magnetic Resonance	at different timepoints (1-month, 6-month, 12-months)
Secondary	Left ventricular ejection fraction assessed by Echocardiography	Left ventricular ejection fraction (unit of measurement: %) assessed by Echocardiography	at different timepoints (1-month, 6-month, 12-months)
Secondary	Left ventricular diastolic function assessed by Echocardiography	Left ventricular diastolic function assessed by Echocardiography according to Guidelines of European Association of Cardiovascular Imaging / American Society of Echocardiography	at different timepoints (1-month, 6-month, 12-months)
Secondary	Right ventricular systolic function assessed by Echocardiography	Right ventricular systolic function assessed by Echocardiography according to Guidelines of European Association of Cardiovascular Imaging / American Society of Echocardiography	at different timepoints (1-month, 6-month, 12-months)
Secondary	Left ventricular end-diastolic volume assessed by Echocardiography	Left ventricular end-diastolic volume (unit of measurement: ml) assessed by Echocardiography	at different timepoints (1-month, 6-month, 12-months)
Secondary	Left ventricular end-systolic volume assessed by Echocardiography	Left ventricular end-systolic volume (unit of measurement: ml) assessed by Echocardiography	at different timepoints (1-month, 6-month, 12-months)
Secondary	Serum troponin	Serum high-sensitivity cardiac troponin I levels (unit of measurement: ng/L)	at different timepoints (1-month, 6-month, 12-months)
Secondary	Serum B-type natriuretic peptide (BNP)	Serum B-type natriuretic peptide (BNP) (unit of measurement: pg/mL)	at different timepoints (1-month, 6-month, 12-months)
Secondary	Serum N-terminal-pro hormone B-type natriuretic peptide (NT-proBNP)	Serum N-terminal-pro hormone B-type natriuretic peptide (NT-proBNP) levels (unit of measurement: pg/mL)	at different timepoints (1-month, 6-month, 12-months)
Secondary	All-cause mortality	All-cause mortality	at 12-month follow-up
Secondary	Cardiovascular mortality	Cardiovascular mortality or death will be defined as any death due to immediate cardiovascular cause (e.g. myocardial infarction, low-output failure, arrhythmia). Unwitnessed death and death of unknown cause will be classified as cardiac death.	at 12-month follow-up
Secondary	Myocardial infarction	Myocardial infarction will be defined according to the 3rd Universal Definition.	at 12-month follow-up
Secondary	Cerebrovascular events	Cerebrovascular events will be defined as follows: Transient ischemic attack: rapidly developed clinical signs of global disturbance of cerebral function lasting fewer <24 hours, regardless of the presence of an acute clinically relevant brain lesion in imaging.; Ischemic stroke: rapidly developed clinical signs of focal or global disturbance of cerebral function lasting >24 hours with imaging of an acute clinically relevant brain lesion.; Intracerebral haemorrhage: diagnosis must be confirmed by cerebral imaging.	at 12-month follow-up
Secondary	Hospitalization for heart failure	Hospitalization for heart failure will be defined as any unplanned hospital readmission due to signs and symptoms of heart failure.	at 12-month follow-up