Clinical trial NCT05728632: Cardioprotective Effects of Nebivolol Versus Placebo in Patients Undergoing Chemotherapy With Anthracyclines
Official title: Cardioprotective Effects of Nebivolol Versus Placebo in Patients Undergoing Chemotherapy With Anthracyclines (CONTROL Trial)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Breast Cancer
Lymphoma, Large B-Cell, Diffuse
Cardiotoxicity
Left Ventricular Dysfunction
Chemotherapy Effect
Keywords: anthracycline chemotherapy
nebivolol
cardio-oncology
cancer therapy-related cardiovascular toxicity
cardiac magnetic resonance
primary prevention
cardioprotection
cardiotoxicity
Lead sponsor: Humanitas Hospital, Italy
Sponsor class: OTHER
Collaborators: name: Agenzia Italiana del Farmaco
First posted: 2023-02-15
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants are randomized 1:1 to two groups in parallel for the duration of the study
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Left Ventricular Ejection Fraction reduction assessed by Cardiac Magnetic Resonance
timeFrame: from baseline to 12 months
Secondary outcomes:
measure: Left ventricular ejection fraction assessed by Cardiac Magnetic Resonance
timeFrame: at 12-month follow-up
measure: Myocardial fibrosis assessed by Cardiac Magnetic Resonance
timeFrame: at 12-month follow-up
measure: Myocardial edema assessed by Cardiac Magnetic Resonance
timeFrame: at 12-month follow-up
measure: Right ventricular ejection fraction assessed by Cardiac Magnetic Resonance
timeFrame: at 12-month follow-up
measure: Left ventricular end-diastolic volume assessed by Cardiac Magnetic Resonance
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: Left ventricular end-systolic volume assessed by Cardiac Magnetic Resonance
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: Left ventricular mass assessed by Cardiac Magnetic Resonance
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: Left ventricular ejection fraction assessed by Echocardiography
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: Left ventricular diastolic function assessed by Echocardiography
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: Right ventricular systolic function assessed by Echocardiography
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: Left ventricular end-diastolic volume assessed by Echocardiography
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: Left ventricular end-systolic volume assessed by Echocardiography
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: Serum troponin
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: Serum B-type natriuretic peptide (BNP)
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: Serum N-terminal-pro hormone B-type natriuretic peptide (NT-proBNP)
timeFrame: at different timepoints (1-month, 6-month, 12-months)
measure: All-cause mortality
timeFrame: at 12-month follow-up
measure: Cardiovascular mortality
timeFrame: at 12-month follow-up
measure: Myocardial infarction
timeFrame: at 12-month follow-up
measure: Cerebrovascular events
timeFrame: at 12-month follow-up
measure: Hospitalization for heart failure
timeFrame: at 12-month follow-up
Other outcomes:
Locations:
city: Rozzano
country: Italy
facility: IRCCS Humanitas Research Hospital
state: Milan
Study officials:
affiliation: IRCCS Humanitas Research Hospital, Rozzano-Milan, Italy
name: Gianluigi Condorelli, MD,PhD,Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: IRCCS Humanitas Research Hospital, Rozzano-Milan, Italy
name: Giulio G Stefanini, MD,PhD,Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: IRCCS Humanitas Research Hospital, Rozzano-Milan, Italy
name: Carmelo Carlo-Stella, MD,Prof
role: PRINCIPAL_INVESTIGATOR
References: