Use of Dapagliflozin in Primary Prevention of Cardiotoxicity of Anthracycline Chemotherapy in Breast Cancer Patients

NCT ID: NCT07245069

Last Updated: 2025-11-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-02-01
• Study Completion Date: 2029-02-28

Brief Summary

The goal of this randomized, double-blind, placebo-controlled clinical trial is to determine whether dapagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, can help prevent anthracycline-induced cardiotoxicity caused by anthracycline chemotherapy in adult women with breast cancer receiving (neo)adjuvant treatment.

The main questions the study aims to answer are:

i) Does dapagliflozin reduce the decline in left ventricular function (measured by LVEF, GLS, and myocardial work) during and after anthracycline therapy? ii) Does dapagliflozin lessen the deteriorating effect of chemotherapy on endothelial function and arterial stiffness? iii) Does dapagliflozin effect levels of cardiac injury and inflammation biomarkers (e.g., hs-troponin T, NT-proBNP, ST-2, GDF-15, galectin-3, IL-6, MPO)?

Researchers will compare dapagliflozin 10 mg daily with placebo to see whether those receiving dapagliflozin experience less heart and vascular impairment during treatment.

Participants will:

• Take either dapagliflozin or placebo once daily during anthracycline chemotherapy.
• Undergo heart and vascular ultrasound, and a 6-minute walk test before chemotherapy and again at 24 and 52 weeks.
• Provide blood samples before, during and after chemotherapy to measure cardiac biomarkers.
• Complete multiple questionnaires on quality of life.

Detailed Description

Anthracycline-based chemotherapy remains a cornerstone of (neo)adjuvant treatment for breast cancer but is limited by a well-recognized risk of cardiotoxicity. This injury may manifest as left ventricular systolic dysfunction, abnormalities in myocardial deformation, impaired myocardial work efficiency, endothelial dysfunction, or increased arterial stiffness. Changes often occur early during treatment and may progress to clinically significant heart failure months or years after completion of chemotherapy. Current preventive strategies focus primarily on strict control of cardiovascular risk factors, as no pharmacologic intervention has consistently demonstrated efficacy in preventing anthracycline-induced cardiotoxicity.

SGLT-2 inhibitors, including dapagliflozin, have demonstrated robust cardiovascular benefits across diverse populations, independent of diabetes status. Clinical trials in heart failure and mechanistic studies indicate that SGLT-2 inhibition favorably affects myocardial energetics, reduces oxidative stress and inflammation, improves endothelial function, and modulates myocardial remodeling. Retrospective observational data in patients exposed to anthracyclines suggest fewer cardiac events among individuals using SGLT-2 inhibitors, but no prospective randomized trial has evaluated this potential cardioprotective effect.

This randomized, double-blind, placebo-controlled clinical trial is designed to determine whether dapagliflozin can attenuate cardiac and vascular deterioration associated with anthracycline chemotherapy in adults with breast cancer. Approximately 100 participants scheduled to receive four cycles of anthracycline-based (neo)adjuvant chemotherapy will be randomized (1:1) to receive dapagliflozin 10 mg once daily or matching placebo. Treatment will begin prior to or at the initiation of chemotherapy and continue according to protocol-defined duration.

Baseline evaluation includes transthoracic echocardiography with quantification of left ventricular ejection fraction (LVEF, using the modified biplane Simpson method), global longitudinal strain (GLS, via speckle-tracking in three apical views), and myocardial work indices derived from noninvasive blood pressure and strain analysis. Vascular ultrasonography will assess endothelial function through brachial artery flow-mediated dilation (FMD) and arterial stiffness via carotid pulse wave velocity (PWV) and stiffness index β. Functional capacity will be measured using the 6-minute walk test. Participants will also provide blood samples for a comprehensive biomarker panel including markers of myocardial injury (high-sensitivity troponin), hemodynamic stress (NT-proBNP), myocardial remodeling (ST-2, GDF-15, galectin-3), and inflammation (IL-6, myeloperoxidase). Quality of life will be assessed using EQ-5D, KCCQ, and SF-36 questionnaires.

All assessments (cardiac imaging, vascular studies, functional testing, and biomarker sampling) will be repeated at 24 and 52 weeks following initiation of chemotherapy, with an additional biomarker time point after two chemotherapy cycles and at the end of anthracycline treatment. This protocol enables characterization of both acute and subacute trajectories of myocardial and vascular injury.

The primary objective is to determine whether dapagliflozin reduces the degree of anthracycline-related left ventricular dysfunction, particularly reflected in GLS and myocardial work indices. Secondary objectives include evaluating effects on LVEF, endothelial function (FMD), arterial stiffness (PWV, stiffness β), biomarker profiles, functional capacity, and patient-reported outcomes. Safety monitoring will include systematic assessment of adverse events related to dapagliflozin, such as genitourinary infections, volume depletion, hypotension, and rare ketoacidosis. All participants will be monitored according to predefined stopping criteria and standard clinical safety procedures.

By integrating advanced cardiac and vascular phenotyping with serial biomarker profiling, this study aims to generate high-quality evidence on whether dapagliflozin provides meaningful primary prevention of anthracycline-induced cardiotoxicity. If beneficial, this approach could inform future cardio-oncology guidelines and improve cardiovascular safety for patients undergoing anthracycline chemotherapy.

Conditions

Heart Failure; Anthracycline-induced Cardiac Toxicity; Endothelial Function (FMD); Arterial Stiffness; Breast Cancer

Study Design

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

Study Groups

Dapagliflozin 10 mg Daily

Participants randomized to this arm will receive dapagliflozin 10 mg orally once daily for a total duration of 52 weeks (1 year). Study medication will begin before or at the start of anthracycline chemotherapy and will continue throughout chemotherapy and the post-treatment follow-up period, according to protocol.

Group Type: EXPERIMENTAL

Dapagliflozin 10 mg

Intervention Type: DRUG

Forgixa® 10 mg daily

Placebo

Participants randomized to this arm will receive a matching placebo orally once daily for a total duration of 52 weeks (1 year). Placebo will be initiated before or at the start of anthracycline chemotherapy and continued throughout chemotherapy and the 1-year protocol-defined follow-up period.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Lactose tablet daily

Interventions

Dapagliflozin 10 mg

Forgixa® 10 mg daily

Intervention Type: DRUG

Placebo

Lactose tablet daily

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Adults ≥18 years.
• Histologically confirmed breast cancer with planned (neo)adjuvant anthracycline-based chemotherapy (4 cycles of epirubicin + cyclophosphamide or doxorubicin + cyclophosphamide).
• Eligible to start dapagliflozin or placebo prior to or at initiation of chemotherapy.
• Able to perform baseline echocardiography, vascular ultrasound (FMD and carotid stiffness), 6-minute walk test, and biomarker sampling.
• Willing and able to provide written informed consent.

Exclusion Criteria

• Known heart failure (any prior diagnosis of HF).
• Clinically significant valvular heart disease.
• Prior exposure to chemotherapy or radiotherapy to the left chest.
• Type 1 diabetes mellitus.
• Symptomatic hypotension.
• History of recurrent urinary tract infections.
• History of diabetic ketoacidosis or ketonemia.
• Severe hepatic impairment (ALT, AST, ALP >3× upper limit of normal).
• Severe renal impairment (eGFR <20 mL/min/1.73 m²).
• Known allergy or intolerance to SGLT-2 inhibitors.
• Any use of SGLT-2 inhibitor therapy within 3 months prior to enrollment.
• Pregnancy or breastfeeding.
• Any condition that, in the investigator's judgment, could interfere with study participation, safety, or completion.

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

Sponsors

University Medical Centre Ljubljana

OTHER

Sponsor Role: lead

Responsible Party

Jure Tršan

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

University Medical Centre Ljubljana

Ljubljana, , Slovenia

Site Status: RECRUITING

Countries

Slovenia

Central Contacts

Jure Tršan

Role: CONTACT

jure.trsan@gmail.com

Slovenia ext. +3861 5228011

Facility Contacts

Jure Tršan

Role: primary

jure.trsan@kclj.si

+3861 5228011

Other Identifiers

0120-383/2024-2711-3

Identifier Type: -

Identifier Source: org_study_id