Dapagliflozin for the primary prevention of chemotherapy induced cardiotoxicity in breast cancer patients treated with neo-adjuvant anthracycline-based chemotherapy: design of the multi-center phase II randomized PROTECT trial

Dapagliflozin for the primary prevention of chemotherapy induced cardiotoxicity in breast cancer patients treated with neo-adjuvant anthracycline-based chemotherapy: design of the multi-center phase II randomized PROTECT trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Dapagliflozin for the primary prevention of chemotherapy induced cardiotoxicity in breast cancer patients treated with neo-adjuvant anthracycline-based chemotherapy: design of the multi-center phase II randomized PROTECT trial A. Greco, V. Quagliariello, G. Rizzo, F. Turazza, C. Mascolo, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4664535/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Their clinical effectiveness of anthracyclines may be thwarted by the development of cardiotoxicity progressively leading to heart failure (HF) and compromising the quality of life and overall survival of breast cancer (BC) patients. Sequential therapy regimen of anthracyclines and human epidermal growth factor receptor (HER2) blocking agents, such as trastuzumab, is associated to higher risk of cardiotoxicity compared to monotherapy regimen. Sodium glucose cotransporter 2 inhibitors (SGLT2i) exert several cardiometabolic benefits in HF with reduced and preserved ejection fraction through the systemic reduction of insulin, visceral fat, chemokines and growth factors involved in cardiovascular diseases. Recent studies in preclinical models of anthracycline-induced cardiotoxicity concluded that SGLT2i are able to prevent ejection fraction reduction and myocardial inflammation and fibrosis. A very recent retrospective study indicates that SGLT2i were associated with lower rate of cardiac events among diabetic patients with cancer treated with anthracyclines. Based on this background we sought to conduct a randomized clinical trial testing SGLT2i in patients with BC treated with anthracyclines+/- trastuzumab. Methods: PROTECT trial is a phase II “proof of concept”, multicentre, randomized 1:1, open label, parallel-groups study, designed to evaluate if the SGLT2i dapagliflozin reduces chemotherapy-induced cardiotoxicity in participants with BC treated with (neo-) adjuvant Anthracycline-based chemotherapy +/- trastuzumab. Chemotherapy-naive patients (18-70 years) scheduled for antracycline +/- trastuzumab treatment in the (neo-)adjuvant setting for stage I-III BC will be randomized using a web-based system stratified by the use of trastuzumab to follow a chemotherapy regimen plus the SGLT2i Dapagliflozin (10 mg/die) (active group) or chemotherapy regimen plus standard of care (control group). During follow up period, patients developing asymptomatic or symptomatic systolic disfunction will be treated according to good clinical practice. From randomization, to the third, sixth, twelfth and eighteenth months, echocardiographic and cardiological visits will be performed associated to blood analysis for quantification of cardiotoxicity biomarkers, estimated glomerular filtration rate and systemic inflammation. Discussion: PROTECT study aims to reduce cadiovascular events in BC through the oral administration of SGLT2i Dapagliflozin and to investigate on its systemic cardio-metabolic benefits. Trial registration: ClinicalTrials.gov NCT06341842 (EudraCT Number 2022-003377-28). Registered on 19 March 2024. Cardiovascular disease Risk factors Breast Cancer Sodium glucose cotransporter 2 inhibitors (SGLT2i) cardiotoxicity anthracycline anti-HER2 therapy Figures Figure 1 Figure 2 Introduction Background and rational Despite improved survival of patients with cancer, chemotherapy has also increased morbidity and mortality due to treatment side effects ( 1 ). Anthracyclines (AC) are among the most widely used chemotherapeutic agents and have been shown to be effective in a wide range of tumors, in particular breast cancer. Their clinical effectiveness, however, may be thwarted by the development of cardiotoxicity that negatively affects patients’ outcomes and seriously limits their oncological therapeutic opportunities ( 2 ). Anthracyclines are associated with a dose dependent cardiotoxicity ( 1 ). Cancer patients treated with anthracyclines at 400 mg/m2 and 700 mg/m2 are exposed to a 5% and 48% risk of heart failure. Mechanisms of acute and chronic anthracyclines-mediated adverse events involves ferroptosis, endothelial damages, apoptosis, fibrosis and myocardial inflammation mediated by overexpression of NF-kB mediated pathways. Notably, short-term induced myocardial damages due to doxorubicin are well reported in the clinical scenario, resulting in the need of cardioprotective strategies in primary prevention in patients with cancer. Cardiotoxicity from combination therapies is a clinical problem of extreme significance in oncology; a relevant example is the additive cardiotoxicity from the combination of anthracyclines and trastuzumab in HER2 + breast cancer( 3 – 10 ). Based on these data, as well as on the limited clinical effectiveness of conventional cardiovascular drugs (e.g. beta-blockers and RAAS inhibitors), the discovery of new cardioprotective agents in these patients could be of key importance to avoid discontinuation or interruption of anticancer therapies thus increasing overall survival. In the last twenty years several randomized and observational trials tried to study a prophylactic intervention in order to avoid drug-induced cardiotoxicity and the onset of heart failure ( 11 – 14 ). A meta-analysis of 15 randomized clinical trials on patients receiving chemotherapy ( 15 ), showed a significant, but small, benefit of neurohormonal therapies in reducing decline in LV systolic function among patients undergoing chemotherapy. Sodium Glucose-Cotransporter Type 2 inhibitors (SGLT2i) have beneficial properties, including the improvement of systolic and diastolic functions, increases in calcium homeostasis, reduction of afterload and oxidative stress, improvement of mitochondrial functions in cardiomyocytes, increases in ketone bodies, overall resulting in an improved energy metabolism of cardiac cells, reduction of insulin and uric acid levels as well as of epicardial and visceral fat ( 16 – 20 ) (Fig. 1 ). Dapagliflozin (DAPA) is a selective SGLT2 inhibitor with multiple beneficial properties in patients with cardiovascular diseases (CVD) ( 21 – 23 ). In DAPA-HF TRIAL ( 21 ), DAPA reduced hospitalizations for heart failure and death from cardiovascular causes in patients with heart failure and reduced ejection fraction. In DEFINE-trial, DAPA improved heart failure-related health status and reduced natriuretic peptides in patients with heart failure with reduced ejection fraction ( 22 ). In the DELIVER trial, in diabetic patients with heart failure and preserved ejection fraction, DAPA reduced significantly cardiovascular death and urgent heart failure visits ( 23 ). A very recent retrospective study in cancer patients with diabetes treated with anthracyclines, SGLT2i reduced heart failure admissions, new cardiomyopathies, arrhythmias and heat failure incidence ( 24 ). Dapagliflozin could have high potential to prevent anthracyclines-mediated cardiotoxicity in cancer patients without diabetes through its cardio-renal benefits ( 25 – 26 ). To our knowledge no trial has evaluated the beneficial effects of DAPA in a specific set of patients treated with (neo-) adjuvant Anthracycline-based chemotherapy +/- trastuzumab. Methods Study design and objectives PROTECT trial is a phase II “proof of concept”, multicentre, randomized 1:1, open label, parallel-groups study, designed to evaluate if dapagliflozin reduces chemotherapy-induced cardiotoxicity (CTRCD) in participants with breast cancer treated with (neo-) adjuvant Anthracycline-based chemotherapy +/- trastuzumab. The study aims to describe an efficacy for dapagliflozin compared to standard of care. The study design is shown in Fig. 2 . The study involves two cancer centers in Italy (Table 1 ) and it started on November 2023. This study was approved by the ethic board of the Italian Medicine Agency (AIFA), and by that of each recruiting hospitals, such as EudraCT Number 2022-003377-28. The study has been registered with ClinicalTrials.gov (registration date and number: 2024-03-19 and NCT06341842). Table 1 List of participating Centers Center Role PI Fondazione IRCCS Policlinico San Matteo Coordinator Laura Scelsi Istituto Nazionale Tumori - IRCCS - Fondazione "G.Pascale" Participant Nicola Maurea The new 2022 ESC Cardio-Oncology Guidelines ( 10 ) classified Cancer therapy-related cardiac dysfunction (CTRCD) in: Asymptomatic CTRCD Severe: New LVEF reduction to < 40% Moderate : New LVEF reduction by ≥ 10 percentage points to an LVEF of 40–49% OR New LVEF reduction by 15% from baseline OR new rise in cardiac biomarkers (cTnI/cTnT > 99th percentile, BNP ≥ 35 pg/mL, NT-proBNP ≥ 125 pg/mL or new significant rise from baseline beyond the biological and analytical variation of the assay used). Mild: LVEF ≥ 50% AND new relative decline in GLS by > 15% from baseline AND/OR new rise in cardiac biomarkers (cTnI/cTnT > 99th percentile, BNP ≥ 35 pg/mL, NT-proBNP ≥ 125 pg/mL or new significant rise from baseline beyond the biological and analytical variation of the assay used). Symptomatic CTRCD: specifically HF, which is a clinical syndrome consisting of cardinal symptoms (e.g. breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles, and peripheral oedema) and has traditionally been divided into distinct phenotypes based on the measurement of LVEF: ≤40%= HFrEF; 41–49%=HFmrEF; ≥50%=HFpEF. The purpose of this study is to evaluate whether dapagliflozin reduces chemotherapy induced cardiotoxicity in participants with breast cancer treated with (neo-)adjuvant anthracycline-based chemotherapy +/- trastuzumab. The study seeks primarily to assess whether the administration of dapagliflozin is associated with a lower rate of asymptomatic and symptomatic CTRCD during 18 months. The key secondary objective is to assess whether the administration of dapagliflozin is associated with a lower rate of asymptomatic CTRCD during 18 months. The primary and key secondary outcome will be measured using transthoracic echocardiography and cardiac biomarkers. For this purpose we calculate during transthoracic echocardiography LVEF (%) and GLS (%), according to definition of CRTCD in ESC Cardio-Oncology Guidelines ( 10 ). The study secondary objectives will be: 1) Difference in severe, moderate and mild asymptomatic CTRCD between the two groups during 18 months according to the background therapy with AC with or without TZ and with or without the use of any of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers for their potential cardioprotective role on cardiotoxicity development (subgroup analysis) ( 11 – 15 ); 2) Difference in symptomatic CTRCD between the two groups during 18 months according to the background therapy with AC with or without TZ (subgroup analysis) 3) Change from baseline of at least of one grade of diastolic disfunction (according to ESC guidelines ( 27 ), appendix 1 ) during 18 months. 4) Change from baseline in end diastolic and systolic left ventricular volumes and in left atrial volume during 18 months. 5) Change in plasma levels of the bio-humoral markers between baseline and follow-up at three, six, twelve and eighteen months: • NT-pro-BNP • hsTNI • CKD-EPI eGFR • hsCRP The safety outcome include: decline in eGFR under 25 ml/min/1.7 mq; documented clinical hypoglycaemic events; premature interruption of trial drug due to recurrent genito-urinary tract infections; premature interruption of trial drug due to symptomatic hypotension; cancer relapse; new cancer events. Participants We will consider all consecutive chemotherapy-naive patients, scheduled for ACT +/- trastuzumab treatment for stage I-III breast cancer. These patients will be referred to Cardiology Unit by Hospital Oncologists. Inclusion criteria : Chemotherapy-naive patients scheduled for antracycline +/- trastuzumab treatment in the (neo-) adjuvant setting for stage I-III breast cancer. Adult women between 18 and 70 years of age eGFR > 25 ml/min/1.7 mq ECOG score 0–2 Consent form signed. Female patients of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a negative result from a serum pregnancy test performed within 7 days of randomization and on the day of first study treatment prior to the initiation of study treatment. Women of childbearing potential must agree to use highly effective contraceptive measures from the time of informed consent through 7 months after last dose of study drug. (More detailed information in the section 7.1 of the protocol). Exclusion criteria : Left ventricular ejection fraction (LVEF) < 53%. Valvular heart disease. Previous malignancy requiring treatment with anthracyclines or chest radiotherapy. Life expectancy ≤ 12 weeks. Currently pregnant (confirmed with positive pregnancy test performed from − 7 to -1 days prior to start study drug) or unwilling to adopt highly effective contraceptive method Currently breast-feeding women History of hypersensitivity to dapagliflozin or any of the excipients of the product History of Diabetic Ketoacidosis (DKA) requiring medical intervention (e.g. emergency room visit and/or hospitalization) within 1 month prior to enrolment visit. Type 1 diabetes mellitus Interventions The eligible patients who voluntarily sign the consent form will be randomized using a web-based system stratified by the use of trastuzumab to: Active group: chemotherapy regimen plus dapagliflozin (10 mg/die) Control group: chemotherapy regimen plus standard of care. During follow up period, if a patient develops asymptomatic or symptomatic systolic dysfunction should be treated according to good clinical practice Assessment measures Evaluations will take place at baseline (T1), after chemotherapy and at 3-6-12-18 months. The timing and frequency of the study visits, including assessment time windows, are presented in the table of study procedures and assessments (Table 2 ). Table 2 study procedures and assessments Cardiovascular parameters Screening Basal - Randomization (prior CT) Treatment period (during and post-CT) End of trial Visit V1 V2 V3 V4 V5 V6 Days -30 to -1 -5 to -1 90 +/- 6 180 +/-6 360 +/- 6 540 +/- 6 Informed Consent X Examination of inclusion and exclusion criteria X Randomization X Medical History Collection Of The Following Data : • Demography • Age • Sex • Height • Weight • Evaluation Of Any Previous Reported Allergy • Cardiovascular Risk Factors* • Oncological History, Any Other Chemo-Radiotherapy Administered In The Past Medical History • Other Comorbidities A warning collection of the whole patient’s past medical history X Clinical Procedures • Physical Examination • Height • Weight • Pressure Arteriosue • Heart Rate Twelve-Lead Electrocardiogram X X X X X Blood sample for laboratory tests examined in the local laboratory ** : X X X X X Transthoracic ecocardiography X X X X X Concomitant therapy and intervention X X X X X SAFETY EVALUATION Adverse events related to the study medication X X X X X X Investigational Product X X X X Outcomes • Primary outcome • Secondary outcome X X X X Outcome of interest Xa *Arterial Hypertension, Smoking Habits, Family History For Cardiovascular Disease, Dyslipidemia And Diabetes ** Full blood count; Creatinine; Urea; CKD-EPI; eGFR; Sodium;Potassium; GOT; GPT; Total bilirubin; Direct and indirect bilirubin; Alkaline phosphatase; Creatine Kinase (CK); NT-pro-BNP; TNI-hs I;CRP-hs;Cytokines Xa: post breast surgery Participant timeline Recruitment started in October 2023 at Fondazione IRCCS Policlinico San Matteo, Pavia. Enrollment is about 12 months with follow-up period of 18 months. Total duration from first in last out is 30 months. The data collected from the participants and the follow-up timeline are presented in Table 2 . Sample size The sample size is computed based on the primary endpoint and makes use of the data reported in the literature [10]. At 18 months, we expect a cumulative incidence of CTRCD of 35% in the control arm, corresponding to an event-free survival rate of 65%. With 316 patients (158 per arm) we will be able to elicit an increase in event-free survival in the dapaglifozin arm up to 80% (hazard ratio, HR 0.52, 78 events) with a power of 80 and type I error (2-tailed) of 5%. This sample size accounts for a 10% dropout rate and the log rank test to compare event-free survivals. For calculation we used the Stata command: power log rank .65 .80, wdprob(.1) power(.80) alpha(0.05) Data management, collection and monitoring All protocol-required information collected during the study will be entered by the investigator in the electronic case report forms (CRF). Specifically, the CRF will be based on the REDCap platform ( https://projectredcap.org/ ). The investigator should complete the CRF as soon as possible after information is collected. An explanation should be given for all missing data. The completed CRF will be reviewed and signed by the investigator. The main investigator will continuously monitor data. Statistical analyses All analyses will be performed using the Stata software (release 18, StataCorp, College Station, TX, USA); they will be detailed in the statistical analysis plan. Continuous data will be described with the mean and standard deviation or the median and quartiles, if skewed. Categorical data will be described as counts and percent for each categories. Descriptions will be performed separately for each treatment group. A 2-sided p-value < 0.05 will be considered statistically significant. Variables may be log-transformed for the purpose of the analysis. Briefly, the logrank test will be used to compare cardiac toxicity free survival. Cox regression will be used to compute HR and 95%CI. Regression models for repeated measures will be used to compare changes in biomarkers over time; details are provided in table X. Table 3 Planned analyses Primary Endpoint Analysis Cumulative incidence of CTRCD The cumulative incidence of CTRCD per 100 person year will be reported by arm. Cumulative event-free survival will be computed and plotted using the Kaplan Meier method and compared with the logrank test. Cox regression models will be fitted to derive the HR and its 95% confidence interval. Huber-White robust standard errors will be computed to account for intra-centre lack of independence. In a sensitivity analysis of the primary endpoint, we will evaluate the modifying effect of trastuzumab, by including an interaction term of trastuzumab and treatment in the Cox model Key secondary endpoint Cumulative incidence of asymptomatic CTRCD This endpoint will be analyzed as described for the primary endpoint Secondary endpoints 1 Difference in severe, moderate and mild asymptomatic CTRCD between the two groups during 18 months according to the background therapy with AC with or without TZ (subgroup analysis) and according to the background therapy with cardioprotective drugs We will evaluate the modifying effect of background therapy, by including an interaction term of background therapy and treatment in the Cox model described in the sensitivity analysis of the primary endpoint. 2 Difference in symptomatic CTRCD between the two groups during 18 months according to the background therapy with AC with or without TZ (subgroup analysis) We will evaluate the modifying effect of background therapy, by including an interaction term of background therapy and treatment in the Cox model described in the sensitivity analysis of the primary endpoint. 3 Change from baseline of at least of one grade of diastolic dysfunction (according to ESC guidelines (41, appendix 2) during 18 months. The proportion of patients with a change at least one grade will be compared using a random effect regression model for longitudinal binomial data 4 Change from baseline in end diastolic and systolic left ventricular volumes and in left atrial volume during 18 months. The two group will be compared using a random effect regression model for longitudinal data. Log-transformation may be applied if needed 5 Change in plasma levels of the bio-humoral markers between baseline and follow-up at three, six, twelve and eighteen months: NT-pro-BNP, hsTNI, CKD-EPI eGFR, hsCRP The two group will be compared using a random effect regression model for longitudinal data. Log-transformation may be applied if needed Research ethic approval The study adheres to the Declaration of Helsinki on medical research protocols and ethics, the ICH-GCP as well as all national legal and regulatory requirements. Discussion This is the first trial to examine the safety and efficacy of dapagliflozin in breast cancer patients treated with (neo-) adjuvant anthracycline-based chemotherapy +/- trastuzumab. It will allow to investigate the potential beneficial properties of SGLT2i in patients with cancer at risk of cardiovascular complications, leading to the discovery of a new pharmacological tool in the primary prevention of cardiotoxicity from cardiotoxic therapies used in clinical oncology. Abbreviations AC Anthracyclines CI Confidence interval CKD-EPI Chronic Kidney Disease Epidemiology Collaboration CRF Case Report Form CTRCD Cancer therapy-related cardiac dysfunction CV CardioVascular DM Diabetes mellitus DT Deceleration Time eCRF Electronic Case Report Form eGFR Estimated Glomerular Filtration Rate ESC European Society of Cardiology GCP Good Clinical Practice GLS Global Longitudinal Strain GOT Glutamic-Oxaloacetic Transaminase GPT Glutamic-Piruvic Transaminase HER-2 Human Epidermal growth factor Receptor type 2 HF Heart Failure HFrEF Heart Failure with reduced Ejection Fraction hs CRP High Sensivity C-Reactive Protein hs-TnI High Sensitivity Troponin I HR Hazard ratio LVEF Left Ventricular Ejection Fraction NT-pro-BNP N-terminal pro b-type natriuretic peptide NYHA New York Heart Association OMT Optimal Medical Therapy PI Principal Investigator QOL Quality of Life RAAS Renin Angiotensin-Aldosterone System RCT Randomized Controlled Trial SGLT-2 Sodium-Glucose Transporter 2 SGLT2i Sodium-Glucose Transporter-2 Inhibitors T1DM Type-1 Diabetes Mellitus TZ Trastuzumab WHO World Healt Organization Declarations Acknowledgements: Not applicable. Funding: project was financed with funds allocated by the Ministry of Health for the “Ricerca Corrente” project active at the IRCCS Fondazione San Matteo oF Pavia (ref. RC 08076023 (DE 5/D.G./998/2023)). Availability of data and material : None declared. Authors’ contributions: The study was designed by L. Scelsi, A. Greco and G. Rizzo. The principal investigator of the study is L. Scelsi. A.Greco and V. Quagliariello were the major contributors in writing the manuscript. C. Klersy designed the statistical methods of the study. All authors participated in writing and revising the manuscript. All authors read and approved the final manuscript. Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics approval and consent to participate The Ethics Committee of Fondazione IRCCS Policlinico San Matteo has approved the study and its consent to participate (number 0008491/23). The study will be conducted in accordance with the Declaration of Helsinki. All researchers are trained and certified in Good Clinical Practices. A written informed consent will be taken from all participants. References Anchit B, et al. Anthracycline-Induced Cardiotoxicity: Causes, Mechanisms, and Prevention. Adv Exp Med Biol. 2020;1257:181–92. Cardinale D, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131(22):1981–8. Role of cardiovascular imaging. in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC). 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Sodium-Glucose Co-Transporter-2 Inhibitors and Cardiac Outcomes Among Patients Treated With Anthracyclines. JACC Heart Fail. 2022;10(8):559–67. 10.1016/j.jchf.2022.03.006 . Theresa AMD, ESC Scientific Document Group., 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC, European Heart Journal, Volume 42, Issue 36, 21 September 2021, Pages 3599–3726. Cherney DZI, et al. Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double‐blind, crossover trial. Lancet Diabetes Endocrinol. 2020;8:582–93. 10.1016/S2213-8587(20)30162-5 . Sherif F, Nagueh, et al. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J – Cardiovasc Imaging. 2016;17:1321–60. Additional Declarations No competing interests reported. Supplementary Files Appendix1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4664535","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":327566213,"identity":"5ab06619-3832-45f9-91cf-d9837852af35","order_by":0,"name":"A. Greco","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"A.","middleName":"","lastName":"Greco","suffix":""},{"id":327566214,"identity":"a6562c27-3865-4b24-a9d9-8f7368298eaf","order_by":1,"name":"V. Quagliariello","email":"","orcid":"","institution":"Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale","correspondingAuthor":false,"prefix":"","firstName":"V.","middleName":"","lastName":"Quagliariello","suffix":""},{"id":327566215,"identity":"2328335f-f4ad-499d-955d-cfcf91545b0a","order_by":2,"name":"G. Rizzo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYJCCA0AshyFCUIsxEDM2wJQeIKgHCBIbkLXgtUbegffhwR9/bNLnTzv8/PGHChsGc4kExsMf8GgxPMBucECCJy13w+00w4YDZ9IYLGck4HeYYQMbwwEDicO5G6QTDBsOth1mMDhzgAgtCQaH0+Vnp39sOPiPCC3yDEAtBxIOJzDczgHa0gDUcrwBvxYDZjaGgw0H0gw33M4pnHHmWBqPZXsj0E/4bGlvY/4IDDF5oMM2fKiosZEzZ2Y+/KECny2H0QR4DIDxg0cD0BYMaQO86kfBKBgFo2AkAgCvm1b7B3s1AAAAAABJRU5ErkJggg==","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":true,"prefix":"","firstName":"G.","middleName":"","lastName":"Rizzo","suffix":""},{"id":327566216,"identity":"066aa378-1991-4fca-96a8-05d3bf97227d","order_by":3,"name":"F. Turazza","email":"","orcid":"","institution":"Istituto Nazionale Tumori-IRCCS","correspondingAuthor":false,"prefix":"","firstName":"F.","middleName":"","lastName":"Turazza","suffix":""},{"id":327566217,"identity":"37102e09-07e0-4df4-b8d2-b0f60f8ee2c1","order_by":4,"name":"C. Mascolo","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"C.","middleName":"","lastName":"Mascolo","suffix":""},{"id":327566218,"identity":"add2459f-1de3-4db1-8c68-8683eb5367e8","order_by":5,"name":"C. Pelosi","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"C.","middleName":"","lastName":"Pelosi","suffix":""},{"id":327566219,"identity":"5145e82f-0c06-4e19-a4b6-ca3656da2754","order_by":6,"name":"M. C. Galiazzo","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"M.","middleName":"C.","lastName":"Galiazzo","suffix":""},{"id":327566220,"identity":"20f3df8c-83b2-4c3f-95a8-77267498272f","order_by":7,"name":"M. Acquaro","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"M.","middleName":"","lastName":"Acquaro","suffix":""},{"id":327566221,"identity":"437e338e-19f9-46d3-9005-c3551c8a37f0","order_by":8,"name":"A. Lasagna","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"A.","middleName":"","lastName":"Lasagna","suffix":""},{"id":327566222,"identity":"2ebb33e6-4a42-4a5f-bbf4-66420867c99c","order_by":9,"name":"L. Perrone","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"L.","middleName":"","lastName":"Perrone","suffix":""},{"id":327566223,"identity":"f0b72b97-1f91-4d76-ac9b-494a83064a0d","order_by":10,"name":"M. Amici","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"M.","middleName":"","lastName":"Amici","suffix":""},{"id":327566224,"identity":"69e72279-f1f2-4ce9-adb1-1be5a82be9a7","order_by":11,"name":"C. Klersy","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"C.","middleName":"","lastName":"Klersy","suffix":""},{"id":327566225,"identity":"780d56db-ff9d-46f7-b050-ef7229775b83","order_by":12,"name":"S. Ghio","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"S.","middleName":"","lastName":"Ghio","suffix":""},{"id":327566226,"identity":"a1803502-d323-4103-b4f5-c9a21846e858","order_by":13,"name":"L. De Luca","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"L.","middleName":"","lastName":"De Luca","suffix":""},{"id":327566227,"identity":"9691de5c-fc84-494c-b060-454378615bd8","order_by":14,"name":"N. Maurea","email":"","orcid":"","institution":"Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale","correspondingAuthor":false,"prefix":"","firstName":"N.","middleName":"","lastName":"Maurea","suffix":""},{"id":327566228,"identity":"ea43de88-9de9-4616-90cc-c5540cf99335","order_by":15,"name":"L. Scelsi","email":"","orcid":"","institution":"Fondazione Policlinico San Matteo, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"L.","middleName":"","lastName":"Scelsi","suffix":""}],"badges":[],"createdAt":"2024-07-01 00:27:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4664535/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4664535/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":61006098,"identity":"e9138b1d-a936-4c20-805d-c297dbe33eeb","added_by":"auto","created_at":"2024-07-24 13:47:46","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":66092,"visible":true,"origin":"","legend":"\u003cp\u003eBeneficial properties of SGLT2i\u003c/p\u003e","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4664535/v1/a6109f1fcf9892c70e401eb0.jpeg"},{"id":61006095,"identity":"238145c3-0a7b-4b58-929d-f56f3fe6535c","added_by":"auto","created_at":"2024-07-24 13:47:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":46153,"visible":true,"origin":"","legend":"\u003cp\u003eTrial scheme\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4664535/v1/482548204fceaee9f6156fc5.png"},{"id":75593930,"identity":"550ed097-c020-4db1-bdbf-de07aed4dfa8","added_by":"auto","created_at":"2025-02-06 07:32:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1321198,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4664535/v1/41b77548-0e2a-4169-a8fb-d29158b03a4a.pdf"},{"id":61006097,"identity":"59db4644-a1f4-4748-ad1f-dcc9b30c9b78","added_by":"auto","created_at":"2024-07-24 13:47:46","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":290542,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4664535/v1/68b27331537304bea48915f7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Dapagliflozin for the primary prevention of chemotherapy induced cardiotoxicity in breast cancer patients treated with neo-adjuvant anthracycline-based chemotherapy: design of the multi-center phase II randomized PROTECT trial","fulltext":[{"header":"Introduction","content":"\u003ch2\u003eBackground and rational\u003c/h2\u003e\u003cp\u003eDespite improved survival of patients with cancer, chemotherapy has also increased morbidity and mortality due to treatment side effects (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Anthracyclines (AC) are among the most widely used chemotherapeutic agents and have been shown to be effective in a wide range of tumors, in particular breast cancer. Their clinical effectiveness, however, may be thwarted by the development of cardiotoxicity that negatively affects patients\u0026rsquo; outcomes and seriously limits their oncological therapeutic opportunities (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Anthracyclines are associated with a dose dependent cardiotoxicity (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Cancer patients treated with anthracyclines at 400 mg/m2 and 700 mg/m2 are exposed to a 5% and 48% risk of heart failure. Mechanisms of acute and chronic anthracyclines-mediated adverse events involves ferroptosis, endothelial damages, apoptosis, fibrosis and myocardial inflammation mediated by overexpression of NF-kB mediated pathways. Notably, short-term induced myocardial damages due to doxorubicin are well reported in the clinical scenario, resulting in the need of cardioprotective strategies in primary prevention in patients with cancer. Cardiotoxicity from combination therapies is a clinical problem of extreme significance in oncology; a relevant example is the additive cardiotoxicity from the combination of anthracyclines and trastuzumab in HER2\u0026thinsp;+\u0026thinsp;breast cancer(\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Based on these data, as well as on the limited clinical effectiveness of conventional cardiovascular drugs (e.g. beta-blockers and RAAS inhibitors), the discovery of new cardioprotective agents in these patients could be of key importance to avoid discontinuation or interruption of anticancer therapies thus increasing overall survival.\u003c/p\u003e \u003cp\u003eIn the last twenty years several randomized and observational trials tried to study a prophylactic intervention in order to avoid drug-induced cardiotoxicity and the onset of heart failure (\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). A meta-analysis of 15 randomized clinical trials on patients receiving chemotherapy (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), showed a significant, but small, benefit of neurohormonal therapies in reducing decline in LV systolic function among patients undergoing chemotherapy.\u003c/p\u003e \u003cp\u003eSodium Glucose-Cotransporter Type 2 inhibitors (SGLT2i) have beneficial properties, including the improvement of systolic and diastolic functions, increases in calcium homeostasis, reduction of afterload and oxidative stress, improvement of mitochondrial functions in cardiomyocytes, increases in ketone bodies, overall resulting in an improved energy metabolism of cardiac cells, reduction of insulin and uric acid levels as well as of epicardial and visceral fat (\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDapagliflozin (DAPA) is a selective SGLT2 inhibitor with multiple beneficial properties in patients with cardiovascular diseases (CVD) (\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). In DAPA-HF TRIAL (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), DAPA reduced hospitalizations for heart failure and death from cardiovascular causes in patients with heart failure and reduced ejection fraction. In DEFINE-trial, DAPA improved heart failure-related health status and reduced natriuretic peptides in patients with heart failure with reduced ejection fraction (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In the DELIVER trial, in diabetic patients with heart failure and preserved ejection fraction, DAPA reduced significantly cardiovascular death and urgent heart failure visits (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). A very recent retrospective study in cancer patients with diabetes treated with anthracyclines, SGLT2i reduced heart failure admissions, new cardiomyopathies, arrhythmias and heat failure incidence (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Dapagliflozin could have high potential to prevent anthracyclines-mediated cardiotoxicity in cancer patients without diabetes through its cardio-renal benefits (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). To our knowledge no trial has evaluated the beneficial effects of DAPA in a specific set of patients treated with (neo-) adjuvant Anthracycline-based chemotherapy +/- trastuzumab.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and objectives\u003c/h2\u003e \u003cp\u003ePROTECT trial is a phase II \u0026ldquo;proof of concept\u0026rdquo;, multicentre, randomized 1:1, open label, parallel-groups study, designed to evaluate if dapagliflozin reduces chemotherapy-induced cardiotoxicity (CTRCD) in participants with breast cancer treated with (neo-) adjuvant Anthracycline-based chemotherapy +/- trastuzumab. The study aims to describe an efficacy for dapagliflozin compared to standard of care.\u003c/p\u003e \u003cp\u003eThe study design is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe study involves two cancer centers in Italy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and it started on November 2023.\u003c/p\u003e \u003cp\u003eThis study was approved by the ethic board of the Italian Medicine Agency (AIFA), and by that of each recruiting hospitals, such as EudraCT Number 2022-003377-28. The study has been registered with ClinicalTrials.gov (registration date and number: 2024-03-19 and NCT06341842).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eList of participating Centers\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCenter\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRole\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePI\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFondazione IRCCS Policlinico San Matteo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCoordinator\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLaura Scelsi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIstituto Nazionale Tumori - IRCCS - Fondazione \"G.Pascale\"\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParticipant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNicola Maurea\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe new 2022 ESC Cardio-Oncology Guidelines (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) classified Cancer therapy-related cardiac dysfunction (CTRCD) in:\u003c/p\u003e \u003cp\u003eAsymptomatic CTRCD\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eSevere: New LVEF reduction to \u0026lt;\u0026thinsp;40%\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eModerate : New LVEF reduction by \u0026ge;\u0026thinsp;10 percentage points to an LVEF of 40\u0026ndash;49% OR New LVEF reduction by \u0026lt;\u0026thinsp;10 percentage points to an LVEF of 40\u0026ndash; 49% AND either new relative decline in GLS by \u0026gt;\u0026thinsp;15% from baseline OR new rise in cardiac biomarkers (cTnI/cTnT\u0026thinsp;\u0026gt;\u0026thinsp;99th percentile, BNP\u0026thinsp;\u0026ge;\u0026thinsp;35 pg/mL, NT-proBNP\u0026thinsp;\u0026ge;\u0026thinsp;125 pg/mL or new significant rise from baseline beyond the biological and analytical variation of the assay used).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMild: LVEF\u0026thinsp;\u0026ge;\u0026thinsp;50% AND new relative decline in GLS by \u0026gt;\u0026thinsp;15% from baseline AND/OR new rise in cardiac biomarkers (cTnI/cTnT\u0026thinsp;\u0026gt;\u0026thinsp;99th percentile, BNP\u0026thinsp;\u0026ge;\u0026thinsp;35 pg/mL, NT-proBNP\u0026thinsp;\u0026ge;\u0026thinsp;125 pg/mL or new significant rise from baseline beyond the biological and analytical variation of the assay used).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eSymptomatic CTRCD: specifically HF, which is a clinical syndrome consisting of cardinal symptoms (e.g. breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles, and peripheral oedema) and has traditionally been divided into distinct phenotypes based on the measurement of LVEF: \u0026le;40%= HFrEF; 41\u0026ndash;49%=HFmrEF; \u0026ge;50%=HFpEF.\u003c/p\u003e \u003cp\u003eThe purpose of this study is to evaluate whether dapagliflozin reduces chemotherapy induced cardiotoxicity in participants with breast cancer treated with (neo-)adjuvant anthracycline-based chemotherapy +/- trastuzumab.\u003c/p\u003e \u003cp\u003eThe study seeks primarily to assess whether the administration of dapagliflozin is associated with a lower rate of asymptomatic and symptomatic CTRCD during 18 months. The key secondary objective is to assess whether the administration of dapagliflozin is associated with a lower rate of asymptomatic CTRCD during 18 months.\u003c/p\u003e \u003cp\u003eThe primary and key secondary outcome will be measured using transthoracic echocardiography and cardiac biomarkers. For this purpose we calculate during transthoracic echocardiography LVEF (%) and GLS (%), according to definition of CRTCD in ESC Cardio-Oncology Guidelines (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe study secondary objectives will be: 1) Difference in severe, moderate and mild asymptomatic CTRCD between the two groups during 18 months according to the background therapy with AC with or without TZ and with or without the use of any of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers for their potential cardioprotective role on cardiotoxicity development (subgroup analysis) (\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e); 2) Difference in symptomatic CTRCD between the two groups during 18 months according to the background therapy with AC with or without TZ (subgroup analysis) 3) Change from baseline of at least of one grade of diastolic disfunction (according to ESC guidelines (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), \u003cspan refid=\"Sec13\" class=\"InternalRef\"\u003eappendix 1\u003c/span\u003e) during 18 months. 4) Change from baseline in end diastolic and systolic left ventricular volumes and in left atrial volume during 18 months. 5) Change in plasma levels of the bio-humoral markers between baseline and follow-up at three, six, twelve and eighteen months: \u0026bull; NT-pro-BNP \u0026bull; hsTNI \u0026bull; CKD-EPI eGFR \u0026bull; hsCRP\u003c/p\u003e \u003cp\u003eThe safety outcome include: decline in eGFR under 25 ml/min/1.7 mq; documented clinical hypoglycaemic events; premature interruption of trial drug due to recurrent genito-urinary tract infections; premature interruption of trial drug due to symptomatic hypotension; cancer relapse; new cancer events.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eWe will consider all consecutive chemotherapy-naive patients, scheduled for ACT +/- trastuzumab treatment for stage I-III breast cancer. These patients will be referred to Cardiology Unit by Hospital Oncologists.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInclusion criteria\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e Chemotherapy-naive patients scheduled for antracycline +/- trastuzumab treatment in the (neo-) adjuvant setting for stage I-III breast cancer.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAdult women between 18 and 70 years of age\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eeGFR\u0026thinsp;\u0026gt;\u0026thinsp;25 ml/min/1.7 mq\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eECOG score 0\u0026ndash;2\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eConsent form signed.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFemale patients of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a negative result from a serum pregnancy test performed within 7 days of randomization and on the day of first study treatment prior to the initiation of study treatment. Women of childbearing potential must agree to use highly effective contraceptive measures from the time of informed consent through 7 months after last dose of study drug. (More detailed information in the section 7.1 of the protocol).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eExclusion criteria\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eLeft ventricular ejection fraction (LVEF)\u0026thinsp;\u0026lt;\u0026thinsp;53%.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eValvular heart disease.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePrevious malignancy requiring treatment with anthracyclines or chest radiotherapy.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eLife expectancy\u0026thinsp;\u0026le;\u0026thinsp;12 weeks.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCurrently pregnant (confirmed with positive pregnancy test performed from \u0026minus;\u0026thinsp;7 to -1 days prior to start study drug) or unwilling to adopt highly effective contraceptive method\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCurrently breast-feeding women\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHistory of hypersensitivity to dapagliflozin or any of the excipients of the product\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHistory of Diabetic Ketoacidosis (DKA) requiring medical intervention (e.g. emergency room visit and/or hospitalization) within 1 month prior to enrolment visit.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eType 1 diabetes mellitus\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eThe eligible patients who voluntarily sign the consent form will be randomized using a web-based system stratified by the use of trastuzumab to:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eActive group: chemotherapy regimen plus dapagliflozin (10 mg/die)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e Control group: chemotherapy regimen plus standard of care.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eDuring follow up period, if a patient develops asymptomatic or symptomatic systolic dysfunction should be treated according to good clinical practice\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAssessment measures\u003c/h2\u003e \u003cp\u003eEvaluations will take place at baseline (T1), after chemotherapy and at 3-6-12-18 months.\u003c/p\u003e \u003cp\u003eThe timing and frequency of the study visits, including assessment time windows, are presented in the table of study procedures and assessments (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003estudy procedures and assessments\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular parameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eScreening\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eBasal - Randomization\u003c/p\u003e \u003cp\u003e(prior CT)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eTreatment period\u003c/p\u003e \u003cp\u003e(during and post-CT)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eEnd of trial\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisit\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eV1\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u003cem\u003eV2\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eV3\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003eV4\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eV5\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cem\u003eV6\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDays\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-30 to -1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e-5 to -1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90 +/- 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e180 +/-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e360 +/- 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e540 +/- 6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInformed Consent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExamination of inclusion and exclusion criteria\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRandomization\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedical History\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eCollection Of The Following Data\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eDemography\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eHeight\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eWeight\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eEvaluation Of Any Previous Reported Allergy\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eCardiovascular Risk Factors*\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eOncological History, Any Other Chemo-Radiotherapy Administered In The Past Medical History\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eOther Comorbidities\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eA warning collection of the whole patient\u0026rsquo;s past medical history\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical Procedures\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003ePhysical Examination\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eHeight\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eWeight\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003ePressure Arteriosue\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eHeart Rate\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eTwelve-Lead Electrocardiogram\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBlood sample for laboratory tests examined in the local laboratory **\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTransthoracic ecocardiography\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eConcomitant therapy and intervention\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSAFETY EVALUATION\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eAdverse events related to the study medication\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInvestigational Product\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOutcomes\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003ePrimary outcome\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; \u003cb\u003eSecondary outcome\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOutcome of interest\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eXa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e*Arterial Hypertension, Smoking Habits, Family History For Cardiovascular Disease, Dyslipidemia And Diabetes\u003c/p\u003e \u003cp\u003e** Full blood count; Creatinine; Urea; CKD-EPI; eGFR; Sodium;Potassium; GOT; GPT; Total bilirubin; Direct and indirect bilirubin; Alkaline phosphatase; Creatine Kinase (CK); NT-pro-BNP; TNI-hs I;CRP-hs;Cytokines\u003c/p\u003e \u003cp\u003eXa: post breast surgery\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eParticipant timeline\u003c/h2\u003e \u003cp\u003eRecruitment started in October 2023 at Fondazione IRCCS Policlinico San Matteo, Pavia. Enrollment is about 12 months with follow-up period of 18 months. Total duration from first in last out is 30 months.\u003c/p\u003e \u003cp\u003eThe data collected from the participants and the follow-up timeline are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThe sample size is computed based on the primary endpoint and makes use of the data reported in the literature [10]. At 18 months, we expect a cumulative incidence of CTRCD of 35% in the control arm, corresponding to an event-free survival rate of 65%. With 316 patients (158 per arm) we will be able to elicit an increase in event-free survival in the dapaglifozin arm up to 80% (hazard ratio, HR 0.52, 78 events) with a power of 80 and type I error (2-tailed) of 5%. This sample size accounts for a 10% dropout rate and the log rank test to compare event-free survivals. For calculation we used the Stata command: power log rank .65 .80, wdprob(.1) power(.80) alpha(0.05)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eData management, collection and monitoring\u003c/h2\u003e \u003cp\u003eAll protocol-required information collected during the study will be entered by the investigator in the electronic case report forms (CRF). Specifically, the CRF will be based on the REDCap platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://projectredcap.org/\u003c/span\u003e\u003cspan address=\"https://projectredcap.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The investigator should complete the CRF as soon as possible after information is collected. An explanation should be given for all missing data. The completed CRF will be reviewed and signed by the investigator. The main investigator will continuously monitor data.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eAll analyses will be performed using the Stata software (release 18, StataCorp, College Station, TX, USA); they will be detailed in the statistical analysis plan. Continuous data will be described with the mean and standard deviation or the median and quartiles, if skewed. Categorical data will be described as counts and percent for each categories. Descriptions will be performed separately for each treatment group. A 2-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 will be considered statistically significant. Variables may be log-transformed for the purpose of the analysis. Briefly, the logrank test will be used to compare cardiac toxicity free survival. Cox regression will be used to compute HR and 95%CI. Regression models for repeated measures will be used to compare changes in biomarkers over time; details are provided in table X.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlanned analyses\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary Endpoint\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnalysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCumulative incidence of CTRCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe cumulative incidence of CTRCD per 100 person year will be reported by arm. Cumulative event-free survival will be computed and plotted using the Kaplan Meier method and compared with the logrank test. Cox regression models will be fitted to derive the HR and its 95% confidence interval. Huber-White robust standard errors will be computed to account for intra-centre lack of independence.\u003c/p\u003e \u003cp\u003eIn a sensitivity analysis of the primary endpoint, we will evaluate the modifying effect of trastuzumab, by including an interaction term of trastuzumab and treatment in the Cox model\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKey secondary endpoint\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCumulative incidence of asymptomatic CTRCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThis endpoint will be analyzed as described for the primary endpoint\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSecondary endpoints\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 Difference in severe, moderate and mild asymptomatic CTRCD between the two groups during 18 months according to the background therapy with AC with or without TZ (subgroup analysis) and according to the background therapy with cardioprotective drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWe will evaluate the modifying effect of background therapy, by including an interaction term of background therapy and treatment in the Cox model described in the sensitivity analysis of the primary endpoint.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 Difference in symptomatic CTRCD between the two groups during 18 months according to the background therapy with AC with or without TZ (subgroup analysis)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWe will evaluate the modifying effect of background therapy, by including an interaction term of background therapy and treatment in the Cox model described in the sensitivity analysis of the primary endpoint.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 Change from baseline of at least of one grade of diastolic dysfunction (according to ESC guidelines (41, appendix 2) during 18 months.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe proportion of patients with a change at least one grade will be compared using a random effect regression model for longitudinal binomial data\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 Change from baseline in end diastolic and systolic left ventricular volumes and in left atrial volume during 18 months.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe two group will be compared using a random effect regression model for longitudinal data. Log-transformation may be applied if needed\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 Change in plasma levels of the bio-humoral markers between baseline and follow-up at three, six, twelve and eighteen months:\u003c/p\u003e \u003cp\u003eNT-pro-BNP, hsTNI, CKD-EPI eGFR, hsCRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe two group will be compared using a random effect regression model for longitudinal data. Log-transformation may be applied if needed\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eResearch ethic approval\u003c/h2\u003e \u003cp\u003eThe study adheres to the Declaration of Helsinki on medical research protocols and ethics, the ICH-GCP as well as all national legal and regulatory requirements.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first trial to examine the safety and efficacy of dapagliflozin in breast cancer patients treated with (neo-) adjuvant anthracycline-based chemotherapy +/- trastuzumab.\u003c/p\u003e \u003cp\u003eIt will allow to investigate the potential beneficial properties of SGLT2i in patients with cancer at risk of cardiovascular complications, leading to the discovery of a new pharmacological tool in the primary prevention of cardiotoxicity from cardiotoxic therapies used in clinical oncology.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAC Anthracyclines\u003c/p\u003e \u003cp\u003eCI Confidence interval\u003c/p\u003e \u003cp\u003eCKD-EPI Chronic Kidney Disease Epidemiology Collaboration\u003c/p\u003e \u003cp\u003eCRF Case Report Form\u003c/p\u003e \u003cp\u003eCTRCD Cancer therapy-related cardiac dysfunction\u003c/p\u003e \u003cp\u003eCV CardioVascular\u003c/p\u003e \u003cp\u003eDM Diabetes mellitus\u003c/p\u003e \u003cp\u003eDT Deceleration Time\u003c/p\u003e \u003cp\u003eeCRF Electronic Case Report Form\u003c/p\u003e \u003cp\u003eeGFR Estimated Glomerular Filtration Rate\u003c/p\u003e \u003cp\u003eESC European Society of Cardiology\u003c/p\u003e \u003cp\u003eGCP Good Clinical Practice\u003c/p\u003e \u003cp\u003eGLS Global Longitudinal Strain\u003c/p\u003e \u003cp\u003eGOT Glutamic-Oxaloacetic Transaminase\u003c/p\u003e \u003cp\u003eGPT Glutamic-Piruvic Transaminase\u003c/p\u003e \u003cp\u003eHER-2 Human Epidermal growth factor Receptor type 2\u003c/p\u003e \u003cp\u003eHF Heart Failure\u003c/p\u003e \u003cp\u003eHFrEF Heart Failure with reduced Ejection Fraction\u003c/p\u003e \u003cp\u003ehs CRP High Sensivity C-Reactive Protein\u003c/p\u003e \u003cp\u003ehs-TnI High Sensitivity Troponin I\u003c/p\u003e \u003cp\u003eHR Hazard ratio\u003c/p\u003e \u003cp\u003eLVEF Left Ventricular Ejection Fraction\u003c/p\u003e \u003cp\u003eNT-pro-BNP N-terminal pro b-type natriuretic peptide\u003c/p\u003e \u003cp\u003eNYHA New York Heart Association\u003c/p\u003e \u003cp\u003eOMT Optimal Medical Therapy\u003c/p\u003e \u003cp\u003ePI Principal Investigator\u003c/p\u003e \u003cp\u003eQOL Quality of Life\u003c/p\u003e \u003cp\u003eRAAS Renin Angiotensin-Aldosterone System\u003c/p\u003e \u003cp\u003eRCT Randomized Controlled Trial\u003c/p\u003e \u003cp\u003eSGLT-2 Sodium-Glucose Transporter 2\u003c/p\u003e \u003cp\u003eSGLT2i Sodium-Glucose Transporter-2 Inhibitors\u003c/p\u003e \u003cp\u003eT1DM Type-1 Diabetes Mellitus\u003c/p\u003e \u003cp\u003eTZ Trastuzumab\u003c/p\u003e \u003cp\u003eWHO World Healt Organization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eproject was financed with funds allocated by the Ministry of Health for the \u0026ldquo;Ricerca Corrente\u0026rdquo; project active at the IRCCS Fondazione San Matteo oF Pavia (ref. RC 08076023 (DE 5/D.G./998/2023)).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability\u0026nbsp;of\u0026nbsp;data\u0026nbsp;and\u0026nbsp;material\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was designed by L. Scelsi, A. Greco and G. Rizzo. The principal investigator of the study is L. Scelsi. A.Greco and V. Quagliariello were the major contributors in writing the manuscript. C. Klersy designed the statistical methods of the study. All authors participated in writing and revising the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics\u0026nbsp;approval\u0026nbsp;and\u0026nbsp;consent\u0026nbsp;to\u0026nbsp;participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Ethics Committee of Fondazione IRCCS Policlinico San Matteo has approved the study and its consent to participate (number 0008491/23). The study will be conducted in accordance with the Declaration of Helsinki. All researchers are trained and certified in Good Clinical Practices. A written informed consent will be taken from all participants.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAnchit B, et al. Anthracycline-Induced Cardiotoxicity: Causes, Mechanisms, and Prevention. Adv Exp Med Biol. 2020;1257:181\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCardinale D, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131(22):1981\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRole of cardiovascular imaging. in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC). Eur J Heart Fail. 2020;22:1504\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHurvitz SA, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018;19(1):115\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVon Minckwitz G, et al. \u003cem\u003eAPHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer.\u003c/em\u003e N. J Med. 2017;377(2):122\u0026ndash;31. Engl.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSwain SM, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, III 3 study. Lancet Oncol. 2013;14(6):461\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSlamon DJ, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoja L, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;4:CD006243.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuter TM, et al. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol. 2007;25:3859. \u0026ndash;\u0026thinsp;3865.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlexander R, Lyon et al. 2022 \u003cem\u003eESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS): Developed by the task force on cardio-oncology of the European Society of Cardiology (ESC)\u003c/em\u003e. European Heart Journal, 2022; ehac244.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMa Y, et al. Beta-blockers for the primary prevention of anthracycline-induced cardiotoxicity: a meta-analysis of randomized controlled trials. BMC Pharmacol Toxicol. 2019;20(1):18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXavier B, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol. 2013;61(23):2355\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeeta G, et al. 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Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995\u0026ndash;2008.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNassif ME, et al. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial. Circulation. 2019;140:1463\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSolomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Desai AS, Jhund PS, Belohlavek J, Chiang CE, Borleffs CJW, Comin-Colet J, Dobreanu D, Drozdz J, Fang JC, Alcocer-Gamba MA, Al Habeeb W, Han Y, Cabrera Honorio JW, Janssens SP, Katova T, Kitakaze M, Merkely B, O'Meara E, Saraiva JFK, Tereshchenko SN, Thierer J, Vaduganathan M, Vardeny O, Verma S, Pham VN, Wilder\u0026auml;ng U, Zaozerska N, Bachus E, Lindholm D, Petersson M, Langkilde AM. DELIVER Trial Committees and Investigators. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089\u0026ndash;98. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2206286\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2206286\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGongora CA, Drobni ZD, Quinaglia Araujo Costa Silva T, Zafar A, Gong J, Zlotoff DA, Gilman HK, Hartmann SE, Sama S, Nikolaidou S, Suero-Abreu GA, Jacobsen E, Abramson JS, Hochberg E, Barnes J, Armand P, Thavendiranathan P, Nohria A, Neilan TG. Sodium-Glucose Co-Transporter-2 Inhibitors and Cardiac Outcomes Among Patients Treated With Anthracyclines. 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Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double‐blind, crossover trial. Lancet Diabetes Endocrinol. 2020;8:582\u0026ndash;93. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S2213-8587(20)30162-5\u003c/span\u003e\u003cspan address=\"10.1016/S2213-8587(20)30162-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSherif F, Nagueh, et al. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J \u0026ndash; Cardiovasc Imaging. 2016;17:1321\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cardiovascular disease, Risk factors, Breast Cancer, Sodium glucose cotransporter 2 inhibitors (SGLT2i), cardiotoxicity, anthracycline, anti-HER2 therapy","lastPublishedDoi":"10.21203/rs.3.rs-4664535/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4664535/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eTheir clinical effectiveness of anthracyclines may be thwarted by the development of cardiotoxicity progressively leading to heart failure (HF) and compromising the quality of life and overall survival of breast cancer (BC) patients. Sequential therapy regimen of anthracyclines and human epidermal growth factor receptor (HER2) blocking agents, such as trastuzumab, is associated to higher risk of cardiotoxicity compared to monotherapy regimen.\u003c/p\u003e\n\u003cp\u003eSodium glucose cotransporter 2 inhibitors (SGLT2i) exert several cardiometabolic benefits in HF with reduced and preserved ejection fraction through the systemic reduction of insulin, visceral fat, chemokines and growth factors involved in cardiovascular diseases. Recent studies in preclinical models of anthracycline-induced cardiotoxicity concluded that SGLT2i are able to prevent ejection fraction reduction and myocardial inflammation and fibrosis. A very recent retrospective study indicates that SGLT2i were associated with lower rate of cardiac events among diabetic patients with cancer treated with anthracyclines. Based on this background we sought to conduct a randomized clinical trial testing SGLT2i in patients with BC treated with anthracyclines+/- trastuzumab.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e PROTECT trial is a phase II “proof of concept”, multicentre, randomized 1:1, open label, parallel-groups study, designed to evaluate if the SGLT2i dapagliflozin reduces chemotherapy-induced cardiotoxicity in participants with BC treated with (neo-) adjuvant Anthracycline-based chemotherapy +/- trastuzumab. Chemotherapy-naive patients (18-70 years) scheduled for antracycline +/- trastuzumab treatment in the (neo-)adjuvant setting for stage I-III BC will be randomized using a web-based system stratified by the use of trastuzumab to follow a chemotherapy regimen plus the SGLT2i Dapagliflozin (10 mg/die) (active group) or chemotherapy regimen plus standard of care (control group). During follow up period, patients developing asymptomatic or symptomatic systolic disfunction will be treated according to good clinical practice. From randomization, to the third, sixth, twelfth and eighteenth months, echocardiographic and cardiological visits will be performed associated to blood analysis for quantification of cardiotoxicity biomarkers, estimated glomerular filtration rate \u0026nbsp;and systemic inflammation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion:\u003c/strong\u003e PROTECT study aims to reduce cadiovascular events in BC through the oral administration of SGLT2i Dapagliflozin and to investigate on its systemic cardio-metabolic benefits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinicalTrials.gov NCT06341842 (EudraCT Number 2022-003377-28). Registered on 19 March 2024.\u003c/p\u003e","manuscriptTitle":"Dapagliflozin for the primary prevention of chemotherapy induced cardiotoxicity in breast cancer patients treated with neo-adjuvant anthracycline-based chemotherapy: design of the multi-center phase II randomized PROTECT trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-24 13:47:41","doi":"10.21203/rs.3.rs-4664535/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bac9c8ab-ec42-451d-9449-73d0d00b6980","owner":[],"postedDate":"July 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-06T07:24:05+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-24 13:47:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4664535","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4664535","identity":"rs-4664535","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}