Dapagliflozin for Prevention of Chemotherapy-Induced Cardiotoxicity: a Randomized Controlled Trial

Phase 2

Recruiting

• Conditions: Chemotherapy-induced Cardiotoxicity; Cardiotoxicity
• Interventions: Drug: Dapagliflozin (Forxiga); Other: Placebo

• Registration Number: NCT06888505
• Lead Sponsor: Hawler Medical University

Brief Summary

Brief Summary

Background \& Rationale Anthracyclines, such as doxorubicin, and trastuzumab (Herceptin) are widely used in cancer treatment but are associated with cardiotoxicity, which can lead to left ventricular dysfunction, heart failure, and long-term cardiovascular complications. Anthracycline-induced cardiotoxicity is primarily dose-dependent and often irreversible, resulting from oxidative stress, mitochondrial damage, and apoptosis of cardiomyocytes. In contrast, trastuzumab-induced cardiotoxicity is typically not dose-dependent and is often reversible, occurring due to HER2 receptor blockade in cardiac tissue, impairing myocardial repair mechanisms. The combination of anthracyclines and trastuzumab significantly increases the risk of cardiac dysfunction, necessitating effective cardioprotective strategies.

Dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor (SGLT2i), is approved for type 2 diabetes mellitus and heart failure with reduced ejection fraction (HFrEF) but has demonstrated cardioprotective benefits beyond glucose control. It exerts beneficial effects through reducing oxidative stress, inflammation, and myocardial fibrosis, making it a promising candidate for mitigating chemotherapy-induced cardiotoxicity. This study aims to evaluate Dapagliflozin's potential role in preventing cardiotoxicity associated with anthracycline and/or trastuzumab-based chemotherapy.

Study Design

This randomized, double-blind, placebo-controlled trial will enroll 100 cancer patients receiving anthracycline and/or trastuzumab-based chemotherapy. Participants will be randomly assigned in a 1:1 ratio to one of two groups:

Control Group (n=50): Standard anthracycline-based and/or trastuzumab-based chemotherapy + placebo Intervention Group (n=50): Standard anthracycline-based and/or trastuzumab-based chemotherapy + Dapagliflozin

Objectives \& Outcomes

Primary Outcome:

Change in Left Ventricular Ejection Fraction (LVEF) measured by echocardiography over a 4-month follow-up period.

Secondary Outcomes:

* Serum cardiac biomarkers: Serum Troponin I, Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), and Serum Galectin-3.

* Renal function markers: Serum Creatinine and Blood Urea Nitrogen (BUN).

* Cancer progression marker: Serum Carbohydrate Antigen 15-3 (CA 15-3).

* Incidence of Major Adverse Cardiovascular Events (MACE), including heart failure, myocardial infarction, and arrhythmias.

* Assessment of chemotherapy-related and Dapagliflozin-related adverse effects, including hypoglycemia, hypotension, electrolyte imbalances, and renal function changes.

Patient Follow-Up \& Safety Monitoring Patients will be closely monitored throughout the study with scheduled assessments at baseline, during chemotherapy, and at the 4-month follow-up.

* Cardiac function will be assessed using echocardiography and serum cardiac biomarkers.

* Renal function and metabolic status will be evaluated to ensure Dapagliflozin safety.

* Adverse events will be classified according to the Common Terminology Criteria for Adverse Events (CTCAE).

Significance of the Study By investigating Dapagliflozin's potential role in preventing anthracycline- and/or trastuzumab-induced cardiotoxicity, this study may provide a novel cardioprotective strategy for cancer patients. If successful, this intervention could improve cardiac outcomes, maintain chemotherapy efficacy, and enhance long-term quality of life.

Detailed Description

Detailed Description

Background and Rationale Chemotherapy-induced cardiotoxicity is a significant concern in cancer treatment, particularly with anthracyclines (e.g., doxorubicin) and HER2-targeted therapies like trastuzumab (Herceptin). These agents, while highly effective in treating malignancies, are associated with dose-dependent or reversible cardiac dysfunction, respectively, potentially leading to heart failure, arrhythmias, and long-term cardiovascular complications.

Anthracycline-induced cardiotoxicity is often irreversible, resulting from oxidative stress, mitochondrial dysfunction, and direct cardiomyocyte apoptosis.

Trastuzumab-induced cardiotoxicity is not dose-dependent and is often reversible, primarily occurring due to HER2 receptor blockade in cardiac tissue, impairing myocardial repair mechanisms.

The risk is highest when anthracyclines and trastuzumab are used sequentially, as seen in standard treatment protocols for HER2-positive breast cancer.

Dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor (SGLT2i), is primarily used for type 2 diabetes mellitus and heart failure with reduced ejection fraction (HFrEF). However, emerging evidence suggests cardioprotective properties independent of glucose control, including:

Reduction of oxidative stress and myocardial fibrosis Improvement of mitochondrial efficiency and myocardial metabolism Reduction in systemic and myocardial inflammation Modulation of sodium and calcium handling in cardiomyocytes Given these mechanisms, Dapagliflozin may provide a protective effect against chemotherapy-induced cardiotoxicity, preserving cardiac function without compromising cancer treatment efficacy.

Study Design and Methodology This is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the cardioprotective effects of Dapagliflozin in cancer patients undergoing anthracycline and/or trastuzumab-based chemotherapy.

Study Sites

Primary Location: Azadi Oncology Center affiliated with Hawler Medical University and the Duhok General Health Directorate .

Multicenter Design: This study may extend to additional oncology centers if necessary to achieve enrollment targets.

Study Population

Target Enrollment: 100 participants receiving anthracycline-based and/or trastuzumab-based chemotherapy.

Randomization Ratio: 1:1 (50 patients in each group). Intervention and Control Groups

Control Group (n = 50): Standard chemotherapy + placebo. Dapagliflozin Group (n = 50): Standard chemotherapy + Dapagliflozin (10 mg/day, oral) for four chemotherapy cycles.

Follow-up Period

Duration: 4 months from initiation of chemotherapy. Assessment Intervals: Baseline, during each chemotherapy cycle, and at study completion.

Primary and Secondary Study Endpoints Primary Endpoint

Change in Left Ventricular Ejection Fraction (LVEF) from baseline to post-treatment, measured by echocardiography.

Secondary Endpoints

Cardiac Biomarkers: Serum Troponin I, Serum NT-proBNP, Serum Galectin-3. Cancer Progression: Serum CA 15-3 as a marker of tumor burden. Renal Function: Serum Creatinine, Blood Urea Nitrogen (BUN), estimated glomerular filtration rate (eGFR).

Adverse Events: Incidence of chemotherapy-related and Dapagliflozin-related adverse effects, graded using Common Terminology Criteria for Adverse Events (CTCAE).

Safety and Monitoring Plan Cardiotoxicity Surveillance

Echocardiography: Baseline, mid-treatment, and end of study. Biomarkers: Serial assessment of Troponin I, NT-proBNP, and Galectin-3. Electrocardiogram (ECG): To detect subclinical arrhythmias and QT prolongation. Monitoring for Dapagliflozin-Related Adverse Events

Hypoglycemia, hypotension, and dehydration risks will be evaluated. Renal function will be closely monitored to assess potential nephrotoxicity. Urinary tract infections (UTIs) and ketoacidosis screening will be conducted. Statistical Analysis Plan Sample Size Calculation

A total of 100 patients (50 per group) provides 80% power to detect a significant difference in LVEF decline, assuming an estimated effect size of 10% reduction in cardiotoxicity rates with Dapagliflozin.

Planned Statistical Methods

Descriptive statistics for baseline demographic and clinical characteristics. Comparative analysis using paired t-tests, Wilcoxon signed-rank tests (for non-parametric data), and ANOVA for repeated measures.

Multivariate regression models to control for confounding variables, such as age, baseline cardiac function, and chemotherapy regimen.

Kaplan-Meier survival analysis (if applicable) to evaluate the time-to-event for major adverse cardiac events.

Handling of Missing Data

Multiple imputation techniques will be used to address missing data, ensuring robustness of findings.

Ethical Considerations and Compliance Ethical Approval: The study will adhere to the guidelines of Hawler Medical University's Ethics Committee and the General Directorate of Health.

Informed Consent: Written informed consent will be obtained from all participants before enrollment.

Confidentiality: Patient data will be de-identified and stored securely, ensuring compliance with Good Clinical Practice (GCP) and international research ethics standards.

Ongoing Safety Monitoring: An independent Data and Safety Monitoring Board (DSMB) will oversee interim analyses and evaluate safety data.

Potential Impact and Future Directions

If Dapagliflozin proves effective in mitigating chemotherapy-induced cardiotoxicity, this study could:

Introduce SGLT2 inhibitors as a cardioprotective strategy in cancer patients receiving cardiotoxic chemotherapy.

Improve clinical decision-making for oncologists and cardiologists in managing high-risk patients.

Open pathways for further research into cardioprotective agents beyond traditional heart failure medications.

This study represents a significant advancement in cardio-oncology by integrating a widely available, well-tolerated drug into chemotherapy regimens to potentially improve patient survival and quality of life.

Study Timeline

• Study Start: 2024-09-01
• Status Verified: 2025-03
• Study First Submitted: 2025-03-03
• Study First Submitted QC: 2025-03-20
• Last Update Submitted: 2025-03-20
• Study First Posted: 2025-03-21
• Last Update Posted: 2025-03-21
• Primary Completion: 2025-06-01
• Study Completion: 2025-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• Histologically confirmed breast cancer (or other cancers as relevant to the study).
• Age 18-70 years.
• Planned treatment with anthracycline-based and/or trastuzumab-based chemotherapy.
• Normal kidney function, defined as serum creatinine 0.6-1.2 mg/dL.
• Normal liver function, defined as ALT and AST 10-40 U/L.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Willingness to participate and provide written informed consent.

Exclusion Criteria

• History of symptomatic heart failure (NYHA class III-IV) or prior anthracycline-related cardiac dysfunction.
• Previous use of Dapagliflozin.
• Pregnancy or breastfeeding.
• Severe renal impairment (eGFR < 30 mL/min/1.73m²).
• Uncontrolled diabetes mellitus (HbA1c > 9%).
• Active or recurrent urinary tract infections (UTIs) within the last 6 months.
• Known hypersensitivity to Dapagliflozin or related compounds.
• Concurrent participation in another clinical trial investigating cardioprotective agents.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dapagliflozin Arm	Dapagliflozin (Forxiga)	Participants in this arm will receive Dapagliflozin 10 mg tablets, administered orally once daily, alongside their standard chemotherapy regimen. Dapagliflozin will be continued for four chemotherapy cycles, following the same schedule as chemotherapy administration. The study will assess its cardioprotective effects against chemotherapy-induced cardiac toxicity.
Control Arm	Placebo	Participants in this arm will receive a placebo tablet identical in appearance, dosage form, frequency, and duration to the Dapagliflozin treatment. The placebo will be administered orally once daily alongside the participant's standard chemotherapy regimen for four chemotherapy cycles. The placebo contains no active ingredients and serves as a control to evaluate the cardioprotective efficacy of Dapagliflozin.

Primary Outcome Measures

Name	Time	Method
Left Ventricular Ejection Fraction (LVEF)	Evaluated at baseline and after completion of chemotherapy (approximately after 26 weeks).	Echocardiographic assessment of Left Ventricular Ejection Fraction (LVEF) to evaluate cardiac function and monitor the potential cardioprotective effects of Dapagliflozin in chemotherapy-induced cardiotoxicity.; Measurement Tool: Echocardiography (using a 2D echocardiogram).

Secondary Outcome Measures

Name	Time	Method
Cardiac Troponin I Levels	Assessed at baseline and after chemotherapy (approximately after 26 weeks).	Measurement of serum Troponin I levels to assess myocardial injury and cardiac stress in patients undergoing chemotherapy.; Measurement Tool: Chemiluminescent Immunoassay (CLIA).
NT-proBNP Levels	Assessed at baseline and after chemotherapy (approximately after 26 weeks).	Measurement of serum NT-proBNP levels as an indicator of cardiac stress and dysfunction.; Measurement Tool: Chemiluminescent Immunoassay (CLIA).
Galectin-3 Levels	Assessed at baseline and after chemotherapy (approximately after 26 weeks).	Measurement of serum Galectin-3 levels to evaluate its role in oxidative stress, apoptosis, and tissue remodeling.; Measurement Tool: Enzyme-Linked Immunosorbent Assay (ELISA).
CA 15-3 Levels	Assessed at baseline and after chemotherapy (approximately after 26 weeks).	Measurement of serum CA 15-3 levels to monitor breast cancer cell proliferation.; Measurement Tool: Chemiluminescent immunoassay
Kidney Function Tests	Time Frame: Assessed at baseline and after chemotherapy (approximately after 26 weeks).	Monitoring of serum creatinine and blood urea nitrogen (BUN) to assess renal function and potential nephrotoxicity related to chemotherapy or Dapagliflozin.; Measurement Tool: Automated Biochemical Analyzer for serum creatinine and BUN.
Complete Blood Count (CBC)	Time Frame: Assessed at baseline and after chemotherapy (approximately after 26 weeks).	Monitoring of hematological parameters (e.g., hemoglobin, white blood cells, platelets) to assess overall health, immune function, and tolerability of treatment.; Measurement Tool: Automated Hematology Analyzer (Beckman Coulter analyzers).
Liver Function Tests (LFTs)	Time Frame: Assessed at baseline and after chemotherapy (approximately after 26 weeks).	Monitoring of liver enzymes (e.g., ALT, AST, alkaline phosphatase, bilirubin) to assess liver function and potential hepatotoxicity due to chemotherapy or Dapagliflozin.; Measurement Tool: Chemiluminescent Immunoassay

Trial Locations

Locations (1)

Azadi Oncology Centre; 🇮🇶 Duhok, Iraq