Mitigating Anthracycline-Induced Cardiac Toxicity With Dapagliflozin: A Randomized, Double-Blind, Placebo-Controlled Trial of 10 mg Daily for Four Months
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 94
- 试验地点
- 2
- 主要终点
- Left ventricular function assessed by echocardiography.
研究概览
简要总结
Anthracyclines, such as doxorubicin, are effective anticancer agents but may cause dose-dependent cardiac injury, including early changes in left ventricular function and cardiac biomarkers. Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor with established cardiovascular benefits in heart failure and potential cardioprotective effects beyond glucose lowering, including modulation of oxidative stress, inflammation, myocardial energetics and fibrotic remodeling.
This randomized, double-blind, placebo-controlled phase 2 trial evaluated whether dapagliflozin attenuates early anthracycline-associated cardiac functional and biomarker changes in adults receiving anthracycline-based chemotherapy. A total of 94 participants were randomized in a 1:1 ratio to receive dapagliflozin 10 mg orally once daily plus standard anthracycline-based chemotherapy or matching placebo plus standard anthracycline-based chemotherapy for 4 months. Ninety participants completed the 4-month follow-up and were included in complete-case analyses.
The primary echocardiographic outcome was change in left ventricular function from baseline to 4 months. Left ventricular systolic function was assessed using left ventricular ejection fraction (LVEF) as the principal systolic measure. Transmitral E/A ratio was analyzed as an exploratory filling index because it was consistently available across participants. Tissue Doppler indices and comprehensive diastolic dysfunction grading were not consistently available and were therefore not used for formal diastolic grading in the final analysis.
Secondary outcomes included cardiac troponin I, NT-proBNP, galectin-3, CA 15-3, renal and hepatic function parameters, and adverse events. Echocardiography and laboratory biomarkers were assessed at baseline and 4 months, while adverse events were monitored continuously throughout the study period.
详细描述
Chemotherapy-induced cardiotoxicity is an important concern in cancer care, particularly among patients receiving anthracycline-based chemotherapy. Anthracycline-associated myocardial injury may involve oxidative stress, mitochondrial dysfunction, inflammation, cardiomyocyte injury and myocardial remodeling. Sodium-glucose cotransporter-2 inhibitors have demonstrated cardiovascular benefits in heart failure and may also influence biological pathways relevant to anthracycline-associated cardiac injury.
This randomized, double-blind, placebo-controlled phase 2 trial was designed to evaluate the potential cardioprotective effects of dapagliflozin in adult cancer patients receiving anthracycline-based chemotherapy.
The study was conducted at Azadi Oncology Center, Duhok, Iraq, affiliated with Hawler Medical University and the Duhok General Health Directorate. The center is now known as Omed Oncology Hospital. All participants were recruited at this single site.
A total of 94 participants were randomized in a 1:1 ratio. Forty-seven participants were allocated to dapagliflozin 10 mg orally once daily plus standard anthracycline-based chemotherapy, and 47 participants were allocated to matching placebo plus standard anthracycline-based chemotherapy. Study treatment was continued for 4 months. Four participants withdrew consent during follow-up, leaving 45 participants in each group with complete baseline and 4-month follow-up data for complete-case analyses.
The primary echocardiographic outcome was change in left ventricular function from baseline to 4 months. Left ventricular systolic function was assessed using change in LVEF as the principal systolic measure. The diastolic component was assessed using transmitral E/A ratio, which was consistently available across participants and was analyzed as an exploratory filling index. Tissue Doppler indices and comprehensive ASE/EACVI-based diastolic dysfunction grading were not consistently available and were therefore not used for formal diastolic grading in the final analysis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Participants were randomized using a computer-generated block randomization sequence. Allocation concealment was maintained using sequentially numbered, sealed treatment containers prepared before participant enrollment. Dapagliflozin and placebo tablets were matched in appearance, packaging, and labeling. Participants, care providers, investigators, and outcome assessors were blinded to treatment allocation.
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed breast cancer (or other cancers as relevant to the study).
- •Age 18-70 years.
- •Planned treatment with anthracycline-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-
- •Willingness to participate and provide written informed consent.
排除标准
- •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.
研究组 & 干预措施
Dapagliflozin Arm
Participants in this arm received dapagliflozin 10 mg orally once daily in addition to their standard anthracycline-based chemotherapy regimen.
Dapagliflozin was continued daily for four months (throughout the chemotherapy treatment period).
The study evaluated its potential cardioprotective effects against anthracycline-induced cardiac toxicity using echocardiography, cardiac biomarkers, and safety monitoring.
干预措施: Dapagliflozin (Forxiga) (Drug)
Control Arm
Participants in this arm received a placebo tablet identical in appearance, dosage form, frequency, and duration to dapagliflozin.
The placebo was administered orally once daily for four months, alongside the participant's standard anthracycline-based chemotherapy regimen.
The placebo contained no active ingredients and served as the control to evaluate the cardioprotective efficacy of dapagliflozin.
干预措施: Placebo (Other)
结局指标
主要结局
Left ventricular function assessed by echocardiography.
时间窗: Evaluated at baseline and 4 months after initiation of chemotherapy.
Change in left ventricular function from baseline to 4 months was assessed using left ventricular ejection fraction (LVEF) as the principal systolic measure and transmitral E/A ratio as an exploratory filling index. Tissue Doppler indices and comprehensive diastolic dysfunction grading were not consistently available and were therefore not used for formal diastolic grading in the final analysis.
Left Ventricular Function (Systolic and Diastolic)
时间窗: Evaluated at baseline and 4 months after initiation of chemotherapy.
Echocardiographic assessment of left ventricular systolic function (LVEF) and diastolic function (E/A ratio, diastolic dysfunction grade) to detect anthracycline-induced cardiotoxicity.Measurement Tool: Echocardiography (using a 2D echocardiogram).
次要结局
- NT-proBNP Levels(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- Galectin-3 Levels(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- CA 15-3 Levels(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- Kidney Function Tests(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- Complete Blood Count (CBC)(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- Liver Function Tests (LFTs)(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- Cardiac Troponin I Levels(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- Cardiac Troponin I Levels(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- NT-proBNP Levels(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- Galectin-3 Levels(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- CA 15-3 Levels(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- Kidney Function Tests(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- Complete Blood Count (CBC)(Evaluated at baseline and 4 months after initiation of chemotherapy.)
- Liver Function Tests (LFTs)(Evaluated at baseline and 4 months after initiation of chemotherapy.)
研究者
Hakar abdulkareem saeed
Principal Investigator; PhD Candidate, Hawler Medical University; Lecturer, University of Zakho
Hawler Medical University