A Phase 3, Randomized, Double-blind, Placebo-controlled Study to evaluate Efficacy and Safety of Empagliflozin in the prevention of Cardiotoxicity in Cancer patients undergoing Chemotherapy based on Anthracyclines (EMPACT study)
- Conditions
- Cardiotoxicity. The study population will consist of patients diagnosed with cancer, without history of heart failure and LV ejection fraction (EF) ≥ 50%, scheduled for high dose anthracyclines (doxorubicin ≥240 mg/m2 or epirubicin ≥360 mg/m2) as standard of care (SoC) systemic anticancer treatment.
- Registration Number
- 2024-515495-13-00
- Brief Summary
The primary objective is to evaluate the efficacy of empagliflozin 10 mg versus placebo in prevention of left ventricular (LV) dysfunction in cancer patients receiving high cumulative doses of anthracyclines
- Detailed Description
Malignant neoplasms are the second most common cause of death in Poland. Cancer mortality decreased by 27% over the past 25 years. Improved survival in cancer patients is related to several factors, such as prevention, early detection and the introduction of new chemotherapy regimens. However, the benefits of administration of anti-cancer drugs are partially limited by their adverse effects on the cardiovascular system, resulting in increased morbidity and mortality from complications of this treatment. The most serious toxic effect of chemotherapy is damage to the heart muscle leading to its failure, often referred to as 'cardiotoxicity'. This serious complication remains an unresolved clinical problem. The use of doxorubicin is associated with the development of congestive heart failure even in 48% of patients at the doxorubicin total dose of 700 mg/m2. The only drug approved for the prophylactic treatment of cardiac complications is dexrazoxane. However, it is only recommended for patients with advanced breast cancer receiving doxorubicin or epirubicin who have previously received a cumulative dose of 300 mg/m2 of doxorubicin or a cumulative epirubicin dose of 540 mg/m2, when further anthracycline therapy is required. Dexrazoxane is an expensive drug and may influence the effectiveness of chemotherapy. Routine prophylaxis of myocardial dysfunction is not currently recommended due to insufficient data from randomized clinical trials. So far, the prophylactic effects of such cardiological drugs as: angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), beta-blockers, statins and ranolazine have been studied. The results of these studies are contradictory. Therefore, at present, only symptomatic patients with decreased left ventricular ejection fraction or elevated levels of cardiac biomarkers are eligible for treatment with heart failure medications. Empagliflozin is an orally administered once-daily, highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor proven to treat patients with chronic heart failure of different aetiologies, also with preserved left ventricle systolic function. This drug also has additional nephroprotective, anti-inflammatory and metabolic effects. In recent animal studies, the cardioprotective effect of empagliflozin during the use of anthracyclines was demonstrated.
EMPACT (EMPAgliflozin in prevention of chemotherapy-related CardioToxicity) study is a randomized, multi-center, placebo-controlled, double-blind trial to evaluate efficacy of empagliflozin in prevention of left ventricular (LV) dysfunction in patients receiving high cumulative doses of anthracyclines. Diagnosed with cancer, 220 patients without history of heart failure and LV ejection fraction (EF) ≥ 50%, scheduled for high dose anthracyclines (doxorubicin ≥240 mg/m2 or epirubicin ≥540 mg/m2), will be included in the study. They will be randomized to a 10 mg of empagliflozin once daily or to matching placebo in a 1:1 ratio. The primary objective of the EMPACT study is to assess whether prophylactic SGLT-2 inhibitors may prevent a reduction in LVEF after high doses anthracyclines, as evaluated by serial echocardiography on each visit and cardiovascular magnetic resonance (CMR) performed at randomization and on its completion. The secondary composite endpoint includes: all-cause death, cardiovascular (CV) death, myocardial infarction and ischemic stroke. Additional secondary outcome measures include structural myocardial alterations assessed by CMR, decrease in GLS (global longitudinal strain) in echocardiography and changes in cardiac biomarkers. This is the first study of this type in the world, we hope that the results of this project will change the standards of management of oncological patients and contribute to the improvement of their survival and quality of life.
Recruitment & Eligibility
- Status
- Ongoing, recruiting
- Sex
- Not specified
- Target Recruitment
- 220
Eastern Cooperative Oncology Group (ECOG) performance status from 0 to 2.
≥ 18 years of age at the time of signing the informed consent.
Known neoplastic disease prior to the initiation of chemotherapy with a high dose of anthracyclines (doxorubicin ≥ 240 mg / m2 b.w. or epirubicin ≥ 360 mg / m2 b.w.)
No history of heart failure (left ventricular ejection fraction ≥ 50% as assessed by echocardiography).
Ability to give written informed consent and comply with protocol requirements.
Women of child-bearing age must have a negative serum or urine pregnancy test.
All males and females must consent to the use of effective contraception throughout the study period and after study medication is discontinued.
Women of childbearing potential (WOCBP) must meet and/or agree to all the following for contraception: a. use 2 effective methods of contraception (abstinence, IUD, oral contraceptive, or double barrier device) from informed consent and for at least 6 months after study drug discontinuation. b. agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period.
Sexually active men and their sexual partners must use effective methods of contraception from the moment they sign their informed consent to participate in the study and for at least 3 months after discontinuation of the study drug.
History of heart failure.
Presence of any disease with a life expectancy <1 year in the opinion of the Investigator.
Treatment with any SGLT-2 inhibitor for up to 3 months prior to study enrolment.
Pregnant or lactating females.
Drug or alcohol abuse.
Suspected non-compliance and irregular use of study drug.
Inability to perform cardiac MRI due to, e.g., claustrophobia, weight> 120 kg.
Left ventricle systolic dysfunction assessed by echocardiography (LVEF<50%).
Significant valve disease
Previous chemotherapy or radiation to the chest.
Symptomatic hypotension and / or SBP <100 mmHg at Visit 1 or Visit 2.
Liver disease, as determined by Aspartate aminotransferase (AST) or alanine aminotransferase (ALT), or alkaline phosphatase levels above 3 x upper limit of normal (ULN) at Visit 1.
Renal impairment, defined as eGFR <20 mL / min / 1.73 m2 or dialysis requirement, as determined at Visit 1.
History of ketoacidosis.
Gastrointestinal surgery or gastrointestinal disturbance that could impair drug absorption.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method Time to first event of left ventricular systolic dysfunction. Criterion for the diagnosis of left ventricular systolic dysfunction in echocardiography: reduction of left ventricular ejection fraction (LVEF)> 10 percentage points from baseline to <50% Time to first event of left ventricular systolic dysfunction. Criterion for the diagnosis of left ventricular systolic dysfunction in echocardiography: reduction of left ventricular ejection fraction (LVEF)> 10 percentage points from baseline to <50%
- Secondary Outcome Measures
Name Time Method Overall response rate 1. Composite secondary endpoint • all-cause death • cardiovascular death • myocardial infarction • stroke 2. Other: • decrease in GLS (global longitudinal strain) • structural myocardial alterations in CMR • changes in the concentration of biomarkers in blood samples (Troponin T, NTproBNP) Overall response rate 1. Composite secondary endpoint • all-cause death • cardiovascular death • myocardial infarction • stroke 2. Other: • decrease in GLS (global longitudinal strain) • structural myocardial alterations in CMR • changes in the concentration of biomarkers in blood samples (Troponin T, NTproBNP)
Incidence and intensity of Adverse events (AEs), including serious AEs (SAEs).Withdrawal from study drug due to AEs • Clinically relevant changes in laboratory assessments from baseline. • Clinically relevant new finding or worsening of existing condition on physical examination • Assessment of vital status. AESIs: ketoacidosis, lower limb amputation • Laboratory parameters: hematology, serum chemistry, lipids profile, and urinalysis.Physical Examination •Vital Status: SBP, DBP and pulse rate Incidence and intensity of Adverse events (AEs), including serious AEs (SAEs).Withdrawal from study drug due to AEs • Clinically relevant changes in laboratory assessments from baseline. • Clinically relevant new finding or worsening of existing condition on physical examination • Assessment of vital status. AESIs: ketoacidosis, lower limb amputation • Laboratory parameters: hematology, serum chemistry, lipids profile, and urinalysis.Physical Examination •Vital Status: SBP, DBP and pulse rate
Trial Locations
- Locations (1)
Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy
🇵🇱Warsaw, Poland
Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy🇵🇱Warsaw, PolandAnna BorowiecSite contact225463207Anna.Borowiec@nio.gov.pl