Clinical trial NCT06711185: Effect of DAPAglifozin on MYOcardial Remodeling of Breast CANCER Patients Treated with Anthracycline Based Chemotherapy
Official title: Effect of DAPAglifozin on MYOcardial Remodeling of Breast CANCER Patients Treated with Anthracycline Based Chemotherapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Dapagliflozin
Anthracyclines
chemotherapy induced cardiomyopathy
Lead sponsor: University of Campinas, Brazil
Sponsor class: OTHER
First posted: 2024-12-02
Enrollment: 80
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Prospective, randomized, double-blind, controlled clinical trial to compare the effect of 9 months of treatment with dapagliflozin vs. placebo on anthracycline-induced cardiotoxicity in patients with breast cancer.

Detailed description: Anthracycline-based chemotherapy is the standard treatment for several common cancer types, including breast cancer, lymphoma and sarcoma. However, within 12 months, up to 20% of the 1,000,000 patients worldwide treated with anthracyclines each year have a significant reduction in left ventricular ejection fraction (LVEF), leading to a three to six-fold higher rates of incident heart failure. Once established, anthracycline-induced heart failure carries a poor prognosis with a 2-year survival of only 40%.

Consistent data have established that sodium-glucose transport protein 2 (SGLT2) inhibitors reduce incident heart failure in patients without cancer. There is biological plausibility and animal data to support the hypothesis central to this proposal that SGLT2 will reduce anthracycline-induced cardiotoxicity (AIC). Anthracyclines increase inflammatory cytokines, increase cell death, increase myocardial fibrosis leading to a decrease in the LVEF. In animal and cellular models, SGLT2 inhibitors reduce inflammatory cytokines, increase cell viability, reduce myocardial fibrosis and prevent the decline in LVEF with anthracyclines. There are no preliminary clinical data testing whether SGLT2 inhibitors are cardioprotective during treatment with anthracyclines among patients with breast cancer.

We propose a single-center randomized double-blind placebo-controlled trial, in 80 patients, who will be randomized 1:1 to dapagliflozin 10mg/daily or placebo to determine whether dapagliflozin started prior to anthracyclines reduces AIC in patients breast cancer. The endpoint AIC will be defined as a 6% difference in the change in LVEF between groups within the first 9 months after the start of therapy. LVEF will be measured using the gold-standard, cardiac magnetic resonance (CMR), performed in an established core clinical trials laboratory by expert researchers.

Participants will be recruited over 2 years from a large volume academic oncology network. Myocardial fibrosis is a key intermediary that occurs prior to the development of LV dysfunction. CMR is the gold-standard imaging technique for fibrosis; therefore, to test whether the sub-acute development of myocardial fibrosis can predict the late occurrence of AIC and whether dapagliflozin reduces myocardial fibrosis, we also propose measuring the extent of fibrosis at baseline and 9 months.

We hypothesize that dapagliflozin will attenuate the anthracycline-induced increase in myocardial fibrosis. Secondary and exploratory outcomes will include significant changes in myocardial perfusion assessed by stress CMR, flow-mediated vasodilatation assessed by ultrasound, exercise capacity assessed by cardiopulmonary exercise test, and biomarkers.

If successful, this study will show that dapagliflozin started prior to anthracyclines will preserve the LVEF and will attenuate the anthracycline-induced cardiovascular toxicity.

Eligibility criteria: Inclusion Criteria:

* Female
* Over 18 years old
* Breast cancer
* Chemotherapy as treatment planning and programmed cumulative dose equivalent to 240 mg/m2 of doxorubicin.

Exclusion Criteria:

* Contraindications for performing CMR exams, such as patients with pacemakers or cardiac defibrillators of any type, metal clips for cerebral aneurysms, cochlear implants, and ventriculoperitoneal bypass valves.
* Inability to perform CMR due to claustrophobia.
* Renal failure with a glomerular filtration rate \< 30 ml/min/1.73 m2.
* Previous history of myocardial infarction, congestive heart failure, or myocardial revascularization, whether percutaneous or surgical.
* Previous history of significant valvular heart disease.
* Previous history of cardiomyopathies.

Primary outcomes:
measure: Change in left ventricle ejection fraction
timeFrame: 36 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Campinas
country: Brazil
facility: Hospital de Clinicas da Unicamp
state: SP
Study officials:
affiliation: University of Campinas, Brazil
name: Otavio Rizzi Coelho-Filho, MD, MPH, PhD
role: PRINCIPAL_INVESTIGATOR
References: