Breast Cancer, Heart Failure
Conditions
Keywords
breast cancer, heart failure, ejection fraction, anthracyclines
Brief summary
The purpose of this study is to evaluate the effect of dapagliflozin on the incidence of cancer therapeutics-related cardiac dysfunction in patients with breast cancer receiving anthracycline treatment.
Detailed description
This is a multicentre, randomised, double-blind, placebo-controlled phase III study, evaluating the effect of dapagliflozin versus placebo on prevention of cardiotoxicity in breast cancer patients undergoing anthracycline-based chemotherapy.
Interventions
DRUGDapagliflozin
10 mg tablet q.d
DRUGPlacebo
tablet matching dapagliflozin 10 mg q.d
Sponsors
4th Military Clinical Hospital with Polyclinic, Poland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age \> 18 years and \< 80 years. * Diagnosis of invasive breast cancer \[stage I-III\] and planned anthracycline treatment within 60 days. * Signed Informed Consent to participate in the study.
Exclusion criteria
* Urinary tract infection with the need for treatment with an antibiotic 48 hours before the scheduled start of anthracycline treatment. * Recognised heart failure or symptoms which, in the opinion of the investigator may be a symptom of undiagnosed heart failure. * Left ventricular ejection fraction \< 50% at the time of the screening. * Severe valvular heart disease. * A history of clinically significant arrhythmia, including atrial fibrillation regardless of type (at discretion of the investigator). * A history of stroke. * Cardiomyopathy: congenital, post-inflammatory, toxic, infiltrative (e.g. amyloidosis, sarcoidosis, haemochromatosis), postnatal or hypertrophic. * Pulmonary hypertension. * Uncontrolled arterial pressure or systolic pressure \< 80 mmHg at screening (at the discretion of the investigator). * BMI \> 40 kg/m2. * Diagnosed type 1 or type 2 diabetes or fasting glucose ≥ 126 mg/dl or HbA1C ≥ 6,5% (48 mmol/mol). * Pregnancy or breastfeeding. * Lack of compliance to use highly effective method of birth control. * Expected or possible treatment with epirubicin or liposomal doxorubicin within 12 months. * Taking another study drug or drugs from the group of SGLT2 inhibitors up to 6 months before the screening visit. * Taking semaglutide, liraglutide and metformin during the 30 days preceding the screening visit. * eGFR \< 25 ml/min/1.73m2 according to CKD EPI. * Life expectancy \< 12 months or cancer disease stage IV according to the TNM classification. * Alanine transaminase or aspartate transaminase levels above 2.5 times the local norm. * Anemia with Hemoglobin \< 9 g/dl. * Kidney failure \> G2 (according to KDIGO classification). * Liver disorders, Child-Pugh score \> 4. * Known, active infections with HIV, HBV, HCV, tuberculosis. * Any other condition which, in the opinion of the investigator, makes it impossible to fulfill the requirements for participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary efficacy composite endpoint (cancer therapeutics related cardiac dysfunction) at 12 months. | 12 months | Incidence of cancer therapeutics related cardiac dysfunction defined as: 1. the appearance of heart failure symptoms (NYHA class I-IV) due to an impairment of heart function or structure within 12 months; or 2. asymptomatic decrease in left ventricular ejection fraction \> 10% after 12 months; or 3. asymptomatic decrease in left ventricular ejection fraction \< 10% but up to 40-49% after 12 months; or 4. asymptomatic decrease in global left ventricular longitudinal strain \>15% after 12 months; or 5. asymptomatic increase in biomarkers (troponin I \> upper reference limit (99th centile) and increase of at least 30% from pre-treatment concentration or NTproBNP \> 125 pg/ml and increase of at least 30% from baseline) after 12 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in NTproBNP levels at 6 and 12 months. | 6 and 12 months | Secondary. |
| Secondary efficacy composite endpoint (cancer therapeutics related cardiac dysfunction) at 6 months. | 6 months | Incidence of cancer therapeutics related cardiac dysfunction defined as: 1. emergence of heart failure symptoms (NYHA class I-IV) due to impaired cardiac function or structure at 6 months; or 2. decrease LVEF \> 10% after 6 months; or 3. decrease LVEF \< 10% but to a value of 40-49% after 6 months; or 4. a decrease in global longitudinal strain of \> 15% after 6 months; or 5. asymptomatic increase in biomarkers (troponin I \> upper reference limit (99th centile) and an increase of at least 30% from pre-treatment concentration or NTproBNP \>125pg/ml and an increase of at least 30% from baseline) after 6 months. |
| Change in left ventricular ejection fraction at 6 and 12 months. | 6 and 12 months | Assessed by transthoracic echocardiography. |
| Change in left ventricular diastolic function at 6 and 12 months. | 6 and 12 months | Assessed as the ratio of E/E', i.e. maximum mitral annular inflow velocity during the rapid ventricular filling phase, to maximum mitral annular motion velocity by tissue Doppler during the rapid ventricular filling phase. |
| Occurrence of ionic disorders. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint, defined as occurrence of: * Sodium plasma level of \>150 mmol/L * Potassium plasma level of \>6.0 mmol/L |
| Quality of life at 6 and 12 months assessed using the five-dimensional EQ-5D questionnaire. | 6 and 12 months | The EQ-5D questionnaire consists of two parts: descriptive one, which measures five dimensions of health (mobility, self care, usual activities, pain & discomfort, anxiety & depression) and EQ Visual Analogue Scale numbered from 0 to 100, where higher value indicate better self-reported health. |
| Occurrence of death from any cause. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint. |
| Composite endpoint of cardiovascular events. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint. Occurrence of death from cardiovascular causes, nonfatal myocardial infarction, non-fatal stroke. |
| Change in Troponin I after 6 and 12 months. | 6 and 12 months | Secondary. |
| Occurrence of non-fatal myocardial infarction. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint. |
| Occurrence of non-fatal stroke. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint. |
| Occurrence of hypoglycaemia. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint. Hypoglycaemia is defined as serum glucose level 3 mmol/l (\<54 mg/dl) with coexisting related clinical symptoms. |
| Occurrence of renal failure. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint. Defined as: * sustained (i.e. \>28 days) decline in eGFR ≥50% AND/OR * reaching end stage renal disease defined as: * sustained (i.e. \>28 days) eGFR \<15 mL/min/1.73 m2 * chronic dialysis treatment * receiving a renal transplant AND/OR * renal death |
| Occurrence of hypersensitivity to investigated drug. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint. Any unexpected adverse drug reaction (UADR). |
| Occurrence of allergic reactions. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint. Any hypersensitivity reaction with proven immunological pathomechanism (types I-IV according to Coombs and Gell). |
| Occurrence of infection. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint. Any symptomatic infection (viral, bacterial or fungal). |
| Occurrence of death from any cardiovascular reasons. | 13 months (additional 1 month of safety follow-up after end of treatment). | Secondary safety endpoint. |
Countries
Poland
Contacts
Primary ContactBartosz Krakowiak, PhD, MD
Outcome results
None listed