Breast Cancer Female, Heart Failure
Conditions
Keywords
LCZ696, CMR, Echocardiography, Cardio-oncology, Circulating biomarkers, Breast Cancer, Anthracyclines
Brief summary
Breast cancer is the most common cancer among women. The modern post-surgery treatment with chemotherapy, immunotherapy, radiation and hormone therapy has improved the overall 5-years survival drastically. However, an unwanted effect of the post-surgery treatment is its potentially deleterious effect on the heart resulting in cardiac dysfunction. Angiotensin antagonists are used as part of the heart failure treatment. In smaller studies angiotensin antagonists have shown to have a cardioprotective effect during breast cancer treatment. Sacubitril/valsartan is a potent drug that in addition to an angiotensin antagonist contains a neprilysin inhibitor. Sacubitril/valsartan has proved to be superior to enalapril in chronic heart failure. In this randomized placebo controlled double blind trial we hypothesize that sacubitril/valsartan used concomitantly during anthracycline containing chemotherapy for breast cancer treatment prevents cardiac dysfunction as measured by cardiac magnetic resonance imaging (CMR). PRADA II is a Norwegian multicenter trial intending to recruit 214 patients and follow them for 18 months with CMR, cardiac ultrasound, blood samples, functional capacity tests and health related quality of life questionnaires.
Interventions
DRUGSacubitril/valsartan
Target dose 97/103 mg b.i.d .
Sponsors
University Hospital, Akershus
Oslo University Hospital
University Hospital of North Norway
St. Olavs Hospital
Helse Stavanger HF
Klinbeforsk
Norwegian Cancer Society
Novartis
Torbjorn Omland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized, placebo controlled, double blind design
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women with histological evidence of invasive early breast cancer scheduled for adjuvant therapy with anti-cancer regimens that include anthracyclines * Eastern Cooperative Oncology Group performance status 0-1 * Sinus rhythm
Exclusion criteria
* Age \<18 years * Renal failure, i.e. serum creatinine greater than 133 mol/L (1.5mg/dL) or estimated glomerular filtration rate (eGFR) \< 45 mL/min/1.73m2 * Hyperkalemia, i.e. serum potassium greater than 5.0 mmol/L * Systolic blood pressure \< 100 mgHg * Uncontrolled hypertension * Acute myocardial infarction within the last three months * Contraindication to ACEI or ARB or sacubitril/valsartan, including previous hypersensitivity reaction, angioedema and renal artery stenosis * ACEI, ARB, aldosterone antagonist or sacubitril/valsartan use within 4 weeks of study start * Clear indication for ACEI, ARB, aldosterone antagonist or sacubitril/valsartan therapy, including symptomatic heart failure * History of hemodynamically significant valvular disease * Active liver disease, i.e. alanine aminotransferase or aspartate aminotransferase greater than 1.5 times the upper limit of normal * Participation in another pharmaceutical clinical trial of an investigational medicinal product (IMP) less than 4 weeks prior to inclusion or use of other investigational drugs within 5 halflives of enrollment, whichever is longer * Conditions that would affect the participants to comply with the study protocol as psychiatric or mental disorders, alcohol abuse or other substance abuse, suspected poor drug compliance, language barriers or other factors * Contraindication or inability to undergo CMR examination * Fertile women with inadequate birth control, pregnancy, and/or breastfeeding. Adequate contraception includes oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device or system, vasectomized partner or sexual abstinence. Fertile women are defined as following menarche and until becoming postmenopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause * Life expectancy \< 12 months
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in left ventricular ejection fraction by cardiovascular magnetic resonance | From randomization to end of blinded therapy (18 months) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in left ventricular ejection fraction by echocardiography | From randomization to end of blinded therapy (18 months) | — |
| Change in left ventricular systolic global longitudinal strain by echocardiography | From randomization to end of blinded therapy (18 months) | — |
| Change in left ventricular systolic global longitudinal strain by cardiovascular magnetic resonance (CMR) | From randomization to end of blinded therapy (18 months) | — |
| Incidence of a significant reduction in left ventricular systolic function measured by CMR or echocardiography | From randomization to end of blinded therapy (18 months) | An absolute reduction in LVEF ≥ 5% by CMR or a relative percentage reduction of global longitudinal strain (GLS) \> 15% |
| Incidence of cardiotoxicity measured by CMR or echocardiography | From randomization to end of blinded therapy (18 months) | Absolute reduction in LVEF ≥ 10% to a value below 50% as measured either by CMR or Echocardiography, or incidence of clinical heart failure |
| Change in circulating cardiac biomarkers | From randomization to end of blinded therapy (18 months) | Cardiac biomarkers defined as cardiac troponins I and T measured by high sensitivity assays (hs-TnI and hs-TnT) and N-terminal proB-type natriuretic peptide (NT-proBNP) |
| Change in left ventricular end-systolic volume measured by CMR | From randomization to end of blinded therapy (18 months) | — |
Other
| Measure | Time frame |
|---|---|
| Incidence of adverse events and serious adverse events | From randomization to end of blinded therapy (18 months) |
Countries
Norway
Outcome results
None listed