Clinical trial NCT03760588: Prevention of Cardiac Dysfunction During Breast Cancer Therapy
Official title: PRevention of cArdiac Dysfunction During Adjuvant Breast Cancer Therapy: A Randomized, Placebo-controlled, Multicenter Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer Female
Heart Failure
Keywords: LCZ696
CMR
Echocardiography
Cardio-oncology
Circulating biomarkers
Breast Cancer
Anthracyclines
Lead sponsor: University Hospital, Akershus
Sponsor class: OTHER
Collaborators: name: University Hospital, Akershus
name: Oslo University Hospital
name: University Hospital of North Norway
name: St. Olavs Hospital
name: Helse Stavanger HF
name: Klinbeforsk
name: Norwegian Cancer Society
name: Novartis
First posted: 2018-11-30
Enrollment: 138
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, placebo controlled, double blind design
Primary purpose: PREVENTION

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.


Eligibility criteria: 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

Primary outcomes:
measure: Change in left ventricular ejection fraction by cardiovascular magnetic resonance
timeFrame: From randomization to end of blinded therapy (18 months)
Secondary outcomes:
measure: Change in left ventricular ejection fraction by echocardiography
timeFrame: From randomization to end of blinded therapy (18 months)
measure: Change in left ventricular systolic global longitudinal strain by echocardiography
timeFrame: From randomization to end of blinded therapy (18 months)
measure: Change in left ventricular systolic global longitudinal strain by cardiovascular magnetic resonance (CMR)
timeFrame: From randomization to end of blinded therapy (18 months)
measure: Change in left ventricular end-systolic volume measured by CMR
timeFrame: From randomization to end of blinded therapy (18 months)
measure: Incidence of a significant reduction in left ventricular systolic function measured by CMR or echocardiography
timeFrame: From randomization to end of blinded therapy (18 months)
measure: Incidence of cardiotoxicity measured by CMR or echocardiography
timeFrame: From randomization to end of blinded therapy (18 months)
measure: Change in circulating cardiac biomarkers
timeFrame: From randomization to end of blinded therapy (18 months)
Other outcomes:
measure: Incidence of adverse events and serious adverse events
timeFrame: From randomization to end of blinded therapy (18 months)
Locations:
city: Lørenskog
country: Norway
facility: Akershus University Hospital
city: Stavanger
country: Norway
facility: Stavanger University Hospital
city: Tromsø
country: Norway
facility: University of North Norway
city: Trondheim
country: Norway
facility: St Olavs Hospital
Study officials:
affiliation: University Hospital, Akershus
name: Torbjørn Omland, MD,PhD,MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mecinaj A, Gulati G, Heck SL, Holte E, Fagerland MW, Larsen AI, Blix ES, Geisler J, Wethal T, Omland T. Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial. Cardiooncology. 2021 Sep 27;7(1):33. doi: 10.1186/s40959-021-00115-w.