Prevention of Cardiac Dysfunction During Breast Cancer Therapy (PRADAII)

Torbjorn Omland

Status and phase: Completed; Phase 2

Conditions: Breast Cancer Female; Heart Failure

Treatments: Drug: Sacubitril/valsartan

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03760588

2017-004909-41

Details and patient eligibility

About

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.

Enrollment: 138 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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138 participants in 2 patient groups, including a placebo group

Sacubitril/valsartan

Experimental group

Description:

Sacubitril/valsartan (target dose 97/103 mg b.i.d.) and matching placebo will be provided orally in a 1:1 parallel fashion stratified by study site and for planned treatment with trastuzumab. Dose titration will be performed as follows: Sacubitril/valsartan 24/26 mg b.i.d. will be administered for 2-4 weeks and provided blood pressure \> 100 mmHg, no symptoms of hypotension or other side effects or adverse events (AE), followed by sacubitril/valsartan 49/51 mg b.i.d. for 2-4 weeks. Provided blood pressure \> 100 mmHg, no symptoms of hypotension or other side effects or AE a further uptitration to sacubitril/valsartan 97/103 mg b.i.d. will be performed.

Treatment:

Drug: Sacubitril/valsartan

Placebo

Placebo Comparator group

Description:

Matched to the comparator.

Treatment:

Drug: Sacubitril/valsartan