Prevention of Cardiac Dysfunction During Breast Cancer Therapy (PRADAII)

PRevention of cArdiac Dysfunction During Adjuvant Breast Cancer Therapy: A Randomized, Placebo-controlled, Multicenter Trial

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Breast Cancer Female
• Intervention / Treatment: Drug: Sacubitril/valsartan

• Study Type: Interventional
• Enrollment (Actual): 138
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Lørenskog, Norway, 1478
    • Akershus University Hospital
  • Stavanger, Norway
    • Stavanger University Hospital
  • Tromsø, Norway
    • University of North Norway
  • Trondheim, Norway
    • St Olavs hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sacubitril/valsartan; 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.	Drug: Sacubitril/valsartan; Target dose 97/103 mg b.i.d .; Other Names: Entresto®
Placebo Comparator: Placebo; Matched to the comparator.	Drug: Sacubitril/valsartan; Target dose 97/103 mg b.i.d .; Other Names: Entresto®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in left ventricular ejection fraction by cardiovascular magnetic resonance	From randomization to end of blinded therapy (18 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
Change in left ventricular end-systolic volume measured by 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	An absolute reduction in LVEF ≥ 5% by CMR or a relative percentage reduction of global longitudinal strain (GLS) > 15%	From randomization to end of blinded therapy (18 months)
Incidence of cardiotoxicity measured by CMR or echocardiography	Absolute reduction in LVEF ≥ 10% to a value below 50% as measured either by CMR or Echocardiography, or incidence of clinical heart failure	From randomization to end of blinded therapy (18 months)
Change in circulating cardiac biomarkers	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)	From randomization to end of blinded therapy (18 months)

Other Outcome Measures

Outcome Measure	Time Frame
Incidence of adverse events and serious adverse events	From randomization to end of blinded therapy (18 months)

Collaborators and Investigators

• Sponsor: Torbjorn Omland
• Collaborators: Oslo University Hospital; Novartis; University Hospital of North Norway; Helse Stavanger HF; St. Olavs Hospital; University Hospital, Akershus; Norwegian Cancer Society; Klinbeforsk
• Investigators: Principal Investigator: Torbjørn Omland, MD,PhD,MPH, University Hospital, Akershus

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2019
• Primary Completion (Actual): September 5, 2024
• Study Completion (Actual): September 5, 2024

Study Registration Dates

• First Submitted: November 12, 2018
• First Submitted That Met QC Criteria: November 29, 2018
• First Posted (Actual): November 30, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 10, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Breast Cancer; Echocardiography; Anthracyclines; CMR; Cardio-oncology; LCZ696; Circulating biomarkers
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: 2017-004909-41

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No