Prevention of Cardiac Dysfunction During Breast Cancer Therapy

NCT03760588 | Completed Phase 2 DMC

• 1 other identifier: 2017-004909-41
• Study Type: interventional
• Target: 138
• Locations: 1 country
• Sites: 4

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.

Conditions

Breast Cancer Female; Heart Failure

Keywords

LCZ696; CMR; Echocardiography; Cardio-oncology; Circulating biomarkers; Breast Cancer; Anthracyclines

Outcome Measures

Primary Outcomes (1)

• Change in left ventricular ejection fraction by cardiovascular magnetic resonance

  From randomization to end of blinded therapy (18 months)

Secondary Outcomes (7)

• 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

  From randomization to end of blinded therapy (18 months)

Other Outcomes (1)

• Incidence of adverse events and serious adverse events

  From randomization to end of blinded therapy (18 months)

Study Arms (2)

Sacubitril/valsartan

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Matched to the comparator.

Drug: Sacubitril/valsartan

Interventions

Sacubitril/valsartan DRUG

Target dose 97/103 mg b.i.d .

Also known as: Entresto®

Placebo; Sacubitril/valsartan

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Torbjorn Omland: lead
• University Hospital, Akershus: collaborator
• Oslo University Hospital: collaborator
• University Hospital of North Norway: collaborator
• St. Olavs Hospital: collaborator
• Helse Stavanger HF: collaborator
• Klinbeforsk: collaborator
• Norwegian Cancer Society: collaborator
• Novartis: collaborator

Study Sites (4)

Akershus University Hospital

Lørenskog, 1478, Norway

Location

Stavanger University Hospital

Stavanger, Norway

Location

University of North Norway

Tromsø, Norway

Location

St Olavs Hospital

Trondheim, Norway

Location

Related Publications (2)

• Omland T, Heck SL, Holte E, Lilleaasen AM, Gynnild MN, Fagerland MW, Vinje-Jakobsen V, Naes AL, Blix ES, Larsen AI, Geisler J, Gulati G, Wethal T. Sacubitril/Valsartan and Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: The PRADA II Randomized Clinical Trial. Circulation. 2025 Oct 21;152(16):1136-1145. doi: 10.1161/CIRCULATIONAHA.125.076616. Epub 2025 Aug 29.

  PMID: 40884047 DERIVED

• 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.

  PMID: 34579775 DERIVED

MeSH Terms

Conditions

Heart Failure; Breast Neoplasms

Interventions

sacubitril and valsartan sodium hydrate drug combination

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Torbjørn Omland, MD,PhD,MPH

  University Hospital, Akershus

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: Randomized, placebo controlled, double blind design

Study Record Dates

• First Submitted: November 12, 2018
• First Posted: November 30, 2018
• Study Start: January 31, 2019
• Primary Completion: September 5, 2024
• Study Completion: September 5, 2024
• Last Updated: February 12, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

NO (4)