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Prevention of Cardiac Dysfunction During Breast Cancer Therapy (PRADAII)

Primary Purpose

Breast Cancer Female, Heart Failure

Status

Active

Phase

Phase 2

Locations

Norway

Study Type

Interventional

Intervention

Sacubitril/valsartan

About this trial

This is an interventional prevention trial for Breast Cancer Female focused on measuring LCZ696, CMR, Echocardiography, Cardio-oncology, Circulating biomarkers, Breast Cancer, Anthracyclines

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept 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

Sites / Locations

Akershus University Hospital
Stavanger University Hospital
University of North Norway
St Olavs Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Sacubitril/valsartan

Placebo

Arm 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.

Matched to the comparator.

Outcomes

Primary Outcome Measures

Change in left ventricular ejection fraction by cardiovascular magnetic resonance

Secondary Outcome Measures

Change in left ventricular ejection fraction by echocardiography

Change in left ventricular systolic global longitudinal strain by echocardiography

Change in left ventricular systolic global longitudinal strain by cardiovascular magnetic resonance (CMR)

Change in left ventricular end-systolic volume measured by CMR

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%

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

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)

Full Information

NCT ID

NCT03760588

First Posted

November 12, 2018

Last Updated

March 16, 2023

Sponsor

Torbjorn Omland

Collaborators

University Hospital, Akershus, Oslo University Hospital, University Hospital of North Norway, St. Olavs Hospital, Helse Stavanger HF, Klinbeforsk, Norwegian Cancer Society, Novartis

1. Study Identification

Unique Protocol Identification Number

NCT03760588

Brief Title

Prevention of Cardiac Dysfunction During Breast Cancer Therapy

Acronym

PRADAII

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

January 14, 2019 (Actual)

Primary Completion Date

September 14, 2024 (Anticipated)

Study Completion Date

September 14, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Torbjorn Omland

Collaborators

University Hospital, Akershus, Oslo University Hospital, University Hospital of North Norway, St. Olavs Hospital, Helse Stavanger HF, Klinbeforsk, Norwegian Cancer Society, Novartis

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Cancer Female, Heart Failure

Keywords

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

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Randomized, placebo controlled, double blind design

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

214 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Sacubitril/valsartan

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Matched to the comparator.

Intervention Type

Drug

Intervention Name(s)

Sacubitril/valsartan

Other Intervention Name(s)

Entresto®

Intervention Description

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

Primary Outcome Measure Information:

Title

Change in left ventricular ejection fraction by cardiovascular magnetic resonance

Time Frame