Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA)

Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: A Randomized, Placebo-controlled, 2x2 Factorial, Double Blind Trial of Candesartan and Metoprolol

Women treated for breast cancer are at increased risk for cardiovascular disease, including heart failure. In this study, by using magnetic resonance imaging (MRI), the investigators want to assess if heart failure medications such as beta blockers and angiotensin receptor blockers can prevent cardiac dysfunction during early breast cancer therapy.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Breast Cancer
• Intervention / Treatment: Drug: Metoprolol; Drug: Placebo; Drug: Placebo; Drug: Candesartan

Detailed Description

Breast cancer is one of the most common malignancies in women. Recent progress in the detection and treatment of breast cancer has resulted in survival gains, but a consequence of therapeutic advances is an increasing number of long-term survivors who may be at risk for development of cardiovascular disease. Several studies suggest that women treated for breast cancer may be at increased risk for cardiovascular disease, the probable causes being multi-factorial. Importantly, therapies for breast cancer, including radiotherapy, anti-HER-2 regimens and certain chemotherapeutic regimens, may increase the risk of subsequent cardiovascular disease, including atherosclerotic disease, left ventricular dysfunction, and heart failure.

In the current study we propose to undertake a randomized, placebo-controlled, 2x2 factorial, double-blind trial to assess whether left ventricular dysfunction and/or injury is preventable, completely or partly, by the concomitant administration of the angiotensin receptor blocker (ARB), candesartan, and the beta blocker, metoprolol, during postoperative chemotherapy and radiotherapy.

The proposed study addresses an important clinical problem in a large patient group. Thus, the possibility of preventing cardiovascular side effects of contemporary therapy for breast cancer is important both clinically and scientifically.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Lørenskog, Norway, 1478
    • Akershus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Women aged 18-70 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Serum creatinine < 140 μmol/L or estimated creatinine clearance > 60 ml/min (using the modification of diet and renal disease (MDRD) formula)
• Systolic blood pressure >= 110 mgHg and < 170 mmHg
• LVEF >= 50%

Exclusion Criteria:

• Hypotension, defined as systolic blood pressure < 110 mmHg
• Bradycardia, defined as heart rate < 50 b.p.m.
• Prior anthracycline chemotherapy regimen
• Prior malignancy requiring chemotherapy or radiotherapy
• Symptomatic heart failure
• Systolic dysfunction (LVEF < 50%)
• Clinically significant coronary artery disease, valvular heart disease, significant arrhythmias, or conduction delays.
• Uncontrolled arterial hypertension defined as systolic blood pressure > 170 mm Hg
• Treatment with ACEI, ARB or beta-blocker within the last 4 weeks prior to study start
• Intolerance to ACEI, ARB or beta-blocker
• Uncontrolled concomitant serious illness
• Pregnancy or breastfeeding
• Active abuse of drugs or alcohol
• Suspected poor compliance
• Inability to tolerate the MRI scanning protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Metoprolol; Tablet, target dose 100 mg once daily	Drug: Metoprolol; Tablet, target dose 100 mg once daily
PLACEBO_COMPARATOR: Placebo for Metoprolol; Tablet, target dose 100 mg once daily	Drug: Placebo; Tablet, target dose 100 mg once daily; Drug: Placebo; Tablet, 32 mg once daily
EXPERIMENTAL: Candesartan; Tablet, target dose 32 mg once daily	Drug: Candesartan; Tablet, target dose 32 mg once daily
PLACEBO_COMPARATOR: Placebo for Candesartan; Tablet, target dose 32 mg once daily	Drug: Placebo; Tablet, target dose 100 mg once daily; Drug: Placebo; Tablet, 32 mg once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in left ventricular ejection fraction, as assessed by cardiac MRI	Baseline and end of study (up to 72 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in contrast enhancement by MRI		Baseline and approximately 4 weeks
Change in left 2D global strain, as assessed by echocardiography		Baseline and end of study (up to 72 weeks)
Incidence of clinical of heart failure or objective left ventricular dysfunction	Left ventricular dysfunction defined as ejection fraction < 55% by cardiac MRI	Up to 72 weeks
Change in biochemical markers of cardiac injury, i.e. hs-cTnT		Baseline and end of study (up to 72 weeks)
Change in left ventricular diastolic function, as assessed by echocardiography	Diastolic function assessed by e/e'	Baseline and end of study (up to 72 weeks)
Change in biochemical markers of cardiac function, i.e. NT-proBNP		Baseline and end of study (up to 72 weeks)
Change in contrast enhancement, as assessed by cardiac MRI		Baseline and end of study (up to 72 weeks)

Collaborators and Investigators

• Sponsor: University Hospital, Akershus
• Collaborators: University of Oslo; AstraZeneca; Norwegian Cancer Society
• Investigators: Study Director: Stein Vaaler, University Hospital, Akershus

Publications and helpful links

General Publications

• Heck SL, Mecinaj A, Ree AH, Hoffmann P, Schulz-Menger J, Fagerland MW, Gravdehaug B, Rosjo H, Steine K, Geisler J, Gulati G, Omland T. Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2x2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol. Circulation. 2021 Jun 22;143(25):2431-2440. doi: 10.1161/CIRCULATIONAHA.121.054698. Epub 2021 May 16.
• Gulati G, Heck SL, Rosjo H, Ree AH, Hoffmann P, Hagve TA, Norseth J, Gravdehaug B, Steine K, Geisler J, Omland T. Neurohormonal Blockade and Circulating Cardiovascular Biomarkers During Anthracycline Therapy in Breast Cancer Patients: Results From the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) Study. J Am Heart Assoc. 2017 Nov 8;6(11):e006513. doi: 10.1161/JAHA.117.006513.
• Heck SL, Gulati G, Ree AH, Schulz-Menger J, Gravdehaug B, Rosjo H, Steine K, Bratland A, Hoffmann P, Geisler J, Omland T. Rationale and design of the prevention of cardiac dysfunction during an Adjuvant Breast Cancer Therapy (PRADA) Trial. Cardiology. 2012;123(4):240-7. doi: 10.1159/000343622. Epub 2012 Nov 30.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (ACTUAL): September 1, 2014
• Study Completion (ACTUAL): September 1, 2014

Study Registration Dates

• First Submitted: September 5, 2011
• First Submitted That Met QC Criteria: September 13, 2011
• First Posted (ESTIMATE): September 14, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): October 22, 2014
• Last Update Submitted That Met QC Criteria: October 21, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: Trastuzumab; Anthracyclines
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Metoprolol; Candesartan
• Other Study ID Numbers: 2709001/90005