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

• ClinicalTrials.gov Identifier: NCT01434134
• Recruitment Status: Completed
• First Posted: September 14, 2011
• Last Update Posted: October 22, 2014
• Sponsor: University Hospital, Akershus
• Collaborators: University of Oslo; Norwegian Cancer Society; AstraZeneca
• Information provided by (Responsible Party): Torbjorn Omland, University Hospital, Akershus

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Heart Failure	Drug: Metoprolol; Drug: Placebo; Drug: Candesartan	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: A Randomized, Placebo-controlled, 2x2 Factorial, Double Blind Trial of Candesartan and Metoprolol
• Study Start Date: September 2011
• Actual Primary Completion Date: September 2014
• Actual Study Completion Date: September 2014

Arms and Interventions

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
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, 32 mg once daily

Outcome Measures

Primary Outcome Measures :

1. Change in left ventricular ejection fraction, as assessed by cardiac MRI [ Time Frame: Baseline and end of study (up to 72 weeks) ]

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Norway

Akershus University Hospital

Lørenskog, Norway, 1478

Sponsors and Collaborators

University Hospital, Akershus

University of Oslo

Norwegian Cancer Society

AstraZeneca

Investigators

• Study Director: Stein Vaaler; University Hospital, Akershus

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gulati G, Heck SL, Røsjø 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). pii: e006513. doi: 10.1161/JAHA.117.006513.

Heck SL, Gulati G, Ree AH, Schulz-Menger J, Gravdehaug B, Røsjø 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.

• Responsible Party: Torbjorn Omland, Professor of Medicine, University Hospital, Akershus
• ClinicalTrials.gov Identifier: NCT01434134
• Other Study ID Numbers: 2709001/90005
• First Posted: September 14, 2011
• Last Update Posted: October 22, 2014
• Last Verified: October 2014

Keywords provided by Torbjorn Omland, University Hospital, Akershus:

Anthracyclines; Trastuzumab

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Metoprolol; Candesartan; Anti-Arrhythmia Agents; Antihypertensive Agents; Sympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists