Clinical trial NCT01708798: Study of the Effect of Eplerenone on Heart Function in Women Receiving Anthracycline Chemotherapy for Breast Cancer
Official title: A Prospective Randomized Placebo-controlled Study of the Effect of Eplerenone on Left Ventricular Diastolic Function in Women Receiving Anthracycline Therapy for Breast Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Breast Cancer
Keywords: Diastolic heart failure
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Canadian Cancer Society (CCS)
name: Pfizer
First posted: 2012-10-17
Enrollment: 44
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Doxorubicin and other anthracyclines are commonly used to treat breast cancer and other types of cancer. Unfortunately, they can cause heart muscle damage, resulting in scarring, abnormal contraction and relaxation, and heart failure symptoms. This side effect occurs more frequently at higher doses, and limits the total dose that can be given to cancer patients. Eplerenone is an oral medication that prevents or reverses heart damage in other disease states, and is commonly used to treat heart failure. This study will investigate the use of eplerenone to protect the heart from these harmful side effects of doxorubicin.

Few therapies have been shown to prevent heart damage in patients receiving anthracyclines. Small studies have suggested that other heart failure medications (ACE inhibitors, beta-blockers) may reduce the incidence of cardiac toxicity, but eplerenone and other drugs in its class (aldosterone antagonists) have not previously been studied. Eplerenone inhibits enzyme pathways that cause scarring of the heart, and animal studies suggest that anthracyclines cause damage through these same pathways.

This study aims to investigate whether eplerenone protects the heart from the harmful effects of doxorubicin chemotherapy. Specifically, it will measure the effect that eplerenone has on heart muscle relaxation. It will randomly assign women undergoing chemotherapy with doxorubicin to one of two groups: one group will receive eplerenone, and the other group will receive placebo (sugar) pills. The subjects will not know which type of pills they are taking. Heart muscle relaxation will be measured at baseline, after completion of chemotherapy (8-12 weeks), and after 6 months. There will also be various blood tests measured in the study subjects, to determine whether there might be certain blood tests that identify patients at particularly high risk of heart toxicity after doxorubicin therapy.


Eligibility criteria: Inclusion Criteria:

* Stage I-III breast cancer
* Scheduled to undergo treatment with doxorubicin-based chemotherapy regimen
* Able to provide informed consent

Exclusion Criteria:

* Use of anthracycline agents other than doxorubicin
* Baseline LVEF ≤50% by any modality (nuclear, echo, MRI)
* Atrial fibrillation or flutter
* Mitral valve disease (More than mild mitral stenosis or regurgitation, previous mitral valve replacement or repair)
* Inability to obtain adequate echo images for required analysis
* Hyperkalemia (K+ \>5.0)
* Glomerular filtration rate (GFR) \<30 ml/min/1.73m2
* Uncontrolled hypertension, defined as having a systolic blood pressure \> 180 mmHg and/or a diastolic blood pressure \>110 mmHg
* Symptomatic hypotension or systolic blood pressure \<85 mmHg
* History of hypersensitivity to eplerenone or spironolactone
* Significant hepatic disease (e.g., previously documented positive serology for viral hepatitis) or aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \>3 times the upper limits of normal
* Concomitant treatment with spironolactone, potassium-sparing diuretics, potassium supplements, or strong inhibitors of cytochrome P450 3A4 (CYP3A4) (i.e. ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir)
* History of alcohol and/or any other drug abuse
* Women who are either pregnant, lactating or of childbearing potential and not using an acceptable method of contraception
* Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial

Primary outcomes:
measure: Change in average E' (averaged septal E' and lateral E')
timeFrame: 6 months
Secondary outcomes:
measure: Development of worsening diastolic function
timeFrame: 6 months
measure: Development of worsening systolic function
timeFrame: 6 months
measure: Change in septal E'
timeFrame: 6 months
measure: Change in lateral E'
timeFrame: 6 months
measure: Change in E/E'
timeFrame: 6 months
measure: Change in E/A
timeFrame: 6 months
measure: Change in left atrial volume index
timeFrame: 6 months
measure: Change in left ventricular ejection fraction (LVEF)
timeFrame: 6 months
measure: Biomarkers
timeFrame: Baseline, 1 week, 2 weeks, 4 weeks, 6 months
Other outcomes:
measure: Incidence of hyperkalemia
timeFrame: 6 months
measure: Incidence of adverse events leading to discontinuation of study drug
timeFrame: 6 months
measure: Signal-averaged ECG (SAECG) changes
timeFrame: Baseline, 8-12 weeks, 6 months
measure: Exercise stress test
timeFrame: Baseline, 6 months
measure: Genetic predictors of cardiotoxicity and of response to eplerenone
timeFrame: 6 months
measure: ECG changes
timeFrame: Pre- and post-chemotherapy infusions (over 8-12 weeks)
measure: Global longitudinal strain (GLS)
timeFrame: 6 months
Locations:
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency, Vancouver Centre
state: British Columbia
Study officials:
affiliation: University of British Columbia
name: Sean A Virani, MD, MSc, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of British Columbia
name: Margot Davis, MD
role: PRINCIPAL_INVESTIGATOR
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