Study of the Effect of Eplerenone on Heart Function in Women Receiving Anthracycline Chemotherapy for Breast Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Prospective Randomized Placebo-controlled Study of the Effect of Eplerenone on Left Ventricular Diastolic Function in Women Receiving Anthracycline Therapy for Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Eplerenone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>One tablet by mouth daily. If serum potassium level is <5.0 mmol/L at four weeks, increase to two tablets by mouth daily. If estimated glomerular filtration rate (eGFR) is between 30-49 ml per min per 1.73m2, initial dose is: one tablet by mouth every other day. If serum potassium level is <5.0 mmol/L at four weeks, increase to one tablet by mouth daily. | Drug: Placebo<br> <br> |
| Experimental: Eplerenone<br>Eplerenone 25 mg tablet by mouth daily. If serum potassium level is <5.0 mmol/L at four weeks, increase to two 25 mg tablets by mouth daily. If estimated glomerular filtration rate (eGFR) is between 30-49 ml per min per 1.73m2, initial dose is: eplerenone 25 mg tablet by mouth every other day. If serum potassium level is <5.0 mmol/L at four weeks, increase to 25 mg tablet by mouth daily. | Drug: Eplerenone<br> <br> * Other names: Inspra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in average E' (averaged septal E' and lateral E') | The average early diastolic tissue velocity of the mitral valve annulus measured by tissue Doppler echocardiography (averaged velocities of the mitral annulus measured at the lateral edge and the septal edge) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Development of worsening diastolic function | Development of worsening diastolic function, defined as a decline by at least one American Society of Echocardiography gradation of diastolic dysfunction | 6 months | 
| Development of worsening systolic function | Development of worsening systolic function, defined as a decline in LVEF of ≥10% to ≤50% | 6 months | 
| Change in septal E' | Change in early diastolic tissue velocity of the septal mitral annulus (E', measured by tissue Doppler echocardiography) | 6 months | 
| Change in lateral E' | Change in early diastolic tissue velocity of the lateral mitral annulus (E', measured by tissue Doppler echocardiography) | 6 months | 
| Change in E/E' | Change in the ratio of early diastolic mitral inflow velocity (E, measured by pulse wave Doppler echocardiography) to the average early diastolic tissue velocity of the mitral annulus (E', measured by tissue Doppler echocardiography) | 6 months | 
| Change in E/A | Change in the ratio of peak early diastolic mitral inflow velocity (E) to peak mitral inflow velocity during atrial systole (A), both measured by pulse wave Doppler echocardiography | 6 months | 
| Change in left atrial volume index | Change in the left atrial volume index, defined as the left atrial volume measured on the 2D echocardiogram indexed to body surface area | 6 months | 
| Change in left ventricular ejection fraction (LVEF) | Change in LVEF, measured by echocardiogram using Simpson's method | 6 months | 
| Biomarkers | Change in biomarkers of myocardial injury, inflammation, and collagen turnover as predictors of cardiotoxicity | Baseline, 1 week, 2 weeks, 4 weeks, 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diastolic heart failure