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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01708798
• Other study ID #: H12-00185
• Status: Terminated
• Phase: Phase 2/Phase 3
• First received: October 15, 2012
• Last updated: January 3, 2017
• Start date: May 2014
• Est. completion date: November 2016

Study information

• Verified date: January 2017
• Source: University of British Columbia
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 44
• Est. completion date: November 2016
• Est. primary completion date: November 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Eplerenone

• Placebo

Locations

Country	Name	City	State
Canada	British Columbia Cancer Agency, Vancouver Centre	Vancouver	British Columbia

Sponsors (3)

Lead Sponsor	Collaborator
University of British Columbia	Canadian Cancer Society Research Institute (CCSRI), Pfizer

Country where clinical trial is conducted

Canada, 

References & Publications (38)

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* Note: There are 38 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of hyperkalemia	Incidence of hyperkalemia defined as serum potassium >5.5 mmol/L	6 months	Yes
Other	Incidence of adverse events leading to discontinuation of study drug	Incidence of adverse events leading to discontinuation of study drug, including hypotension, dizziness, hyperkalemia, or renal failure	6 months	Yes
Other	Signal-averaged ECG (SAECG) changes	Change in late potentials measured on SAECG	Baseline, 8-12 weeks, 6 months	No
Other	Exercise stress test	Change in QT/RR interval slope, exercise capacity, peak heart rate, heart rate recovery, ventricular arrhythmias during exercise, ventricular arrhythmias during recovery, presence of ischemia	Baseline, 6 months	No
Other	Genetic predictors of cardiotoxicity and of response to eplerenone	Genetic predictors of cardiotoxicity and of response to eplerenone	6 months	No
Other	ECG changes	Change in QT interval, arrhythmias	Pre- and post-chemotherapy infusions (over 8-12 weeks)	No
Other	Global longitudinal strain (GLS)	Change in GLS from baseline to 6 months	6 months	No
Primary	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	No
Secondary	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	No
Secondary	Development of worsening systolic function	Development of worsening systolic function, defined as a decline in LVEF of =10% to =50%	6 months	No
Secondary	Change in septal E'	Change in early diastolic tissue velocity of the septal mitral annulus (E', measured by tissue Doppler echocardiography)	6 months	No
Secondary	Change in lateral E'	Change in early diastolic tissue velocity of the lateral mitral annulus (E', measured by tissue Doppler echocardiography)	6 months	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Change in left ventricular ejection fraction (LVEF)	Change in LVEF, measured by echocardiogram using Simpson's method	6 months	No
Secondary	Biomarkers	Change in biomarkers of myocardial injury, inflammation, and collagen turnover as predictors of cardiotoxicity	Baseline, 1 week, 2 weeks, 4 weeks, 6 months	No