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

January 3, 2017 updated by: University of British Columbia

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

44

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 4E6
        • British Columbia Cancer Agency, Vancouver Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
PLACEBO_COMPARATOR: Placebo

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
EXPERIMENTAL: Eplerenone

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
Other Names:
  • Inspra

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in average E' (averaged septal E' and lateral E')
Time Frame: 6 months
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
Time Frame: 6 months
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
Time Frame: 6 months
Development of worsening systolic function, defined as a decline in LVEF of ≥10% to ≤50%
6 months
Change in septal E'
Time Frame: 6 months
Change in early diastolic tissue velocity of the septal mitral annulus (E', measured by tissue Doppler echocardiography)
6 months
Change in lateral E'
Time Frame: 6 months
Change in early diastolic tissue velocity of the lateral mitral annulus (E', measured by tissue Doppler echocardiography)
6 months
Change in E/E'
Time Frame: 6 months
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
Time Frame: 6 months
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
Time Frame: 6 months
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)
Time Frame: 6 months
Change in LVEF, measured by echocardiogram using Simpson's method
6 months
Biomarkers
Time Frame: Baseline, 1 week, 2 weeks, 4 weeks, 6 months
Change in biomarkers of myocardial injury, inflammation, and collagen turnover as predictors of cardiotoxicity
Baseline, 1 week, 2 weeks, 4 weeks, 6 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of hyperkalemia
Time Frame: 6 months
Incidence of hyperkalemia defined as serum potassium >5.5 mmol/L
6 months
Incidence of adverse events leading to discontinuation of study drug
Time Frame: 6 months
Incidence of adverse events leading to discontinuation of study drug, including hypotension, dizziness, hyperkalemia, or renal failure
6 months
Signal-averaged ECG (SAECG) changes
Time Frame: Baseline, 8-12 weeks, 6 months
Change in late potentials measured on SAECG
Baseline, 8-12 weeks, 6 months
Exercise stress test
Time Frame: Baseline, 6 months
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
Genetic predictors of cardiotoxicity and of response to eplerenone
Time Frame: 6 months
Genetic predictors of cardiotoxicity and of response to eplerenone
6 months
ECG changes
Time Frame: Pre- and post-chemotherapy infusions (over 8-12 weeks)
Change in QT interval, arrhythmias
Pre- and post-chemotherapy infusions (over 8-12 weeks)
Global longitudinal strain (GLS)
Time Frame: 6 months
Change in GLS from baseline to 6 months
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of British Columbia

Collaborators

Pfizer
Canadian Cancer Society (CCS)

Investigators

  • Principal Investigator: Sean A Virani, MD, MSc, MPH, University of British Columbia
  • Principal Investigator: Margot Davis, MD, University of British Columbia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2014

Primary Completion (ACTUAL)

November 1, 2016

Study Completion (ACTUAL)

November 1, 2016

Study Registration Dates

First Submitted

October 15, 2012

First Submitted That Met QC Criteria

October 15, 2012

First Posted (ESTIMATE)

October 17, 2012

Study Record Updates

Last Update Posted (ESTIMATE)

January 5, 2017

Last Update Submitted That Met QC Criteria

January 3, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H12-00185

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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