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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by University of British Columbia
Sponsor:
Collaborators:
Canadian Cancer Society Research Institute (CCSRI)
Pfizer
Information provided by (Responsible Party):
University of British Columbia
ClinicalTrials.gov Identifier:
NCT01708798
First received: October 15, 2012
Last updated: June 11, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Breast Cancer
Drug: Eplerenone
Phase 2
Phase 3

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

Resource links provided by NLM:


Further study details as provided by University of British Columbia:

Primary Outcome Measures:
  • Change in average E' (averaged septal E' and lateral E') [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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)


Secondary Outcome Measures:
  • Development of worsening diastolic function [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Development of worsening diastolic function, defined as a decline by at least one American Society of Echocardiography gradation of diastolic dysfunction

  • Development of worsening systolic function [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Development of worsening systolic function, defined as a decline in LVEF of ≥10% to ≤50%

  • Change in septal E' [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Change in early diastolic tissue velocity of the septal mitral annulus (E', measured by tissue Doppler echocardiography)

  • Change in lateral E' [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Change in early diastolic tissue velocity of the lateral mitral annulus (E', measured by tissue Doppler echocardiography)

  • Change in E/E' [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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)

  • Change in E/A [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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

  • Change in left atrial volume index [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Change in the left atrial volume index, defined as the left atrial volume measured on the 2D echocardiogram indexed to body surface area

  • Change in left ventricular ejection fraction (LVEF) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Change in LVEF, measured by echocardiogram using Simpson's method

  • Biomarkers [ Time Frame: Baseline, 1 week, 2 weeks, 4 weeks, 6 months ] [ Designated as safety issue: No ]
    Change in biomarkers of myocardial injury, inflammation, and collagen turnover as predictors of cardiotoxicity


Other Outcome Measures:
  • Incidence of hyperkalemia [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Incidence of hyperkalemia defined as serum potassium >5.5 mmol/L

  • Incidence of adverse events leading to discontinuation of study drug [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Incidence of adverse events leading to discontinuation of study drug, including hypotension, dizziness, hyperkalemia, or renal failure

  • Signal-averaged ECG (SAECG) changes [ Time Frame: Baseline, 8-12 weeks, 6 months ] [ Designated as safety issue: No ]
    Change in late potentials measured on SAECG

  • Exercise stress test [ Time Frame: Baseline, 6 months ] [ Designated as safety issue: No ]
    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

  • Genetic predictors of cardiotoxicity and of response to eplerenone [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Genetic predictors of cardiotoxicity and of response to eplerenone

  • ECG changes [ Time Frame: Pre- and post-chemotherapy infusions (over 8-12 weeks) ] [ Designated as safety issue: No ]
    Change in QT interval, arrhythmias

  • Global longitudinal strain (GLS) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Change in GLS from baseline to 6 months


Estimated Enrollment: 78
Study Start Date: May 2014
Estimated Study Completion Date: May 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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 Name: Inspra

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01708798

Contacts
Contact: Sean A Virani, MD, MSc 604-875-5092 svirani@telus.net
Contact: Margot K Davis, MD 650-690-5667 margot.k.davis@gmail.com

Locations
Canada, British Columbia
British Columbia Cancer Agency, Vancouver Centre Recruiting
Vancouver, British Columbia, Canada, V5Z 4E6
Sponsors and Collaborators
University of British Columbia
Canadian Cancer Society Research Institute (CCSRI)
Pfizer
Investigators
Principal Investigator: Sean A Virani, MD, MSc, MPH University of British Columbia
Principal Investigator: Margot Davis, MD University of British Columbia
  More Information

Publications:

Responsible Party: University of British Columbia
ClinicalTrials.gov Identifier: NCT01708798     History of Changes
Other Study ID Numbers: H12-00185
Study First Received: October 15, 2012
Last Updated: June 11, 2014
Health Authority: Canada: Health Canada

Keywords provided by University of British Columbia:
Diastolic heart failure

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Eplerenone
Aldosterone Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 26, 2014