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Trial record 1 of 1 for:    NCT01708798
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Study of the Effect of Eplerenone on Heart Function in Women Receiving Anthracycline Chemotherapy for Breast Cancer

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ClinicalTrials.gov Identifier: NCT01708798
Recruitment Status : Terminated (Futility)
First Posted : October 17, 2012
Last Update Posted : January 5, 2017
Sponsor:
Collaborators:
Canadian Cancer Society Research Institute (CCSRI)
Pfizer
Information provided by (Responsible Party):
University of British Columbia

Tracking Information
First Submitted Date  ICMJE October 15, 2012
First Posted Date  ICMJE October 17, 2012
Last Update Posted Date January 5, 2017
Study Start Date  ICMJE May 2014
Actual Primary Completion Date November 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 15, 2012)
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)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2013)
  • 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
  • Development of worsening systolic function [ Time Frame: 6 months ]
    Development of worsening systolic function, defined as a decline in LVEF of ≥10% to ≤50%
  • 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)
  • 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)
  • 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)
  • 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
  • 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
  • Change in left ventricular ejection fraction (LVEF) [ Time Frame: 6 months ]
    Change in LVEF, measured by echocardiogram using Simpson's method
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: October 15, 2012)
  • 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
  • Development of worsening systolic function [ Time Frame: 6 months ]
    Development of worsening systolic function, defined as a decline in LVEF of ≥10% to ≤50%
  • 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)
  • 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)
  • 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)
  • 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
  • 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
  • Change in left ventricular ejection fraction (LVEF) [ Time Frame: 6 months ]
    Change in LVEF, measured by echocardiogram using Simpson's method
  • Serum troponin-I level [ Time Frame: Baseline and 1 week ]
  • Serum B-type natriuretic peptide (BNP) level [ Time Frame: Baseline and 1 week ]
  • Serum aldosterone level [ Time Frame: Baseline, week 1, week 2, week 4 ]
  • Serum Procollagen III N-Terminal Propeptide (PIIINP) level [ Time Frame: Baseline, week 1, week 2, week 4 ]
  • Serum Procollagen I N-Terminal Propeptide (PINP) level [ Time Frame: Baseline, 1 week, 2 weeks, 4 weeks ]
  • Serum interleukin-6 level [ Time Frame: Baseline, week 1, week 2, week 4 ]
Current Other Pre-specified Outcome Measures
 (submitted: June 11, 2014)
  • Incidence of hyperkalemia [ Time Frame: 6 months ]
    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 ]
    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 ]
    Change in late potentials measured on SAECG
  • 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
  • Genetic predictors of cardiotoxicity and of response to eplerenone [ Time Frame: 6 months ]
    Genetic predictors of cardiotoxicity and of response to eplerenone
  • ECG changes [ Time Frame: Pre- and post-chemotherapy infusions (over 8-12 weeks) ]
    Change in QT interval, arrhythmias
  • Global longitudinal strain (GLS) [ Time Frame: 6 months ]
    Change in GLS from baseline to 6 months
Original Other Pre-specified Outcome Measures
 (submitted: October 15, 2012)
  • Incidence of hyperkalemia [ Time Frame: 6 months ]
    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 ]
    Incidence of adverse events leading to discontinuation of study drug, including hypotension, dizziness, hyperkalemia, or renal failure
 
Descriptive Information
Brief Title  ICMJE Study of the Effect of Eplerenone on Heart Function in Women Receiving Anthracycline Chemotherapy for Breast Cancer
Official Title  ICMJE A Prospective Randomized Placebo-controlled Study of the Effect of Eplerenone on Left Ventricular Diastolic Function in Women Receiving Anthracycline Therapy for Breast Cancer
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: Eplerenone
    Other Name: Inspra
  • Drug: Placebo
Study Arms  ICMJE
  • 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.

    Intervention: 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.

    Intervention: Drug: Eplerenone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: January 3, 2017)
44
Original Estimated Enrollment  ICMJE
 (submitted: October 15, 2012)
78
Actual Study Completion Date  ICMJE November 2016
Actual Primary Completion Date November 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01708798
Other Study ID Numbers  ICMJE H12-00185
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of British Columbia
Study Sponsor  ICMJE University of British Columbia
Collaborators  ICMJE
  • Canadian Cancer Society Research Institute (CCSRI)
  • Pfizer
Investigators  ICMJE
Principal Investigator: Sean A Virani, MD, MSc, MPH University of British Columbia
Principal Investigator: Margot Davis, MD University of British Columbia
PRS Account University of British Columbia
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP