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Breast CancerPhase 2/3NCT01708798

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

A Phase 2/3 study testing Eplerenone in people with Breast Cancer, run by University of British Columbia at 1 site in Canada.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Breast Cancer
What is being tested?
Eplerenone
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
44 participants
Where
1 siteCanada
Study dates
May 2014to Nov 2016
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Stage I-III breast cancer
  • Scheduled to undergo treatment with doxorubicin-based chemotherapy regimen
  • Able to provide informed consent

Who cannot join

  • 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)
Show all 15Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

Canada1 site

  • British Columbia Cancer Agency, Vancouver Centre

    Vancouver, British Columbia, V5Z 4E6

Other trials in Canada

About this study

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

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.

Conditions
Breast Cancer
Being tested
Eplerenone, Placebo
Keywords
Diastolic heart failure
Medical subject headings
Breast Neoplasms, Heart Failure, Diastolic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EplerenoneDrug

    Also called Inspra

  • PlaceboDrug

Study groups in NCT01708798
Study groupRoleWhat they receive
PlaceboPlacebo comparatorOne 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.
Receives: Drug: Placebo
EplerenoneExperimentalEplerenone 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.
Receives: Drug: Eplerenone

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    Measured: 6 months

Secondary outcomes (9)

  1. 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

    Measured: 6 months

  2. Development of worsening systolic function

    Development of worsening systolic function, defined as a decline in LVEF of ≥10% to ≤50%

    Measured: 6 months

  3. Change in septal E'

    Change in early diastolic tissue velocity of the septal mitral annulus (E', measured by tissue Doppler echocardiography)

    Measured: 6 months

  4. Change in lateral E'

    Change in early diastolic tissue velocity of the lateral mitral annulus (E', measured by tissue Doppler echocardiography)

    Measured: 6 months

  5. 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)

    Measured: 6 months

  6. 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

    Measured: 6 months

  7. 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

    Measured: 6 months

  8. Change in left ventricular ejection fraction (LVEF)

    Change in LVEF, measured by echocardiogram using Simpson's method

    Measured: 6 months

  9. Biomarkers

    Change in biomarkers of myocardial injury, inflammation, and collagen turnover as predictors of cardiotoxicity

    Measured: Baseline, 1 week, 2 weeks, 4 weeks, 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Oct 2012 (estimated)
  2. Study startMay 2014
  3. Primary completionNov 2016
  4. Study completionNov 2016

Why it stopped: Futility

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
44 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01708798
Sponsor's protocol ID
H12-00185
Status last verified
Jan 2017
First submitted
15 Oct 2012
Last updated
5 Jan 2017
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, Muggia FM. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979 Nov;91(5):710-7. doi: 10.7326/0003-4819-91-5-710.

    PubMed 496103

  • Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, Jones SE, Wadler S, Desai A, Vogel C, Speyer J, Mittelman A, Reddy S, Pendergrass K, Velez-Garcia E, Ewer MS, Bianchine JR, Gams RA. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol. 1997 Apr;15(4):1318-32. doi: 10.1200/JCO.1997.15.4.1318.

    PubMed 9193323

  • Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol. 2005 Dec;131(5):561-78. doi: 10.1111/j.1365-2141.2005.05759.x.

    PubMed 16351632

  • Kizaki K, Ito R, Okada M, Yoshioka K, Uchide T, Temma K, Mutoh K, Uechi M, Hara Y. Enhanced gene expression of myocardial matrix metalloproteinases 2 and 9 after acute treatment with doxorubicin in mice. Pharmacol Res. 2006 Apr;53(4):341-6. doi: 10.1016/j.phrs.2006.01.001. Epub 2006 Feb 7.

    PubMed 16455267

  • Goetzenich A, Hatam N, Zernecke A, Weber C, Czarnotta T, Autschbach R, Christiansen S. Alteration of matrix metalloproteinases in selective left ventricular adriamycin-induced cardiomyopathy in the pig. J Heart Lung Transplant. 2009 Oct;28(10):1087-93. doi: 10.1016/j.healun.2009.06.025.

    PubMed 19782292

  • Spallarossa P, Altieri P, Garibaldi S, Ghigliotti G, Barisione C, Manca V, Fabbi P, Ballestrero A, Brunelli C, Barsotti A. Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase. Cardiovasc Res. 2006 Feb 15;69(3):736-45. doi: 10.1016/j.cardiores.2005.08.009. Epub 2005 Oct 6.

    PubMed 16213474

  • Zhao Y, McLaughlin D, Robinson E, Harvey AP, Hookham MB, Shah AM, McDermott BJ, Grieve DJ. Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with Doxorubicin chemotherapy. Cancer Res. 2010 Nov 15;70(22):9287-97. doi: 10.1158/0008-5472.CAN-10-2664. Epub 2010 Sep 30.

    PubMed 20884632

  • Clark JE, Sarafraz N, Marber MS. Potential of p38-MAPK inhibitors in the treatment of ischaemic heart disease. Pharmacol Ther. 2007 Nov;116(2):192-206. doi: 10.1016/j.pharmthera.2007.06.013. Epub 2007 Jul 24.

    PubMed 17765316

  • Bellahcene M, Jacquet S, Cao XB, Tanno M, Haworth RS, Layland J, Kabir AM, Gaestel M, Davis RJ, Flavell RA, Shah AM, Avkiran M, Marber MS. Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor. J Am Coll Cardiol. 2006 Aug 1;48(3):545-55. doi: 10.1016/j.jacc.2006.02.072. Epub 2006 Jul 12.

    PubMed 16875982

  • Martos R, Baugh J, Ledwidge M, O'Loughlin C, Conlon C, Patle A, Donnelly SC, McDonald K. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation. 2007 Feb 20;115(7):888-95. doi: 10.1161/CIRCULATIONAHA.106.638569. Epub 2007 Feb 5.

    PubMed 17283265

  • Klappacher G, Franzen P, Haab D, Mehrabi M, Binder M, Plesch K, Pacher R, Grimm M, Pribill I, Eichler HG, et al. Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol. 1995 May 1;75(14):913-8. doi: 10.1016/s0002-9149(99)80686-9.

    PubMed 7733000

  • Host NB, Jensen LT, Bendixen PM, Jensen SE, Koldkjaer OG, Simonsen EE. The aminoterminal propeptide of type III procollagen provides new information on prognosis after acute myocardial infarction. Am J Cardiol. 1995 Nov 1;76(12):869-73. doi: 10.1016/s0002-9149(99)80251-3.

    PubMed 7484822

  • Di Zhang A, Nguyen Dinh Cat A, Soukaseum C, Escoubet B, Cherfa A, Messaoudi S, Delcayre C, Samuel JL, Jaisser F. Cross-talk between mineralocorticoid and angiotensin II signaling for cardiac remodeling. Hypertension. 2008 Dec;52(6):1060-7. doi: 10.1161/HYPERTENSIONAHA.108.117531. Epub 2008 Nov 3.

    PubMed 18981328

  • Hori Y, Yoshioka K, Kanai K, Hoshi F, Itoh N, Higuchi S. Spironolactone decreases isoproterenol-induced ventricular fibrosis and matrix metalloproteinase-2 in rats. Biol Pharm Bull. 2011;34(1):61-5. doi: 10.1248/bpb.34.61.

    PubMed 21212518

  • Rude MK, Duhaney TA, Kuster GM, Judge S, Heo J, Colucci WS, Siwik DA, Sam F. Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertension. 2005 Sep;46(3):555-61. doi: 10.1161/01.HYP.0000176236.55322.18. Epub 2005 Jul 25.

    PubMed 16043662

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Eplerenone in people with Breast Cancer, run by University of British Columbia at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 5 Jan 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Futility). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in average E' (averaged septal E' and lateral E') (time frame: 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01708798, which also lists 38 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jan 2017.

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