Eplerenone for Subclinical Cardiomyopathy in Duchenne Muscular Dystrophy

NCT ID: NCT01521546

Last Updated: 2016-11-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-29
• Study Completion Date: 2016-06-30

Brief Summary

Duchenne muscular dystrophy (DMD), the most common muscular dystrophy, leads to skeletal and cardiac muscle damage. Treatment of pulmonary complications has improved survival; however, heart muscle disease or cardiomyopathy has emerged as a leading cause of death, typically by the third decade. Although myocardial changes begin early, clinically significant heart disease is rarely detected in the first decade of life. Consequently, DMD cardiomyopathy frequently goes unrecognized (and untreated) until advanced (and irreversible).

Current DMD cardiovascular care guidelines recommend beta-blockers and angiotensin converting enzyme inhibitors (ACEIs) when decreased ejection fraction (EF) is noted by echocardiography (echo); however, this strategy has not significantly improved outcomes. Our team has recently made a breakthrough in a mouse study, showing in a model that causes the same heart muscle disease in humans with DMD adding an old medicine traditionally used for high blood pressure and late-stage heart failure can actually prevent heart muscle damage. Because of this drug's proven safety in both children and adults, it is ready to be studied immediately in an RCT in patients with DMD to hopefully show, as we did in mice, that we can prevent the devastating consequences of heart muscle damage.

Detailed Description

Duchenne Muscular dystrophy (DMD) is a deadly X-linked disease affecting 1 in 3,500 males. DMD patients suffer significant disability due to skeletal myopathy and excess death due to cardiomyopathy. Current guidelines advocate initiating cardioprotective treatment with evident global cardiac dysfunction, yet this treatment paradigm has not improved survival much beyond the third decade of life. Potentially promising approaches like gene therapy will take considerable time to improve outcomes. Recently completed studies in a DMD mouse model at our institution indicate that existing drugs known as aldosterone antagonists, typically reserved for advanced heart failure patients, preserve skeletal and cardiac muscle function at 80% of normal. Clinical studies at many centers including ours have shown that high-resolution, noninvasive cardiac magnetic resonance (CMR) detects subclinical myocardial fibrosis and abnormal regional function prior to global functional abnormalities. Combining findings from these preclinical and clinical studies, we plan to execute a randomized, controlled clinical trial (RCT) of eplerenone plus background therapy vs. background therapy alone in patients with DMD. We expect that the aldosterone antagonist eplerenone compared to standard therapy significantly delays progressive cardiomyopathy and skeletal myopathy using highly reproducible imaging biomarkers selected for efficient sample size design, to ultimately reduce disability and death.

Conditions

Duchenne Muscular Dystrophy

Keywords

Duchenne muscular dystrophy; cardiomyopathy; aldosterone antagonist

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

eplerenone

active study drug

Group Type: ACTIVE_COMPARATOR

eplerenone

Intervention Type: DRUG

25mg tablet, once daily by mouth for 12 months

sugar pill

placebo

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

one tablet by mouth daily for 12 months

Interventions

eplerenone

25mg tablet, once daily by mouth for 12 months

Intervention Type: DRUG

placebo

one tablet by mouth daily for 12 months

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• DMD patients age 7 years and older (and able to complete cardiac MRI without sedation) with preserved left ventricular (LV) systolic function and abnormal heart muscle by late post-gadolinium imaging (LGE)

Exclusion Criteria

• renal insufficiency (GFR <40 mL/min/m2)
• non-MR compatible implants (e.g. neurostimulator, AICD)
• severe claustrophobia
• allergy to gadolinium contrast
• prior use of or known allergy to epleronone
• use of potassium-sparing diuretics
• serum potassium level of >5.0 mmol/L

• Minimum Eligible Age: 7 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Ballou Skies

OTHER

Sponsor Role: collaborator

Subha Raman

OTHER

Sponsor Role: lead

Responsible Party

Subha Raman

Professor of Medicine

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Subha V Raman, MD, MSEE

Role: PRINCIPAL_INVESTIGATOR

Ohio State University

Locations

Mattel Children's Hospital and David Geffen School of Medicine at UCLA

Los Angeles, California, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

The Ohio State University Medical Center

Columbus, Ohio, United States

Countries

United States

References

Raman SV, Hor KN, Mazur W, He X, Kissel JT, Smart S, McCarthy B, Roble SL, Cripe LH. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: results of a two-year open-label extension trial. Orphanet J Rare Dis. 2017 Feb 20;12(1):39. doi: 10.1186/s13023-017-0590-8.

Reference Type: DERIVED

PMID: 28219442 (View on PubMed)

Raman SV, Hor KN, Mazur W, Halnon NJ, Kissel JT, He X, Tran T, Smart S, McCarthy B, Taylor MD, Jefferies JL, Rafael-Fortney JA, Lowe J, Roble SL, Cripe LH. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015 Feb;14(2):153-61. doi: 10.1016/S1474-4422(14)70318-7. Epub 2014 Dec 30.

Reference Type: DERIVED

PMID: 25554404 (View on PubMed)

Other Identifiers

2011H0251

Identifier Type: -

Identifier Source: org_study_id