E-SCAR DMD: Eplerenone for Subclinical Cardiomyopathy in Duchenne Muscular Dystrophy

• Sponsor: Subha Raman (Other)
• Overall Status: Completed
• CT.gov ID: NCT01521546
• Collaborator: Ballou Skies (Other)
• Enrollment: 42
• Locations: 3
• Arms: 2
• Duration (Months): 52
• Patients Per Site: 14
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Duchenne Muscular Dystrophy	Drug: eplerenone; Drug: placebo	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Early Treatment With Aldosterone Antagonism Attenuates Cardiomyopathy in Duchenne Muscular Dystrophy
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: eplerenone active study drug	Drug: eplerenone; 25mg tablet, once daily by mouth for 12 months
Placebo Comparator: sugar pill placebo	Drug: placebo; one tablet by mouth daily for 12 months

Outcome Measures

Primary Outcome Measures

1. 12-month Change in Myocardial Strain [baseline and 12 months]

   a sensitive measurement of heart function using cardiac MRI, change was 12 months minus baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mattel Children's Hospital and David Geffen School of Medicine at UCLA	Los Angeles	California	United States	90095-1743
2	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States
3	The Ohio State University Medical Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Subha Raman
• Ballou Skies

Investigators

• Principal Investigator: Subha V Raman, MD, MSEE, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Journal article

Publications

None provided.

• Responsible Party: Subha Raman, Professor of Medicine, Ohio State University
• ClinicalTrials.gov Identifier: NCT01521546
• Other Study ID Numbers: 2011H0251
• First Posted: Jan 30, 2012
• Last Update Posted: Nov 8, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by Subha Raman, Professor of Medicine, Ohio State University: Duchenne muscular dystrophy; cardiomyopathy; aldosterone antagonist
• Additional relevant MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne; Cardiomyopathies; Eplerenone

Study Results

Participant Flow

Pre-assignment Detail	Enrollment was required prior to assignment.

Arm/Group Title	Placebo	Eplerenone
Arm/Group Description	placebo placebo: one tablet by mouth daily for 12 months	active study drug eplerenone: 25mg tablet, once daily by mouth for 12 months
Period Title: Overall Study
STARTED	22	20
COMPLETED	20	20
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Eplerenone	Placebo	Total
Arm/Group Description	active study drug eplerenone: 25mg tablet, once daily by mouth for 12 months	placebo placebo: one tablet by mouth daily for 12 months	Total of all reporting groups
Overall Participants	20	22	42
Age (years) [Median (Inter-Quartile Range) ]
Age	14.5	15.0	15.0
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	20 100%	22 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	12-month Change in Myocardial Strain
Description	a sensitive measurement of heart function using cardiac MRI, change was 12 months minus baseline.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Eplerenone
Arm/Group Description	placebo: one tablet by mouth daily for 12 months	eplerenone one tablet by mouth daily for 12 months
Measure Participants	20	20
Median (Inter-Quartile Range) [percent change in heart dimension]	2.2	1.0

Adverse Events

Arm/Group Title	Placebo		Eplerenone
Arm/Group Description	placebo one tablet daily for 12 months		eplerenone one tablet daily for 12 months
All Cause Mortality
	Placebo		Eplerenone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Eplerenone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/22 (4.5%)		0/20 (0%)
Vascular disorders
death due to fat embolism	1/22 (4.5%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Eplerenone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/22 (9.1%)		1/20 (5%)
Nervous system disorders
headache coincident with seasonal allergies	0/22 (0%)		1/20 (5%)
Psychiatric disorders
anxiety	1/22 (4.5%)		0/20 (0%)
Skin and subcutaneous tissue disorders
flushing	1/22 (4.5%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.