Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy Clinical Trial

Official title:

Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02354352
• Other study ID #: 2014H0387
• Status: Completed
• Phase: Phase 3
• Start date: March 20, 2015
• Est. completion date: May 2018

Study information

• Verified date: September 2019
• Source: Ohio State University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study is to demonstrate non-inferiority of spironolactone vs. eplerenone in preserving cardiac and pulmonary function in patients with preserved LV ejection fraction. Males with Duchenne muscular dystrophy (DMD) confirmed clinically and by mutation analysis will be enrolled. Subjects will be randomized to either eplerenone or spironolactone. Subjects will use a drug diary to record daily compliance of taking the study medication as well as any concerns they may have during the study period. Subjects will undergo cardiac magnetic resonance imaging (CMR) and pulmonary function tests (PFT) at baseline and then again at 12 months post enrollment. Subjects will also complete a quality of life questionnaire at baseline and 12 months. Degree of elbow contracture will be measured using a goniometer at baseline and 12 months.

Description:

DMD is an X-linked disorder in which the sarcolemmal protein dystrophin is effectively absent. Males with DMD typically die in the third and fourth decades of life of cardiopulmonary disease. Mouse models of DMD, autopsy data, and in vivo human studies using magnetic resonance-based late gadolinium enhancement imaging (LGE) have shown that progressive myocardial damage is well underway before left ventricular ejection fraction (LV EF) becomes abnormal.

Exertional symptoms and signs of myocardial disease are typically absent as skeletal muscle disease progressively limits functional capacity in affected boys. Thus, cardiac involvement can go undetected until LV dysfunction and myocardial fibrosis are advanced. While echocardiography remains a useful tool to evaluate LV dysfunction, CMR with LGE is advantageous for DMD patients since it identifies myocardial injury before decline in EF is apparent by echocardiography. Further, greater reproducibility affords efficient sample sizes for cardiomyopathy clinical trials in patients with rare diseases. CMR's increasing availability at DMD clinical centers has afforded earlier cardiomyopathy detection, and has helped refine current management to typically include agents such as angiotensin converting enzyme inhibitors (ACEI) once damage is evident. This strategy, however, may not be sufficient, with prior studies showing decline in systolic function with or without ACEI or angiotensin receptor blocker (ARB) therapy.

The investigators previously tested mineralocorticoid receptor antagonism (MRA) added to ACEI while EF was still normal in a mouse model that mimics the myocardial damage seen in DMD patients. This combination significantly reduced myocardial injury and improved (made more negative) LV circumferential strain (Ecc), a sensitive and early marker of LV systolic dysfunction. Additionally, preliminary findings from a recently completed clinical trial suggests efficacy of eplerenone vs. placebo, while further preclinical data suggests greater benefit without concomitant steroid use. Thus, a non-inferiority trial comparing MRAs is needed.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: May 2018
• Est. primary completion date: May 2018
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 7 Years and older

Eligibility

Inclusion Criteria:

• Boys age =7 years with DMD confirmed clinically and by mutation analysis able to undergo cardiac magnetic resonance (CMR) without sedation

• LV EF =45% (+/-5%) by clinically-acquired echocardiography, nuclear scan or cardiac MRI done within 2 weeks of enrollment

Exclusion Criteria:

• Non-MR compatible implants

• Severe claustrophobia

• Gadolinium contrast allergy

• Kidney disease

• Prior use of or allergy to aldosterone antagonist

• Use of other investigational therapy.

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Drug:
• Eplerenone
26 Subjects will take Eplerenone, one 50mg capsule by mouth once daily for 12 months.
• Spironolactone
26 Subjects will take Spironolactone, one 50mg capsule by mouth once daily for 12 months.

Locations

Country	Name	City	State
United States	University of Colorado	Aurora	Colorado
United States	The Ohio State University Medical Center	Columbus	Ohio
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Mattel Children's Hospital and David Geffen School of Medicine at UCLA	Los Angeles	California
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	University of Utah	Salt Lake City	Utah

Sponsors (6)

Lead Sponsor	Collaborator
Ohio State University	University of California, Los Angeles, University of Colorado, Denver, University of Kansas Medical Center, University of Utah, Vanderbilt University Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Left Ventricular Strain	a sensitive measure of heart muscle function	12 months