Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy

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.

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.