Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy

Condition(s) targeted: Duchenne Muscular Dystrophy

Intervention: Eplerenone (Drug); Spironolactone (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Ohio State University

Official(s) and/or principal investigator(s):
Subha V Raman, MD, Principal Investigator, Affiliation: Ohio State University

Overall contact:
Subha V Raman, MD, Phone: 614-293-8963, Email: raman.1@osu.edu

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 must also be non-ambulatory and not taking corticosteroids at the time of enrollment. 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.

Official title: Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Left ventricular strain (a sensitive measurement of heart function using cardiac MRI)

Secondary outcome: Forced vital capacity (a measure of pulmonary function)

Detailed 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.

Minimum age: 10 Years. Maximum age: N/A. Gender(s): Male.

Criteria:

Inclusion Criteria:

- Boys age ≥10 years with DMD confirmed clinically and by mutation analysis able to

undergo cardiac magnetic resonance (CMR) without sedation

- LV EF ≥45% by clinically-acquired echocardiography, nuclear scan or cardiac MRI done

within 2 weeks of enrollment

- non-ambulatory

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.

Subha V Raman, MD, Phone: 614-293-8963, Email: raman.1@osu.edu

Mattel Children's Hospital and David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1743, United States; Not yet recruiting
Nancy Halnon, MD, Phone: 310-267-7667, Email: nhalnon@mednet.ucla.edu
Vanessa DePaz, Phone: 310-267-7618, Email: vdepaz@mednet.ucla.edu
Nancy Halnon, MD, Principal Investigator

University of Colorado, Aurora, Colorado 80045, United States; Not yet recruiting
Scott Auerbach, MD, Phone: 720-777-3218, Email: scott.auerbach@childrenscolorado.org
Alison Ballard, PNP, Phone: 720-777-8723, Email: alison.ballard@childrenscolorado.org

The Ohio State University Medical Center, Columbus, Ohio 43210, United States; Recruiting
Beth McCarthy, BSRT(R)(CV), Phone: 614-688-8020, Email: beth.mccarthy@osumc.edu
Subha V Raman, MD, MSEE, Phone: 614-293-8963, Email: raman.1@osu.edu
Subha V Raman, MD, Principal Investigator
Linda H Cripe, MD, Sub-Investigator

University of Utah, Salt Lake City, Utah 84113, United States; Not yet recruiting
Michael Puchalski, MD, Phone: 801-213-7652, Email: michael.puchalski@hsc.utah.edu
Ashley Snyder, Phone: 801-587-9104, Email: ashley.snyder@hsc.utah.edu

Starting date: January 2015
Last updated: February 23, 2015