Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy
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.
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
|Official Title:||Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy|
- Left ventricular strain (a sensitive measurement of heart function using cardiac MRI) [ Time Frame: 12 months ] [ Designated as safety issue: No ]a sensitive measurement of heart function using cardiac MRI
- Forced vital capacity (a measure of pulmonary function) [ Time Frame: 12 months ] [ Designated as safety issue: No ]a measure of pulmonary function
- muscle injury blood biomarkers (blood measures of muscle damage and repair) [ Time Frame: 12 months ] [ Designated as safety issue: No ]blood measures of muscle damage and repair
|Study Start Date:||January 2015|
|Estimated Study Completion Date:||September 2017|
|Estimated Primary Completion Date:||September 2017 (Final data collection date for primary outcome measure)|
Active Comparator: Eplerenone
Eplerenone is an aldosterone antagonist used as an adjunct in the management of chronic heart failure. It is marketed under the trade name Inspra. Eplerenone is a potassium-sparing diuretic.
26 Subjects will take Eplerenone, one 50mg capsule by mouth once daily for 12 months.
Other Name: Inspra
Active Comparator: Spironolactone
Spironolactone is an aldosterone antagonist used as an adjunct in the management of chronic heart failure. It is marketed under the trade name Aldactone. Spironolactone is a potassium-sparing diuretic.
26 Subjects will take Spironolactone, one 50mg capsule by mouth once daily for 12 months.
Other Name: Aldactone
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02354352
|Contact: Subha V Raman, MDfirstname.lastname@example.org|
|Contact: Beth McCarthy, BSRT(R)||email@example.com|
|United States, California|
|Mattel Children's Hospital and David Geffen School of Medicine at UCLA||Not yet recruiting|
|Los Angeles, California, United States, 90095-1743|
|Contact: Nancy Halnon, MD 310-267-7667 firstname.lastname@example.org|
|Contact: Vanessa DePaz 310-267-7618 email@example.com|
|Principal Investigator: Nancy Halnon, MD|
|United States, Colorado|
|University of Colorado||Not yet recruiting|
|Aurora, Colorado, United States, 80045|
|Contact: Scott Auerbach, MD 720-777-3218 firstname.lastname@example.org|
|Contact: Alison Ballard, PNP 720-777-8723 email@example.com|
|United States, Ohio|
|The Ohio State University Medical Center||Recruiting|
|Columbus, Ohio, United States, 43210|
|Contact: Beth McCarthy, BSRT(R)(CV) 614-688-8020 firstname.lastname@example.org|
|Contact: Subha V Raman, MD, MSEE 614-293-8963 email@example.com|
|Principal Investigator: Subha V Raman, MD|
|Sub-Investigator: Linda H Cripe, MD|
|United States, Utah|
|University of Utah||Not yet recruiting|
|Salt Lake City, Utah, United States, 84113|
|Contact: Michael Puchalski, MD 801-213-7652 firstname.lastname@example.org|
|Contact: Ashley Snyder 801-587-9104 email@example.com|
|Principal Investigator:||Subha V Raman, MD||Ohio State University|