Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy

NCT ID: NCT02354352

Last Updated: 2019-10-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-03-20
• Study Completion Date: 2018-05-31

Brief 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.

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.

Conditions

Duchenne Muscular Dystrophy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Eplerenone

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

Spironolactone

Intervention Type: DRUG

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

Interventions

Eplerenone

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

Intervention Type: DRUG

Spironolactone

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

Intervention Type: DRUG

Other Intervention Names

Inspra; Aldactone

Eligibility Criteria

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.

• Minimum Eligible Age: 7 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

University of California, Los Angeles

OTHER

Sponsor Role: collaborator

University of Utah

OTHER

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: collaborator

University of Kansas Medical Center

OTHER

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: collaborator

Ohio State University

OTHER

Sponsor Role: lead

Responsible Party

Subha Raman

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Subha V Raman, MD

Role: PRINCIPAL_INVESTIGATOR

Ohio State University

Locations

Mattel Children's Hospital and David Geffen School of Medicine at UCLA

Los Angeles, California, United States

University of Colorado

Aurora, Colorado, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

The Ohio State University Medical Center

Columbus, Ohio, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

University of Utah

Salt Lake City, Utah, United States

Countries

United States

References

Raman SV, Hor KN, Mazur W, Cardona A, He X, Halnon N, Markham L, Soslow JH, Puchalski MD, Auerbach SR, Truong U, Smart S, McCarthy B, Saeed IM, Statland JM, Kissel JT, Cripe LH. Stabilization of Early Duchenne Cardiomyopathy With Aldosterone Inhibition: Results of the Multicenter AIDMD Trial. J Am Heart Assoc. 2019 Oct;8(19):e013501. doi: 10.1161/JAHA.119.013501. Epub 2019 Sep 24.

Reference Type: DERIVED

PMID: 31549577 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2014H0387

Identifier Type: -

Identifier Source: org_study_id