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 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.

Study Overview

• Status: Completed
• Conditions: Duchenne Muscular Dystrophy
• Intervention / Treatment: Drug: Eplerenone; Drug: Spironolactone

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.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095-1743
      • Mattel Children's Hospital and David Geffen School of Medicine at UCLA
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Kansas
    • Kansas City, Kansas, United States, 66103
      • University of Kansas Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Eplerenone; 26 Subjects will take Eplerenone, one 50mg capsule by mouth once daily for 12 months.; Other Names: 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.	Drug: Spironolactone; 26 Subjects will take Spironolactone, one 50mg capsule by mouth once daily for 12 months.; Other Names: Aldactone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricular Strain	a sensitive measure of heart muscle function	12 months

Collaborators and Investigators

• Sponsor: Ohio State University
• Collaborators: University of Colorado, Denver; University of California, Los Angeles; Vanderbilt University Medical Center; University of Kansas Medical Center; University of Utah
• Investigators: Principal Investigator: Subha V Raman, MD, Ohio State University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2015
• Primary Completion (Actual): May 1, 2018
• Study Completion (Actual): May 1, 2018

Study Registration Dates

• First Submitted: January 27, 2015
• First Submitted That Met QC Criteria: February 2, 2015
• First Posted (Estimate): February 3, 2015

Study Record Updates

• Last Update Posted (Actual): October 7, 2019
• Last Update Submitted That Met QC Criteria: September 23, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne; Physiological Effects of Drugs; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone; Eplerenone
• Other Study ID Numbers: 2014H0387

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No