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Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy

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ClinicalTrials.gov Identifier: NCT02354352
Recruitment Status : Completed
First Posted : February 3, 2015
Last Update Posted : August 21, 2018
Sponsor:
Collaborators:
University of California, Los Angeles
University of Utah
University of Colorado, Denver
University of Kansas Medical Center
Vanderbilt University Medical Center
Information provided by (Responsible Party):
Subha Raman, Ohio State University

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.

Condition or disease Intervention/treatment Phase
Duchenne Muscular Dystrophy Drug: Eplerenone Drug: Spironolactone Phase 3

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  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy
Study Start Date : January 2015
Actual Primary Completion Date : May 2018
Actual Study Completion Date : May 2018


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 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.
Drug: Spironolactone
26 Subjects will take Spironolactone, one 50mg capsule by mouth once daily for 12 months.
Other Name: Aldactone




Primary Outcome Measures :
  1. Left ventricular strain (a sensitive measurement of heart function using cardiac MRI) [ Time Frame: 12 months ]
    a sensitive measurement of heart function using cardiac MRI


Secondary Outcome Measures :
  1. Forced vital capacity (a measure of pulmonary function) [ Time Frame: 12 months ]
    a measure of pulmonary function


Other Outcome Measures:
  1. muscle injury blood biomarkers (blood measures of muscle damage and repair) [ Time Frame: 12 months ]
    blood measures of muscle damage and repair



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Ages Eligible for Study:   7 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02354352


Locations
United States, California
Mattel Children's Hospital and David Geffen School of Medicine at UCLA
Los Angeles, California, United States, 90095-1743
United States, Colorado
University of Colorado
Aurora, Colorado, United States, 80045
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66103
United States, Ohio
The Ohio State University Medical Center
Columbus, Ohio, United States, 43210
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37212
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84113
Sponsors and Collaborators
Ohio State University
University of California, Los Angeles
University of Utah
University of Colorado, Denver
University of Kansas Medical Center
Vanderbilt University Medical Center
Investigators
Principal Investigator: Subha V Raman, MD Ohio State University

Responsible Party: Subha Raman, Professor of Medicine, Ohio State University
ClinicalTrials.gov Identifier: NCT02354352     History of Changes
Other Study ID Numbers: 2014H0387
First Posted: February 3, 2015    Key Record Dates
Last Update Posted: August 21, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Muscular Dystrophies
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Spironolactone
Eplerenone
Mineralocorticoid Receptor Antagonists
Diuretics, Potassium Sparing
Sodium Channel Blockers
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics
Natriuretic Agents
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action