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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 : February 11, 2019
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

Tracking Information
First Submitted Date  ICMJE January 27, 2015
First Posted Date  ICMJE February 3, 2015
Last Update Posted Date February 11, 2019
Actual Study Start Date  ICMJE March 20, 2015
Actual Primary Completion Date May 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 2, 2015)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02354352 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2015)
Forced vital capacity (a measure of pulmonary function) [ Time Frame: 12 months ]
a measure of pulmonary function
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 2, 2015)
muscle injury blood biomarkers (blood measures of muscle damage and repair) [ Time Frame: 12 months ]
blood measures of muscle damage and repair
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy
Official Title  ICMJE Therapeutic Potential for Aldosterone Inhibition in Duchenne Muscular Dystrophy
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Duchenne Muscular Dystrophy
Intervention  ICMJE
  • Drug: Eplerenone
    26 Subjects will take Eplerenone, one 50mg capsule by mouth once daily for 12 months.
    Other Name: Inspra
  • Drug: Spironolactone
    26 Subjects will take Spironolactone, one 50mg capsule by mouth once daily for 12 months.
    Other Name: Aldactone
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Eplerenone
  • 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.
    Intervention: Drug: Spironolactone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 2, 2015)
52
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2018
Actual Primary Completion Date May 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 7 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02354352
Other Study ID Numbers  ICMJE 2014H0387
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Subha Raman, Ohio State University
Study Sponsor  ICMJE Ohio State University
Collaborators  ICMJE
  • University of California, Los Angeles
  • University of Utah
  • University of Colorado, Denver
  • University of Kansas Medical Center
  • Vanderbilt University Medical Center
Investigators  ICMJE
Principal Investigator: Subha V Raman, MD Ohio State University
PRS Account Ohio State University
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP