Aldosterone inhibition in DMD

Principal Investigator: Michael Puchalski
Keywords: Duchenne , Muscular Dystrophy , aldosterone Department: Pediatric Administration
IRB Number: 00078373 Co Investigator:  
Specialty: Neurology
Sub Specialties: Muscular Dystrophy
Recruitment Status: Recruiting

Contact Information

Ashley  Snyder
ashley.snyder@hsc.utah.edu
8015879140

Brief Summary

 Primary Objective:

Demonstrate noninferiority of spironolactone vs. eplerenone in preserving cardiac function in DMD patients with preserved LV ejection fraction.

Secondary Objective:

Demonstrate noninferiority of spironolactone vs. eplerenone in preserving pulmonary function in DMD patients with preserved LV ejection fraction.

 

Evaluate biomarkers of muscle injury that predict treatment response.

Hypothesis 1.1: Spironolactone 50 mg qd is noninferior to eplerenone 50mg qd when assessing 12-month change in myocardial strain (Ecc) in DMD patients with preserved ejection fraction.

Hypothesis 1.2a: Less myocardial injury by baseline LGE score predicts greater preservation of Ecc in DMD boys treated with mineralocorticoid receptor antagonist (MRA).

Hypothesis 1.2b: Higher baseline osteopontin, a muscle injury marker, predicts greater Ecc improvement among DMD patients treated with MRA.

Hypothesis 1.3: There is similar decline of forced vital capacity (FVC%) before vs. after treatment with MRA.

For each study participant, change in myocardial strain (Ecc) from baseline to the one-year follow-up will be calculated. To compare Ecc change between DMD patients receiving eplerenone 50mg qd and those receiving spironolactone 50 mg qd in Hypothesis 1.1, we will conduct both graphical and inferential analyses. A side-by-side boxplot for Ecc change will be constructed to illustrate the observed difference between groups. The comparison of Ecc change will be conducted using an independent two-sample t-test when the normality assumption is not violated. If this assumption does not hold, a nonparametric exact Wilcoxon rank sum test will be conducted. Furthermore, analysis of covariance (ANCOVA) will be used to test the equality of the average change of myocardial strain (Ecc) between DMD patients receiving eplerenone 50mg qd and those receiving spironolactone 50 mg qd after adjusting for the baseline myocardial strain (Ecc).

To determine whether the decline in Ecc for DMD patients treated with MRA is negatively associated with baseline LGE score in Hypothesis 1.2a, we will conduct both graphical and inferential analyses. Scatter plot of baseline LGE score and decline in Ecc will be constructed for DMD patients treated with MRA. Pearson's correlation coefficient will be calculated to quantify the magnitude of association between baseline LGE score and decline in Ecc. Further analyses will be conducted by calculating the Spearman's rank correlation coefficient between baseline LGE score and decline in Ecc and regressing Ecc decline on baseline LGE score adjusting for possible confounders such as baseline age, baseline myocardial Ecc, use of beta-blocker, mean blood pressure, and EF.

To determine if the decline in Ecc for DMD patients treated with MRA is positively associated with baseline osteopontin in Hypothesis 1.2b, similar graphical and inferential analyses will be conducted as for Hypothesis 1.3a. Scatter plot of the baseline osteopontin and the decline in Ecc will be constructed for DMD patients treated with MRA to assess whether their relationship is linear. Pearson's correlation coefficient will be calculated to quantify the magnitude of the association. Further analyses will be conducted by calculating the Spearman's rank correlation coefficient between the baseline osteopontin and the decline in Ecc and regressing the Ecc decline on the baseline osteopontin by adjusting for possible confounders such as baseline age, baseline Ecc, use of beta-blocker, mean blood pressure, and EF.

To examine the reduction in the rate of decline of FVC% before vs. after treatment with MRA in Hypothesis 1.3, we will conduct both graphical and inferential analyses. Time plots of FVC% over multiple clinical assessments will be constructed for DMD patients treated with MRA. By including a time knot at the initiation of treatment, we will use a linear spline (piecewise linear) mixed effects model to estimate the rates of decline of FVC% before and after treatment and to test whether the reduction in the rate of decline is significant between pre- and post- treatment periods. A random intercept will be included to account for the within-person correlation in outcomes among multiple clinical assessments. In the model, covariates will be included as potential confounders, such as age and 1-year preenrollment FVC%. For the piecewise linear mixed effects model, the normality assumption for FVC% will be assessed to determine whether a certain transformation of the outcome should be applied.

Inclusion Criteria

i) Boys age ≥7 years with DMD confirmed clinically and by mutation analysis able to undergo cardiac magnetic resonance (CMR) without sedation, ii) LV EF ≥45%±5% by clinically-acquired echocardiography, cardiac nuclear scan or CMR done within months of enrollment, iii).

Exclusion Criteria

Excluded from enrollment are boys with a) non-MR compatible implants, b) severe claustrophobia, c) gadolinium contrast allergy, d) kidney disease, e) prior use of or allergy to aldosterone antagonist, or f) use of other investigational therapy.