Spironolactone Versus Prednisolone in DMD

A Randomized Open Label Trial of Spironolactone Versus Prednisolone in Corticosteroid-naïve Boys With DMD

This is a randomized, open-label, pilot clinical trial of spironolactone suspension versus oral prednisolone for use in Duchenne muscular dystrophy. The goals are to determine the safety of 6 months of treatment with spironolactone treatment int he steroid-naive DMD population as well as to determine if either spironolactone or a standard clinical dose of corticosteroids results in equivalent improvement in time to complete the 100 meter timed test (100M).

Until recently, the only treatment shown to improve strength and preserve ambulation in DMD patients was the use of glucocorticoids, which are accompanied by significant side effects including obesity, cushingoid features, osteoporosis, and behavioral disturbances. Spironolactone is an aldosterone antagonist primarily used as a potassium sparing diuretic that is widely used in the pediatric population, with limited side-effects including gynecomastia and hyperkalemia. Recent studies by Dr. Rafael-Fortney have evaluated the effect of spironolactone treatment in several different mouse models of DMD. Her results show that treatment of these mice demonstrates increased muscle membrane stabilization while reducing the negative side-effects typically associated with standard of care glucocorticoids. This pilot study is designed to determine whether this commonly used medication, spironolactone, may have similar beneficial effects with a lower side effect profile and be applicable to a wider population of DMD patients. The hypothesis for this controlled pilot trial is that spironolactone and prednisolone are of equal efficacy in improving skeletal muscle function over a 6-month period, and that spironolactone will be well tolerated in this patient population. One outcome is that both drugs demonstrate equal efficacy in motor function. This would then serve as pilot data for a longer term study.

Subjects will be randomly assigned to either to the spironolactone treatment group or to the standard clinical dose of corticosteroids.

An anticipated twelve subjects will be prescribed a standard clinical dose of spironolactone of 1 mg/kg/day. The spironolactone will be provided as suspension.

An anticipated twelve subjects will be prescribed a standard clinical dose of prednisolone of 0.75 mg/kg/day or weekend dosing per sites standard of care. The prednisolone will be provided will be provided as suspension.

Spironolactone will be prescribed for 6 months, after which the family and primary care physician will determine to either remain on spironolactone or transfer to prednisolone.

The determination of whether spironolactone has similar efficacy to glucocorticoids in improving muscle strength in steroid naïve DMD patients. This will be determined by measuring the time to complete a 100 meter timed test (100M).

Electrolytes (Sodium, Potassium, Cloride and Carbon dioxide, mmol/L) will be measured on a monthly basis following initiation of either spironolactone or prednisolone.

Secondary outcome measures will be Dynamometry score, which is a summation of maximum voluntary isometric contraction test values for knee flexion, knee extension, elbow flexion, and elbow extension

Inclusion Criteria: Duchenne muscular dystrophy (DMD) patients ≥4 to ≤7 years of age Clinical features of DMD that include proximal predominant weakness and/or gait disturbance Presence of a truncating mutation of the DMD gene in the patient or an affected male relative OR a muscle biopsy that demonstrates <5% dystrophin in the patient or an affected male relative Normal left ventricular ejection fraction by screening echocardiogram Ability to cooperate for testing No prior treatment with glucocorticoids or vamorolone No concomitant experimental therapies Exclusion Criteria: Subject amenable to or currently being treated with eteplirsen, casimersen, or viltolarsen Hyperkalemia at screening History of or ongoing renal failure (elevated creatinine, oliguria, anuria) Hypersensitivity to spironolactone (rash, respiratory distress, arrhythmia, numbness or tingling of extremities) Current treatment with an ACEi Severe peptic ulcer disease or recent gastrointestinal perforations

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