Clinical trial NCT03777319: Spironolactone Versus Prednisolone in DMD
Official title: A Randomized Open Label Trial of Spironolactone Versus Prednisolone in Corticosteroid-naïve Boys With DMD
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Muscular Dystrophy, Duchenne
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
Collaborators: name: Muscular Dystrophy Association
First posted: 2018-12-17
Enrollment: 2
Sex: MALE
Minimum age (years): 4
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects will be randomly assigned to either to the spironolactone treatment group or to the standard clinical dose of corticosteroids.
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Efficacy: Change in Time to Complete a 100 Meter Timed Test.
timeFrame: 6 months
measure: Safety Will be Monitored Through Regular Review of Electrolytes.
timeFrame: 6 months
Secondary outcomes:
measure: Efficacy: Dynamometry Score
timeFrame: 6 months
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: Nationwide Children's Hospital
name: Kevin Flanigan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nationwide Children's Hospital
name: Megan Waldrop, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003725. doi: 10.1002/14651858.CD003725.pub3.
citation: Buck ML. Clinical experience with spironolactone in pediatrics. Ann Pharmacother. 2005 May;39(5):823-8. doi: 10.1345/aph.1E618. Epub 2005 Apr 5.
citation: Rafael-Fortney JA, Chimanji NS, Schill KE, Martin CD, Murray JD, Ganguly R, Stangland JE, Tran T, Xu Y, Canan BD, Mays TA, Delfin DA, Janssen PM, Raman SV. Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in Duchenne muscular dystrophy mice. Circulation. 2011 Aug 2;124(5):582-8. doi: 10.1161/CIRCULATIONAHA.111.031716. Epub 2011 Jul 18.
citation: Janssen PM, Murray JD, Schill KE, Rastogi N, Schultz EJ, Tran T, Raman SV, Rafael-Fortney JA. Prednisolone attenuates improvement of cardiac and skeletal contractile function and histopathology by lisinopril and spironolactone in the mdx mouse model of Duchenne muscular dystrophy. PLoS One. 2014 Feb 13;9(2):e88360. doi: 10.1371/journal.pone.0088360. eCollection 2014.
citation: Lowe J, Floyd KT, Rastogi N, Schultz EJ, Chadwick JA, Swager SA, Zins JG, Kadakia FK, Smart S, Gomez-Sanchez EP, Gomez-Sanchez CE, Raman SV, Janssen PM, Rafael-Fortney JA. Similar efficacy from specific and non-specific mineralocorticoid receptor antagonist treatment of muscular dystrophy mice. J Neuromuscul Dis. 2016;3(3):395-404. doi: 10.3233/JND-160173.
citation: Chadwick JA, Hauck JS, Lowe J, Shaw JJ, Guttridge DC, Gomez-Sanchez CE, Gomez-Sanchez EP, Rafael-Fortney JA. Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target. FASEB J. 2015 Nov;29(11):4544-54. doi: 10.1096/fj.15-276782. Epub 2015 Jul 15.
citation: Chadwick JA, Swager SA, Lowe J, Welc SS, Tidball JG, Gomez-Sanchez CE, Gomez-Sanchez EP, Rafael-Fortney JA. Myeloid cells are capable of synthesizing aldosterone to exacerbate damage in muscular dystrophy. Hum Mol Genet. 2016 Dec 1;25(23):5167-5177. doi: 10.1093/hmg/ddw331.
citation: Alfano LN, Miller NF, Berry KM, Yin H, Rolf KE, Flanigan KM, Mendell JR, Lowes LP. The 100-meter timed test: Normative data in healthy males and comparative pilot outcome data for use in Duchenne muscular dystrophy clinical trials. Neuromuscul Disord. 2017 May;27(5):452-457. doi: 10.1016/j.nmd.2017.02.007. Epub 2017 Feb 17.