Spironolactone Versus Prednisolone in DMD

Muscular Dystrophy, Duchenne Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03777319
• Other study ID #: IRB17-00240
• Status: Terminated
• Phase: Phase 1
• Start date: December 5, 2018
• Est. completion date: November 30, 2021

Study information

• Verified date: October 2023
• Source: Nationwide Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: November 30, 2021
• Est. primary completion date: September 27, 2021
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 4 Years to 7 Years

Eligibility

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

Related Conditions & MeSH terms

• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Drug:
• Spironolactone
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.
• Prednisolone
Prednisolone will be prescribed for 6 months as the clinical standard of care.

Locations

Country	Name	City	State
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of Iowa	Iowa City	Iowa
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Utah	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
Kevin Flanigan	Muscular Dystrophy Association

Country where clinical trial is conducted

United States, 

References & Publications (8)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy: Change in Time to Complete a 100 Meter Timed Test.	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).	6 months
Primary	Safety Will be Monitored Through Regular Review of Electrolytes.	Electrolytes (Sodium, Potassium, Cloride and Carbon dioxide, mmol/L) will be measured on a monthly basis following initiation of either spironolactone or prednisolone.	6 months
Secondary	Efficacy: Dynamometry Score	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	6 months