Spironolactone Versus Prednisolone in DMD

NCT ID: NCT03777319

Last Updated: 2023-10-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 2 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-05
• Study Completion Date: 2021-11-30

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.

Conditions

Muscular Dystrophy, Duchenne

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Spironolactone

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.

Group Type: EXPERIMENTAL

Spironolactone

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

Prednisolone

Intervention Type: DRUG

Prednisolone will be prescribed for 6 months as the clinical standard of care.

Interventions

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.

Intervention Type: DRUG

Prednisolone

Prednisolone will be prescribed for 6 months as the clinical standard of care.

Intervention Type: DRUG

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

• Minimum Eligible Age: 4 Years
• Maximum Eligible Age: 7 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Muscular Dystrophy Association

OTHER

Sponsor Role: collaborator

Kevin Flanigan

OTHER

Sponsor Role: lead

Responsible Party

Kevin Flanigan

Professor of Neurology

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Kevin Flanigan, MD

Role: PRINCIPAL_INVESTIGATOR

Nationwide Children's Hospital

Megan Waldrop, MD

Role: PRINCIPAL_INVESTIGATOR

Nationwide Children's Hospital

Locations

University of Iowa

Iowa City, Iowa, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

University of Utah

Salt Lake City, Utah, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 18254031 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15811903 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21768542 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24551095 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27822449 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26178166 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27798095 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28279570 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IRB17-00240

Identifier Type: -

Identifier Source: org_study_id