Spironolactone Versus Prednisolone in DMD

NCT03777319 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: IRB17-00240
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 4

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).

Conditions

Muscular Dystrophy, Duchenne

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (1)

• Efficacy: Dynamometry Score

  6 months

Study Arms (2)

Spironolactone

EXPERIMENTAL

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.

Drug: Spironolactone

Prednisolone

ACTIVE COMPARATOR

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.

Drug: Prednisolone

Interventions

Spironolactone 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.

Spironolactone

Prednisolone DRUG

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

Prednisolone

Eligibility Criteria

• Age: 4 Years - 7 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Kevin Flanigan: lead
• Muscular Dystrophy Association: collaborator

Study Sites (4)

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

University of Utah

Salt Lake City, Utah, 84108, United States

Location

Related Publications (8)

• 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.

  PMID: 18254031 BACKGROUND

• 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.

  PMID: 15811903 BACKGROUND

• 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.

  PMID: 21768542 BACKGROUND

• 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.

  PMID: 24551095 BACKGROUND

• 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.

  PMID: 27822449 BACKGROUND

• 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.

  PMID: 26178166 BACKGROUND

• 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.

  PMID: 27798095 BACKGROUND

• 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.

  PMID: 28279570 BACKGROUND

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Interventions

Spironolactone; Prednisolone

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienetriols; Pregnadienes

Limitations and Caveats

Full enrollment into the study was unable to be obtained.

Results Point of Contact

• Title: Dr. Kevin Flanigan
• Organization: The Abigal Wexner Research Institute at Nationwide Children's Hospital

kevin.flanigan@nationwidechildrens.org

614-722-5615

Study Officials

• Kevin Flanigan, MD

  Nationwide Children's Hospital

  PRINCIPAL INVESTIGATOR

• Megan Waldrop, MD

  Nationwide Children's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Neurology

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

Study Record Dates

• First Submitted: December 10, 2018
• First Posted: December 17, 2018
• Study Start: December 5, 2018
• Primary Completion: September 27, 2021
• Study Completion: November 30, 2021
• Last Updated: October 23, 2023
• Results First Posted: October 23, 2023

Record last verified: 2023-10

Locations

US (4)