<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03777319</url>
  </required_header>
  <id_info>
    <org_study_id>IRB17-00240</org_study_id>
    <nct_id>NCT03777319</nct_id>
  </id_info>
  <brief_title>Spironolactone Versus Prednisolone in DMD</brief_title>
  <official_title>A Randomized Open Label Trial of Spironolactone Versus Prednisolone in Corticosteroid-naïve Boys With DMD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kevin Flanigan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Muscular Dystrophy Association</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Nationwide Children's Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized, open-label, pilot clinical trial of spironolactone suspension versus&#xD;
      oral prednisolone for use in Duchenne muscular dystrophy. The goals are to determine the&#xD;
      safety of 6 months of treatment with spironolactone treatment int he steroid-naive DMD&#xD;
      population as well as to determine if either spironolactone or a standard clinical dose of&#xD;
      corticosteroids results in equivalent improvement in time to complete the 100 meter timed&#xD;
      test (100M).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Until recently, the only treatment shown to improve strength and preserve ambulation in DMD&#xD;
      patients was the use of glucocorticoids, which are accompanied by significant side effects&#xD;
      including obesity, cushingoid features, osteoporosis, and behavioral disturbances.&#xD;
      Spironolactone is an aldosterone antagonist primarily used as a potassium sparing diuretic&#xD;
      that is widely used in the pediatric population, with limited side-effects including&#xD;
      gynecomastia and hyperkalemia. Recent studies by Dr. Rafael-Fortney have evaluated the effect&#xD;
      of spironolactone treatment in several different mouse models of DMD. Her results show that&#xD;
      treatment of these mice demonstrates increased muscle membrane stabilization while reducing&#xD;
      the negative side-effects typically associated with standard of care glucocorticoids. This&#xD;
      pilot study is designed to determine whether this commonly used medication, spironolactone,&#xD;
      may have similar beneficial effects with a lower side effect profile and be applicable to a&#xD;
      wider population of DMD patients.&#xD;
&#xD;
      The hypothesis for this controlled pilot trial is that spironolactone and prednisolone are of&#xD;
      equal efficacy in improving skeletal muscle function over a 6-month period, and that&#xD;
      spironolactone will be well tolerated in this patient population.&#xD;
&#xD;
      One outcome is that both drugs demonstrate equal efficacy in motor function. This would then&#xD;
      serve as pilot data for a longer term study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Inability to recruit participants.&#xD;
  </why_stopped>
  <start_date type="Actual">December 5, 2018</start_date>
  <completion_date type="Actual">November 30, 2021</completion_date>
  <primary_completion_date type="Actual">September 27, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Subjects will be randomly assigned to either to the spironolactone treatment group or to the standard clinical dose of corticosteroids.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy: Change in time to complete a 100 meter timed test.</measure>
    <time_frame>6 months</time_frame>
    <description>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).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety will be monitored through regular review of electrolytes.</measure>
    <time_frame>6 months</time_frame>
    <description>Electrolytes (Sodium, Potassium, Cloride and Carbon dioxide, mmol/L) will be measured on a monthly basis following initiation of either spironolactone or prednisolone.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy: Dynamometry score</measure>
    <time_frame>6 months</time_frame>
    <description>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; 4-stair climb; North Star Ambulatory Assessment (NSAA); and time to arise from the floor.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Muscular Dystrophy, Duchenne</condition>
  <arm_group>
    <arm_group_label>Spironolactone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Twelve subjects will be prescribed a standard clinical dose of spironolactone of 1 mg/kg/day. The spironolactone will be provided as suspension.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prednisolone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Spironolactone</intervention_name>
    <description>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.</description>
    <arm_group_label>Spironolactone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisolone</intervention_name>
    <description>Prednisolone will be prescribed for 6 months as the clinical standard of care.</description>
    <arm_group_label>Prednisolone</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Duchenne muscular dystrophy (DMD) patients ≥4 to ≤7 years of age&#xD;
&#xD;
          -  Clinical features of DMD that include proximal predominant weakness and/or gait&#xD;
             disturbance&#xD;
&#xD;
          -  Presence of a truncating mutation of the DMD gene in the patient or an affected male&#xD;
             relative OR a muscle biopsy that demonstrates &lt;5% dystrophin in the patient or an&#xD;
             affected male relative&#xD;
&#xD;
          -  Normal left ventricular ejection fraction by screening echocardiogram&#xD;
&#xD;
          -  Ability to cooperate for testing&#xD;
&#xD;
          -  No prior treatment with glucocorticoids or vamorolone&#xD;
&#xD;
          -  No concomitant experimental therapies&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject amenable to or currently being treated with eteplirsen, casimersen, or&#xD;
             viltolarsen&#xD;
&#xD;
          -  Hyperkalemia at screening&#xD;
&#xD;
          -  History of or ongoing renal failure (elevated creatinine, oliguria, anuria)&#xD;
&#xD;
          -  Hypersensitivity to spironolactone (rash, respiratory distress, arrhythmia, numbness&#xD;
             or tingling of extremities)&#xD;
&#xD;
          -  Current treatment with an ACEi&#xD;
&#xD;
          -  Severe peptic ulcer disease or recent gastrointestinal perforations&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>4 Years</minimum_age>
    <maximum_age>7 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kevin Flanigan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Nationwide Children's Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Megan Waldrop, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Nationwide Children's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Iowa</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nationwide Children's Hospital</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <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>
    <PMID>18254031</PMID>
  </reference>
  <reference>
    <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>
    <PMID>15811903</PMID>
  </reference>
  <reference>
    <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>
    <PMID>21768542</PMID>
  </reference>
  <reference>
    <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>
    <PMID>24551095</PMID>
  </reference>
  <reference>
    <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>
    <PMID>27822449</PMID>
  </reference>
  <reference>
    <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>
    <PMID>26178166</PMID>
  </reference>
  <reference>
    <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>
    <PMID>27798095</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>28279570</PMID>
  </reference>
  <verification_date>January 2022</verification_date>
  <study_first_submitted>December 10, 2018</study_first_submitted>
  <study_first_submitted_qc>December 13, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 17, 2018</study_first_posted>
  <last_update_submitted>January 19, 2022</last_update_submitted>
  <last_update_submitted_qc>January 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">January 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Nationwide Children's Hospital</investigator_affiliation>
    <investigator_full_name>Kevin Flanigan</investigator_full_name>
    <investigator_title>Professor of Neurology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Muscular Dystrophies</mesh_term>
    <mesh_term>Muscular Dystrophy, Duchenne</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Spironolactone</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>November 28, 2022</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03777319
org study id: IRB17-00240
nct id: NCT03777319
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
allocation: Randomized
intervention model: Parallel Assignment
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
masking: None (Open Label)
measure: Efficacy: Change in time to complete a 100 meter timed test.
time frame: 6 months
description: 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).
measure: Safety will be monitored through regular review of electrolytes.
time frame: 6 months
description: Electrolytes (Sodium, Potassium, Cloride and Carbon dioxide, mmol/L) will be measured on a monthly basis following initiation of either spironolactone or prednisolone.
measure: Efficacy: Dynamometry score
time frame: 6 months
description: 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; 4-stair climb; North Star Ambulatory Assessment (NSAA); and time to arise from the floor.
arm group label: Spironolactone
arm group type: Experimental
description: Twelve subjects will be prescribed a standard clinical dose of spironolactone of 1 mg/kg/day. The spironolactone will be provided as suspension.
arm group label: Prednisolone
arm group type: Active Comparator
description: 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.
intervention type: Drug
intervention name: Spironolactone
description: 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.
arm group label: Spironolactone
intervention type: Drug
intervention name: Prednisolone
description: Prednisolone will be prescribed for 6 months as the clinical standard of care.
arm group label: Prednisolone
criteria: 
gender: Male
minimum age: 4 Years
maximum age: 7 Years
healthy volunteers: No
last name: Kevin Flanigan, MD
role: Principal Investigator
affiliation: Nationwide Children's Hospital
last name: Megan Waldrop, MD
role: Principal Investigator
affiliation: Nationwide Children's Hospital
facility: 
facility: 
facility: 
facility: 
country: United States
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.
PMID: 18254031
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.
PMID: 15811903
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.
PMID: 21768542
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.
PMID: 24551095
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.
PMID: 27822449
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.
PMID: 26178166
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.
PMID: 27798095
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.
PMID: 28279570
responsible party type: Sponsor-Investigator
investigator affiliation: Nationwide Children's Hospital
investigator full name: Kevin Flanigan
investigator title: Professor of Neurology
mesh term: Muscular Dystrophies
mesh term: Muscular Dystrophy, Duchenne
mesh term: Prednisolone
mesh term: Spironolactone
submitted: November 28, 2022