Weekly Steroids in Muscular Dystrophy
Condition: Limb-girdle Muscular Dystrophy; Becker Muscular Dystrophy
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Dystrophies, Limb-Girdle
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to evaluate the safety and efficacy of oral weekly
      glucocorticoid steroids in patients with Becker Muscular Dystrophy (BMD), an inherited
      disorder in which patients experience weakness of the legs and pelvis, and Limb Girdle
      Muscular Dystrophy (LGMD), an inherited disorder in which patients experience progressive
      muscular weakness predominately in their hip and shoulders. The primary objective is safety
      which we the investigators will measure using laboratory testing and forced vital capacity
      (FVC), a breathing test that measures the strength of your lungs. The secondary objective is
      efficacy which will be measured by a change in MRI muscle mass, improved muscle performance,
      and quality of life.

      The investigators hypothesize that patients who receive oral weekly glucocorticoid steroids
      will have improviements in strength and quality of life compared to their baseline.
      Furthermore, the investigators anticipate that oral weekly glucocorticoid steroids will not
      have significant adverse impact on patients.
    

Detailed description: 
      Glucocorticoid (GC) steroids are a mainstay of therapy for Duchenne Muscular Dystrophy, where
      they have been shown to prolong ambulation in for DMD in random clinical trials (Gloss et
      al., 2016). Dosing regimen vary for DMD, but most trials utilized oral daily dosing at 0.75-
      1 mg/kg of prednisone or deflazacort (Birnkrant et al., 2018). The age at which to begin oral
      glucocorticoids and the age at which to cease steroid use are not well established by
      clinical trial investigation. High dose weekend dosing of oral glucocorticoid steroids has
      also been suggested to be noninferior to daily dosing when evaluated in a year-long study in
      DMD, and this approach is preferred in some settings since related to a reduced side effect
      profile, particularly with respect to behavioral changes which can occur with daily GC
      steroid dosing in children (Escolar et al., 2011). The use of GC steroids for other forms of
      muscular dystrophy, including Becker Muscular Dystrophy (BMD) and the Limb Girdle Muscular
      Dystrophies (LGMDs) is not considered standard of care and has insufficiently been
      investigated by randomized clinical trials (RCT). An RCT of GC steroids in LGMD 2B (DYSF
      mutations) was associated with unfavorable outcomes in the steroid treated group (Walter et
      al., 2013).

      Recently, weekly steroid dosing was investigated in preclinical mouse models of muscular
      dystrophy, including the mdx mouse model of DMD/BMD and two models of LGMD, including LGMD 2B
      (DYSF) and 2C (SGCG) (Quattrocelli et al., 2017a; Quattrocelli et al., 2017b). All three
      models showed improved strength and reduced fibrosis with weekly GC steroid dosing. Moreover,
      in unpublished data, long term studies (24-52 weeks duration) in mice, showed favorable
      results with improved muscle strength in the mdx and DYSF models.

      The investigators propose to carry out an open label safety and efficacy trial of oral weekly
      GC steroids in patients with BMD and LGMD subtypes. Subjects will be recruited based on age,
      molecular diagnosis of BMD and LGMD subtypes, and willingness to participate. Both ambulatory
      and nonambulatory subjects will be included. Subjects will be excluded if they have diabetes
      mellitus, full time ventilator use, or severely compromised cardiac function, including
      symptoms referable to heart failure. Subjects must provide consent.

      Subjects will be asked to take weekly GC oral prednisone dosed based on weight (1mg/kg for
      patients who weigh less than or equal to 70 kg and 0.75 mg/kg for patients who weigh more
      than 70 kg). Subjects will also be instructed to take their weekly prednisone on Mondays
      after their last meal between 7 and 9 PM. Prior to initiation, subjects will provide a blood
      sample for baseline screening including serum chemistries, HgbA1-C, creatine kinase, and
      lipid panel (HDL, LDL, triglycerides, and total cholesterol) and for exploratory biomarkers.
      Subjects will also provide a urine sample to analyze changes in metabolic biomarkers that are
      excreted. Subjects will have a physical exam and medical record review. Subjects will have
      strength testing and complete 10 meter timed run test in addition to a 6 min walk test (if
      ambulatory). Subjects will be asked to complete quality of life questionnaire. At 6 months,
      subjects will be evaluated with a physical exam, strength testing, spirometry, 10 meter timed
      run test and 6 min walk test (if ambulatory), blood draw for serum chemistry, HgbA1-C,
      creatine kinase, lipid panel and for exploratory biomarkers. Subjects will also provide a
      urine specimen to be analyzed for any changes in excretion of metabolic markers as an
      exploratory endpoint. Subjects will be asked to complete a quality of life questionnaire. An
      MRI/ MRS will be performed before starting GC oral prednisone and at 6 months.
    

Intervention name(s): Prednisone
Intervention type(s): Drug
Intervention description(s): Subjects will be asked to take weekly GC oral prednisone dosed based on weight (1mg/kg for patients who weigh less than or equal to 70 kg and 0.75 mg/kg for patients who weigh more than 70 kg). Subjects will also be instructed to take their weekly prednisone on Mondays after their last meal between 7 and 9 PM
Other intervention name(s): Prednisolone
Intervention MeSH terms: Prednisone; Prednisolone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Steroids, Prednisone