Weekly Steroids in Muscular Dystrophy

Study Overview
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Brief Summary
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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
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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.

Official Title
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Open Label Safety and Efficacy of Once Weekly Steroid in Patients With LGMD and Becker Muscular Dystrophy

Conditions
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Limb-girdle Muscular Dystrophy, Becker Muscular Dystrophy

Intervention / Treatment
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* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Becker muscular dystrophy or LGMD2A (CAPN3), LGMD 2B (DYSF), LGMD 2C (SGCG), LGMD2E (SGCB), LGMD2F (SGCD), LGMD 2I (FKRP), LGMD (ANO5). Genetic mutation or muscle biopsy staining required to confirm genetic subtype Ages 18-65 years EKG without evidence of prior infarct or atrial fibrillation done within 2 months of study initiation. Echocardiogram with LVEF >25% done within 6 months of study initiation. Stable medications (same medication and dose) for the previous 3 months Stable pulmonary status for the previous 6 months (No change in FVC by more than 20% in the past 6-months) Exclusion Criteria: Diabetes BMI>35 kg/m2 Cardiac transplantation Myocardia Infarct in the past 2-years from screening Any history of tuberculosis Untreated or uncontrolled (medication and/or dose change in previous month from screening) hypertension A diagnosis of congestive heart failure A diagnosis of chronic kidney disease A diagnosis of untreated hypothyroidism The patient is believed to be at high risk of osteoporosis by the primary investigator Inability to provide consent Full time ventilator dependency Heart failure symptoms or LVEF <25% Orthopedic surgery within the prior year or upcoming elective orthopedic surgery within the 6-months from Day 0. Inability to complete MRI (claustrophobia, metal implants) Pregnant women at screening, women seeking to become pregnant, or men seeking to father a child within 6-months from Day 0 should not participate in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Weekly Steroid<br>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 | Drug: Prednisone<br>* 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<br>* Other names: Prednisolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Glucose | mg/dL, 0-unlimited, higher score indicates worse outcome | Baseline and 6 months (Final Visit) | 
| HbgA1c | % , 0-100, higher score indicates worse outcome | Baseline and 6 months (Final Visit) | 
| Fasting Lipid Profile | cholesterol levels - mg/dL, higher levels indicate worse outcomes | Baseline and 6 months (Final Visit) | 
| Creatine Kinase | units/L, 0-unlimited, higher scores indicate worse outcome | Baseline and 6 months (Final Visit) | 
| Respiratory Changes | Force Vital Capacity (% of predicted value), decrease in FVC indicates declining respiratory function. | Baseline, 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Assessments - NSAD Change | Northstar Assessment for Dysferlinopathy - score out of 58, range from 0 to 58, higher score indicates greater functional ability. | Baseline, Month 6 | 
| 6 Minute Walk Test | number of meters walked in 6 minute period. Higher values indicate more motor function. | Baseline, Month 6 | 
| 10 Meter Run Timed | time in seconds to walk/run 10 meters , less time to run indicates greater motor function | Baseline, Month 6 | 
| Brooke Scale Score | upper extremity assessment, scoring between 1- 6, lower score indicates more upper extremity function | Baseline, Month 6 | 
| Vignos Scale Score | Lower extremity assessment, score from 1-10, lower score indicates more function. | Baseline, Month 6 | 
| Muscle Imaging | MRI of leg muscles to measure changes in muscle fat percentage. The data point was collected by taking fat percentage at 6 months minus fat percentage at baseline with the following equation: (([final fat percentage - initial fat percentage]/initial fat percentage) * 100%)). All participants were included, both ambulatory and nonambulatory, with all genetic subtypes included. Five participants didn't have an MRI scan at 6 months and therefore were not included. Muscles imaged were analyzed for muscle fat changes from baseline to 6 months. Data is limited in interpretation due to various muscle groups in both ambulatory and non-ambulatory patients. | Baseline, 6 months | 
| Bone Density | whole dexa body scan to assess bone density with Z scores (more negative z score indicates increased risk for fractures). Z-score of 0 represents the population mean, and is the average bone density. Positive scores indicate greater bone density and negative scores indicate decreased bone density, which could be clinically correlated with osteoporosis. | Baseline, 6 months | 
| Lean Mass % | whole body dexa scans to assess lean mass % (0- 100 %). Increase lean mass % is the desired outcome. | Baseline, 6 months | 
| Functional Assessments - Upper Limb Strength | Grip strength of the total force (Newtons) in both hands. Participants attempted 3 trials in the right hand that was then averaged to create a right-hand average force score. Then, the participants attempted 3 trials in the left hand that was then averaged to create a left-hand average force score. The right-hand average force score was added to the left-hand average force score to create a total grip strength score. | Baseline and 6 months | 
| Muscle Strength Test | Manual motor testing of the right knee flexion muscle group. | baseline, 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Steroids, Prednisone