Historically Controlled Trial of Corticosteroids in Young Boys With Duchenne Muscular Dystrophy

Phase 2 Historically Controlled Trial of Corticosteroids in Young Boys With Duchenne Muscular Dystrophy

Nationwide Children's Hospital, Northwestern University Feinberg School of Medicine, University of Texas Southwestern Medical Center, University of California, Davis, Nemours Hospital, Orlando, FL

While it has been known for many years that corticosteroid use benefits boys with Duchenne Muscular dystrophy (DMD), most clinicians do not consider treating until after age 3 or 4 years of age. The primary reason for the delay is that daily corticosteroid use has many side effects including short stature, obesity, and osteoporosis. A recent randomized blinded study of weekend oral corticosteroid use over one year showed equal improvement in strength with fewer side effects, particularly as related to growth and cushingoid changes. The investigators will test the efficacy of oral weekend corticosteroid use in infants and young boys with DMD who are under age 30 months. The investigators have demonstrated that the Bayley-III Scales of Infant development shows that infants and young boys in this age group who are untreated decline in abilities when compared to their peers. Here, in this Phase 2 historically controlled trial, the investigators will use these two measures and treat boys at five Muscular Dystrophy Association-DMD centers

Objective. Determine if twice-weekly high dose oral prednisone improves gross motor development in infants and young boys with DMD. The investigators will perform a phase 2 historically controlled trial of oral twice-weekly prednisone (5mg/kg/dose on two consecutive days) in infants and young boys with DMD. Here the investigators propose to study the effect of this therapy in a multicenter trial of boys with DMD who are less than 30 months old at the baseline visit. Each boy will be followed for one year. Aim 1. Determine if treatment improves gross motor function in infants with DMD over a 6-12-month period as measured by the Bayley-III. The Bayley-III infant score is the primary motor clinical endpoint of this therapeutic trial. Secondary outcomes include fine motor function, speech and language, and social function. Aim 2. Determine if treatment improves the Adaptive Behavior Subtest of the Bayley-III (ABS) as scored by the infants' primary caregiver. In the study of untreated boys, the primary caregiver noted clear deficits, predominantly related to areas relevant to gross motor function. The ABS Aim 3. Determine if treatment improves performance on the North Star Ambulatory Assessment (NSAA) for those boys who are ambulatory. Aim 4. Determine if treatment with weekly corticosteroids is tolerated and is safe in boys with DMD who are less than 30 months of age. Objective 2. Determine if ultrasound of biceps and quadriceps using calibrated backscatter improves in infants and young boys with DMD who are treated with oral high dose weekly corticosteroids. Preliminary data of ultrasound imaging in infants and young boys with DMD demonstrate progressive structural damage as measured by calibrated backscatter. The ultrasound studies will be limited to the infants and boys who will enroll at the primary site (Washington University) where Dr. Craig Zaidman has the equipment and expertise to accomplish this aim. Objective 3. Determine if caregiver burden changes with treatment of infants and young boys with DMD. Preliminary data from questionnaires suggests the caregiver burden for the primary caregiver of untreated infant and young boys with DMD is minimal. Assessment of this with in this trial will allow us to discern if this changes with a therapeutic trial.

Prednisolone (5mg per kg) will be taken on two consecutive days, Friday and Saturday mornings each week with breakfast

Bayley III Gross Motor Scaled Score measures motor development. This is normed for typically developing children and follow a bell shaped curve. The scale has mean of 10 +/-3 for children at all ages and is bell shaped. Therefore the two standard deviation range is 16 to 4 with higher values indicated better performance. Lower values have been shown to be common in boys with DMD and it this study the baseline average score was 4.2.

Inclusion Criteria: Appropriate degree of weakness for age, creatine kinase greater than 20 times the upper limit of normal, and genetic mutation known to be causative for Duchenne muscular dystrophy . Appropriate degree of weakness for age, creatine kinase greater than 20 times the upper limit of normal and genetic or biopsy confirmation of Duchenne muscular dystrophy in a primary relative (e.g. brother or maternal uncle). De-identified, genetic studies will be reviewed by collaborator Kevin Flanigan, MD prior to enrollment of subjects. Age at entry: one month through 30 months. Exclusion Criteria: Prior treatment with corticosteroids

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Connolly AM, Zaidman CM, Golumbek PT, Cradock MM, Flanigan KM, Kuntz NL, Finkel RS, McDonald CM, Iannaccone ST, Anand P, Siener CA, Florence JM, Lowes LP, Alfano LN, Johnson LB, Nicorici A, Nelson LL, Mendell JR; MDA DMD Clinical Research Network. Twice-weekly glucocorticosteroids in infants and young boys with Duchenne muscular dystrophy. Muscle Nerve. 2019 Jun;59(6):650-657. doi: 10.1002/mus.26441. Epub 2019 Feb 23.