Pilot study of a virtual weight management program for Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Young people with Duchenne muscular dystrophy (DMD) are at increased risk of obesity. Weight management is important to families; however, several barriers exist. This pilot study aimed to investigate the feasibility and acceptability of a co-designed weight management program for DMD. METHODS: The Supporting Nutrition and Optimizing Wellbeing Program (SNOW-P) was a single-arm diet and behavior weight management intervention delivered via weekly telehealth/phone visits over 6 weeks to young people with DMD and obesity (body mass index (BMI) ≥95th percentile) and their caregivers. Using an online survey, caregivers of boys with DMD were consulted on the structure and topics delivered in SNOW-P. Primary outcomes were feasibility and acceptability; secondary outcomes were weight, physical function, and quality of life at 6- and 12-weeks follow-up. RESULTS: Of nineteen eligible participants, eight were enrolled (median age 11.4 years, range 4.9-15.8), and seven completed the program. Visit attendance was high (88%-100%); most participants reported high satisfaction and that participation was easy. Suggested changes included online and visual DMD-specific resources. At 6-weeks, median change in weight z-scores was -0.01 (IQR: -0.23, 0.17) indicating that on average, weight gain tracked as expected for age. Waist circumference measured by caregivers lacked accuracy and the completion rate of caregiver-reported secondary outcome measures (e.g., food diaries) was low. DISCUSSION: A co-designed, telehealth/phone weight management program appeared to be feasible and acceptable in a small group of boys with DMD. An adapted, hybrid telehealth and face-to-face program is recommended for efficacy testing.

A phase 2 open-label study of the safety and efficacy of weekly dosing of ATL1102 in patients with non-ambulatory Duchenne muscular dystrophy and pharmacology in mdx mice.

BACKGROUND: ATL1102 is a 2'MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4, inhibiting expression of CD49d on lymphocytes, reducing survival, activation and migration to sites of inflammation. Children with DMD have dystrophin deficient muscles susceptible to contraction induced injury, which triggers the immune system, exacerbating muscle damage. CD49d is a biomarker of disease severity in DMD, with increased numbers of high CD49d expressing T cells correlating with more severe and progressive weakess, despite corticosteroid treatment. METHODS: This Phase 2 open label study assessed the safety, efficacy and pharmacokinetic profile of ATL1102 administered as 25 mg weekly by subcutaneous injection for 24 weeks in 9 non-ambulatory boys with DMD aged 10-18 years. The main objective was to assess safety and tolerability of ATL1102. Secondary objectives included the effect of ATL1102 on lymphocyte numbers in the blood, functional changes in upper limb function as assessed by Performance of Upper Limb test (PUL 2.0) and upper limb strength using MyoGrip and MyoPinch compared to baseline. RESULTS: Eight out of nine participants were on a stable dose of corticosteroids. ATL1102 was generally safe and well tolerated. No serious adverse events were reported. There were no participant withdrawals from the study. The most commonly reported adverse events were injection site erythema and skin discoloration. There was no statistically significant change in lymphocyte count from baseline to week 8, 12 or 24 of dosing however, the CD3+CD49d+ T lymphocytes were statistically significantly higher at week 28 compared to week 24, four weeks past the last dose (mean change 0.40x109/L 95%CI 0.05, 0.74; p = 0.030). Functional muscle strength, as measured by the PUL2.0, EK2 and Myoset grip and pinch measures, and MRI fat fraction of the forearm muscles were stable throughout the trial period. CONCLUSION: ATL1102, a novel antisense drug being developed for the treatment of inflammation that exacerbates muscle fibre damage in DMD, appears to be safe and well tolerated in non-ambulant boys with DMD. The apparent stabilisation observed on multiple muscle disease progression parameters assessed over the study duration support the continued development of ATL1102 for the treatment of DMD. TRIAL REGISTRATION: Clinical Trial Registration. Australian New Zealand Clinical Trials Registry Number: ACTRN12618000970246.

Fracture risk and impact in boys with Duchenne muscular dystrophy: A retrospective cohort study.

INTRODUCTION/AIMS: Boys with Duchenne muscular dystrophy (DMD) are at increased risk of fracture. This study investigated the incidence of fractures, factors contributing to risk of first fracture with emphasis on body mass index (BMI), and the impact of fractures on functional capacity in an Australian cohort of boys with DMD. METHODS: A retrospective cohort study included boys with DMD who attended a pediatric neuromuscular clinic from 2011 to 2018. Information regarding fractures, anthropometry measurements, body composition and functional assessment was collected. Factors associated with first fracture risk were analyzed with Cox-proportional hazards. Longitudinal analysis of function post-fracture was also conducted. RESULTS: This study included 155 boys with DMD. At least one fracture occurred in 71 (45%) boys; overall incidence of fractures was 399-per-10,000 persons-years. The first fracture was vertebral in 55%; 41% had non-vertebral fractures and 4% had both. Vertebral fractures occurred in significantly older (12.28 vs 9.28 y) boys with longer exposure to glucocorticoids (5.45 vs 2.50 y) compared to non-vertebral fractures. Boys with a history of fracture(s) had a steeper rate of functional decline (measured by Northstar Ambulatory Assessment score) than those with no recorded fractures. DISCUSSION: A high fracture burden was observed in a large Australian cohort of boys with DMD. Further investigation is required to understand preventative strategies and modifiable risk factors to reduce the incidence of fractures in DMD. The impact on fractures on ambulatory capacity should be closely monitored.

The Relationship between Obesity and Clinical Outcomes in Young People with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder. Young people with DMD have high rates of obesity. There is emerging evidence that a higher BMI may negatively affect clinical outcomes in DMD. This study aimed to explore the relationship between obesity and clinical outcomes in DMD. METHODS: This was a retrospective clinical audit of young people (two-21 years) with DMD. Height and weight were collected to calculate BMI z-scores to classify obesity, overweight and no overweight or obesity (reference category). Cox proportional hazards models determined the impact of obesity at five to nine years on clinical milestones including time to: loss of ambulation, timed function test cut-offs, obstructive sleep apnoea (OSA) diagnosis and first fracture. RESULTS: 158 young people with DMD were included; most (89.9%) were steroid-treated. Mean follow-up was 8.7 ± 4.7 years. Obesity prevalence increased from age five (16.7%) to 11 years (50.6%). Boys with obesity at nine years sustained a fracture earlier (hazard ratio, HR: 2.050; 95% CI: 1.038-4.046). Boys with obesity at six to nine years were diagnosed with OSA earlier (e.g., obesity nine years HR: 2.883; 95% CI: 1.481-5.612). Obesity at eight years was associated with a 10 m walk/run in 7-10 s occurring at an older age (HR: 0.428; 95% CI: 0.207-0.887), but did not impact other physical function milestones. CONCLUSIONS: Although 50% of boys with DMD developed early obesity, the impact of obesity on physical function remains unclear. Obesity puts boys with DMD at risk of OSA and fractures at a younger age. Early weight management interventions are therefore important.

Delivering multidisciplinary neuromuscular care for children via telehealth.

INTRODUCTION/AIMS: In response to coronavirus disease 2019 (COVID-19) pandemic restrictions int 2020, our face-to-face (F2F) multidisciplinary neuromuscular clinic (NMC) transitioned to widespread use of telehealth (TH). This study aimed to (1) understand parent/guardian, child, and clinician perceptions of TH; (2) examine TH-related changes in clinical activity; and (3) use these findings to inform a future model of care for the NMC. METHODS: A clinical audit was undertaken to examine clinical activity throughout 2018-2020. Online surveys were distributed to clinicians and parents of children attending the NMC via TH in 2020. A working group of clinicians created a checklist to guide a future hybrid model of TH and F2F care. RESULTS: Total clinical activity in 2020 was maintained from previous years; 62.8% of all appointments occurred via TH, and 82.3% of patients attended NMC by TH at least once. Ninety-nine parents (30.6% response rate), 52 children, and 17 clinicians (77% response rate) responded to the survey. All groups reported better interaction when F2F compared to TH. Eighty percent of parents identified advantages of TH and reported lower levels of stress. A lack of "hands-on" physical assessment was identified by parents and clinicians as a TH limitation. Most families (68.1% of parents; 58.8% of children) and all clinicians indicated a preference for a mix of TH and F2F NMC appointments in the future. DISCUSSION: This study has informed a checklist to guide future TH use in a new hybrid model of care. Further investigation is required to assess health impacts of TH use in pediatric neuromuscular care.

Characterising gait in paediatric neuromuscular disorders: an observational study of spatio-temporal gait in a clinical cohort.

AIM: Few studies have characterised the relationship between disease and gait function in children and young people with rare neuromuscular disorders (NMDs). This study aimed to describe the relationship between disease and gait in a large paediatric cohort from a neuromuscular outpatient clinic. METHODS: A prospective, cross-sectional study of gait in independently ambulant children and young people aged 4-21 years with a clinical or genetically confirmed NMD. Participants traversed an electronic walkway barefoot and in footwear at self-selected and fast pace. Analysis of disease included a typically developing (TD) reference group. RESULTS: A sample of 113 participants with NMD, mean age 9.5 years (SD 3.1), 28% female, grouped into nine diagnostic subgroups. Eighty percent reported limitations to functional mobility. Children with NMD walked slower, with a shorter and wider step compared to a TD reference group, with moderate to large effect sizes for each of these gait parameters indicative of the clinical significance of these gait deviations. Children with Duchenne muscular dystrophy (DMD) walked slowest with a markedly wide gait pattern. Footwear had little overall effect on gait in children with NMDs. All children could accelerate over short distances. CONCLUSIONS: Gait, notably speed, step length, and width are clinically significant biomarkers of disease in paediatric NMDs, affording objective functional measures in clinical settings and research.Implications for rehabilitationGait should be considered a functional biomarker of disease in children and young people with neuromuscular disorders (NMDs).Comparison of gait in a paediatric neuromuscular cohort indicates that children with Duchenne muscular dystrophy (DMD) walk slowest with a shorter step length and a wider step width which increases with age and disease progression.Measurement of gait speed is a simple, pragmatic tool to monitor disease progression in the outpatient clinical environment and relates to everyday function.In clinical research, gait can be measured as a functional outcome to demonstrate change from disease-modifying interventions and treatments in NMDs.