A Remote Study Using Technology to Assess Outcomes in DMD

Every year, 100 boys are born in the UK with a rare muscle disease called Duchenne muscular dystrophy. These boys cannot make an important muscle protein called dystrophin. They become weaker as they get older and lose the ability to walk as teenagers. This is a life-limiting condition. There is no cure, but medicines are being made that could help these boys make dystrophin. These medicines are most likely to work best in toddlers, before their muscles become damaged. There is no way of testing these medicines in children under four. In older children, it is possible to measure how well and how quickly a child can do movements like sitting up, standing up, and running. Unfortunately, these tests are not suitable for toddlers as they often struggle to listen and do what they are asked to do. Tiredness and mood can also affect their scores. Luckily, there is a new way of testing how well children move. They can wear special watch-like devices on their ankles that record information about their steps as they go about their normal lives. This is a good way of testing how well a child walks. It is now used to test medicines in children over four years old. Our aim is to test whether this device works well in children under four. This study will invite 30 boys with DMD (and their parent/caregiver) and 30 boys without DMD aged 1-3 years old from across the country to join the study. There are no hospital visits. Children will receive the watch-like devices to wear for three blocks of 28-days over six months during their normal daily activities. At the start and end of the study, a physiotherapist will visit the homes of boys with DMD. They will check their movements using other tests. The investigators will find out 1) if young boys are happy to wear the device, 2) how it compares to other tests, and 3) if it can detect changes in walking ability. This study could give us a way to test medicines in younger children. Wearable devices could cut down the travel and stress of tests for boys and their families. Children with learning or behavioural difficulties, and children living far from research centres could now also take part in studies of new medicines. This study could bring us a step closer to treating this life-limiting disease.

Duchenne muscular dystrophy (DMD) is a rare muscle-wasting disease that affects boys, causing progressive disability and premature death. Our study will directly address a significant barrier to progress in the treatment of these patients. DMD is a rare disease that globally affects \~20 per 100,000 live male births. Due to X-linked mutations in the DMD gene, these boys cannot produce functional dystrophin, a fundamental muscle protein. They develop muscle degeneration and progressive weakness, which leads to loss of ambulation in adolescence. Boys subsequently develop cardiorespiratory failure and need ventilation in their 20s. There is no cure for DMD. Multidisciplinary care is focused on delaying disease progression. At 4-6 years old these boys are offered steroids (glucocorticoids), which are the only disease-modifying drug. Their introduction dramatically increased median survival from 18 to 28 years. Nevertheless, long-term use is associated with considerable adverse effects on growth, puberty and bone health. Despite being a rare disease, over the last two decades there have been over 80 drugs developed for the treatment of DMD. However, few drugs have received approval by regulatory agencies, and none have adequately restored dystrophin levels or improved quality of life. Unfortunately, there has been a high failure rate between early-phase and late-phase drug development. Gene-targeted therapies offer hope of an effective treatment but would only benefit \~30% of boys with specific gene mutations. Recently, Vamorolone, a next-generation steroid with fewer adverse effects, has also received regulatory approval. Its safety and efficacy have been demonstrated in patients over four years old. Early treatment is a priority now. There is increasing pressure from patient groups, clinicians, and industry to test treatments in younger boys. Until recently, clinical trials have only included boys over five years old, in whom muscle damage has already begun. Destructive processes underlying the disease begin in utero and muscle remodelling and inflammation are detectable in infancy. Earlier treatment with potential disease-modifying drugs could transform treatment outcomes. Essentially, time is muscle. There is already evidence that boys with DMD benefit from starting steroids earlier, before the age of five. Additionally, pre-symptomatic treatment has been shown to revolutionise the outcomes of another debilitating paediatric neuromuscular disease, spinal muscular atrophy. To treat younger children, there is a need to be able to reliably monitor motor function and treatment effects. Currently, there are no suitable measures of motor function validated in children under four. Toddlerhood is a time of significant neurodevelopment and skill acquisition. Therefore, it is not possible simply use standard tests developed and validated for older children. The 6-minute walk test is the gold standard in DMD. It predicts future decline but has low reliability in children under five. The North Star Ambulatory Assessment (NSAA) is a DMD-specific functional scale administered by physiotherapists, scoring skills like standing, walking, hopping. It has good reliability and validity and is routinely used in clinical practice and trials. A revised version is available for children 2-5 years but has not been validated. These assessments are subjective and reflect a single performance, which can be heavily influenced by motivation, mood, tiredness and illness. They require children's attention, comprehension, cooperation and maximum effort in an unfamiliar testing environment. Therefore, younger children, and children with autistic spectrum or attention deficit disorder (\~30% of the DMD population) are significantly disadvantaged. Until now, these children have mostly been excluded from trials to limit unwanted noise in the data. Wearable devices may hold the solution. Watch-like devices can now precisely track motion. A child can wear these devices on their ankles and continue their normal activities whilst objective data is continuously collected over weeks. Children are under no pressure to perform on a single occasion, and they are unaware of continuous assessment. The devices passively and accurately capture real-world ambulatory ability. Stride velocity 95th centile (SV95C) is an outcome measure that can be calculated from the device data. It represents the speed of the top 5% fastest steps during a recording period - their maximum ambulatory ability. This outcome measure has been thoroughly tested in children over four and is reliable and sensitive to disease progression and treatment effects. It was approved by the European Medicines Agency (EMA) as a primary endpoint in DMD clinical trials in children over four and is increasingly used in trials. This outcome measure has greater potential to benefit children under four, who struggle to complete standard functional assessments designed for older children. There is significant momentum to test drugs in younger boys. Early phase clinical trials are now investigating the safety and pharmacokinetics of genetic therapies in children under four. The next stage is to test their efficacy. Vamorolone, a dissociative steroid, has also recently been approved for children over four. The next step is to test it in younger cohorts. These trials of efficacy cannot proceed without valid outcome measures. The overarching aim of the TODDLER study is to validate SV95C as an outcome measure in ambulant boys with DMD under the age of four, by assessing its feasibility, acceptability and reliability. This study is fundamental to improving the lives of boys with DMD, by facilitating trials of earlier treatment to maximise therapeutic benefit. The Syde® device (Sysnav Healthcare) is a wearable device used to measure SV95C. It has been used in over 70 trials including more than 2,600 participants with 12 different conditions (Sysnav). Over 2,000,000 hours of data have been collected to date. Prof Servais (Joint Lead) led the development and regulatory qualification of SV95C. It has become an established functional outcome measure in children with DMD over four and trusted tool in drug development. SV95C is also used in trials of other neuromuscular (limb-girdle muscular dystrophies, myotubular myopathies) and neurological diseases (Parkinson's, multiple sclerosis). SV95C correlates well with physiotherapist-assessed motor function tests and easily discriminates patients from controls (p\<0.001). Studies have demonstrated its high reliability (intraclass correlation coefficient of successive recordings=0.97). Notably, in a phase 2/3 trial, SV95C demonstrated low variability and greater sensitivity to change over shorter intervals than other functional assessments, and earlier detection of ambulatory decline. These studies provide a framework for validation in younger children. Due to maturational changes in gait, growth and behaviour, the validity and sensitivity of SV95C cannot be assumed in toddlers and merits investigation. The feasibility of implementing SV95C in younger children is supported by data from the ActiLiège Next study. This is a large multicentre European study collecting natural history data in many neuromuscular disorders, including Facioscapulohumeral Muscular Dystrophy, Myotonic Dystrophy 1, Charcot-Marie-Tooth, Centronuclear Myopathy, Congenital Muscular Dystrophy and DMD. Preliminary data from 12 patients with DMD aged 2-4years shows good compliance, with 92.5% wearing it for an acceptable time (\>50 hours). This data has been essential in powering the study. There are minimal risks involved in taking part in this study. The SYDE device is a safe CE-marked device approved for use in children. It has been designed to maximise comfort and avoid any interference with daily activities. The neurodevelopmental and motor assessments which will be performed in the study are safe in children and will be performed under the expert guidance of trained paediatric physiotherapists. Validating endpoints for younger boys will benefit patients by improving the likelihood of success of future clinical trials. Without developmentally-appropriate, sensitive, reliable endpoints, clinical trials will fail to identify the benefit of candidate therapies. As a remote assessment of function, SV95C can promote inclusivity and mitigate selection bias in trials. It will enable families living far from trials or boys who are too immature or inattentive to cooperate with performance-based tests to participate. The TODDLER study has a decentralised study design and aims to validate remote functional assessment, addressing the significant need to reduce the burden of trial participation on patients. The perceived burden of a protocol is the most common reason for declining clinical trial participation. Trials impact the family's quality of life. Reducing the need for in-person assessments will reduce the burden of travel and pressure surrounding performance-based assessments. Due to the variability and sensitivity of traditional motor outcome measures, DMD trials require years of follow-up with intense visit schedules to provide power to demonstrate meaningful outcomes. SV95C could reduce sample sizes and follow-up duration, accelerating the process of drug development.