Duchenne muscular dystrophy (DMD) is a severe, rapidly progressive neuromuscular disorder characterized by muscle weakening. It has an estimated incidence of 1 in 5000 males (1). DMD is caused by out-of-frame mutations in the dystrophin gene, which leads to an absence or deficiency of the protein dystrophin and the degeneration of muscles fibres (2). The absence of dystrophin protein leads to progressive muscle necrosis, loss of independent ambulation by early adolescence, cardiomyopathy, respiratory insufficiency, and premature death in affected individuals (2). Loss of ambulation occurs generally around the age of 12. Several phase 1–3 trials have been conducted over the last 10 years in subjects with DMD (NCT01247207, NCT01540409, and NCT01826474), and four drugs have received regulatory approval: Ataluren, a small molecule that increases full-length dystrophin expression in patients harbouring a nonsense mutations (3), has been approved by the European Medicines Agency (EMA) (3). Eteplirsen, golodirsen, and casimirsen, three antisense oligonucleotides that induce skipping of exon 51, 53, and 45, respectively (4, 5), have been approved by the American Food and Drug Administration (FDA) (6, 7).
The 6-minute walk distance test (6MWT) has been used as a primary outcome in most published pivotal phase 3 trials in ambulant patients with DMD. Other outcomes used include the 4-stair climb (4SC) and functional scales such as the North Star Ambulatory Assessments (NSAA) in which participants are rated on their ability to perform standardized motor function tasks (3, 4, 8–11). In DMD, the high standardized response mean of these different outcome measures, which illustrates the power of these measures to demonstrate a change over a certain period of time, meant that pivotal trials required over 100 patients per group and trial durations of 18 months and 2 years (NCT02851797 and NCT02500381, respectively). To accelerate clinical development and investigate in parallel several approaches without being limited by the number of patients available, it is crucial to validate more powerful outcome measures. This is the case for DMD and for numerous other rare diseases, within or outside the neuromuscular field, such as Angelman syndrome (NCT04259281).
The last decade has seen an increase in the availability of wearable technology for continuous monitoring of health and wellbeing (12). For example, wearable devices that can be used to assess ambulation range from crude step counters to sophisticated multisensory systems (13). Unlike consumer devices, medical devices must demonstrate validated measurement accuracy, sensitivity, and specificity (14). Wearable devices have the potential to provide a complete view of a patient’s condition over a long time period by band-pass filtering day-to-day variation. Therefore, wearable devices provide a complementary approach with a major advantage over hospital-based assessments, which only provide ‘snapshots’ of a patient’s condition that can be affected by fatigue, illness, or lack of motivation.
In this context, we specifically developed a CE-marked class 1 wearable medical device that records passively, in a precise and sensitive way, upper and lower limb movements in everyday life (15, 16). From the capture of any single movement, several outcomes may be extracted. In ambulant patients, the identification and quantification of every individual stride allows for the calculation of the distribution of stride length and stride speed as well as for the analyses of different centiles such as the 95th centile stride velocity (SV95C). These variables are measured in a home-based environment over a 180-hour period and are reliable and highly sensitive to changes in ambulant patients with DMD (17).
Recently, the EMA qualified SV95C as a valid secondary endpoint in clinical trials on ambulant patients with DMD (18). Additional data are needed to qualify the measure as a primary endpoint (17). Wearable technology is or has been used in clinical trials of therapies for spinal muscular atrophy (19, 20), facioscapulohumeral muscular dystrophy (NCT02579239, NCT04004000), limb girdle muscular dystrophy type 2E (NCT02579239), centronuclear myopathy (NCT02057705), and Angelman syndrome (NCT04259281).
To properly interpret the longitudinal evolution of the SV95C over time in patient populations, it is necessary to understand the longitudinal evolution in subjects without muscle conditions within the same age range, in particular between 5 and 18 years old, which is the age range mostly targeted in clinical trials of ambulant DMD patients and during which growth or maturational factors may significantly interfere with measures (21, 22). Therefore, we conducted a longitudinal study in ambulant healthy subjects between 5 and 85 years of age to evaluate the changes in SV95C over 12 months.