Analytical validation of innovative magneto-inertial outcomes: a controlled environment study.

peer reviewe

Application for primary endpoint qualification of the 95th centile of stride velocity (SV95C) in Duchenne muscular dystrophy

peer reviewe

Normative data on spontaneous stride velocity, stride length, and walking activity in a non-controlled environment.

Background: Normative data are necessary for validation of new outcome measures. Recently, the 95th centile of stride speed was qualified by the European Medicines Agency as a valid secondary outcome for clinical trials in subjects with Duchenne muscular dystrophy. This study aims to obtain normative data on spontaneous stride velocity and length in a non-controlled environment and their evolution after 12 months. Method: Ninety-one healthy volunteers (50 females, 41 males), with a mean age of 16 years and 2 months, were recruited and assessed at baseline and 12 months later. The 4-stair climb, 6-min walk test, 10-m walk test and rise from floor assessments were performed. Stride length, stride velocity, and the distance walked per hour were studied in an everyday setting for one month after each evaluation. Results: Of the 91 subjects assessed, 82 provided more than 50 h of recordings at baseline; and 73 subjects provided the same at the end of the year. We observed significant positive correlations of the stride length with age and height of participants, and a significant increase of the median stride length in children after the period. In this group, the 95th centile stride velocity was not correlated with age and was stable after one year. All measures but the 10MWT were stable in adults after a one-year period. Conclusion: This study provides with data on the influence of age, height, and gender on stride velocity and length as well as accounting for natural changes after one year in controls.Actilièg

A Movement Monitor Based on Magneto-Inertial Sensors for Non-Ambulant Patients with Duchenne Muscular Dystrophy: A Pilot Study in Controlled Environment.

UNLABELLED:Measurement of muscle strength and activity of upper limbs of non-ambulant patients with neuromuscular diseases is a major challenge. ActiMyo® is an innovative device that uses magneto-inertial sensors to record angular velocities and linear accelerations that can be used over long periods of time in the home environment. The device was designed to insure long-term stability and good signal to noise ratio, even for very weak movements. In order to determine relevant and pertinent clinical variables with potential for use as outcome measures in clinical trials or to guide therapy decisions, we performed a pilot study in non-ambulant neuromuscular patients. We report here data from seven Duchenne Muscular Dystrophy (DMD) patients (mean age 18.5 ± 5.5 years) collected in a clinical setting. Patients were assessed while wearing the device during performance of validated tasks (MoviPlate, Box and Block test and Minnesota test) and tasks mimicking daily living. The ActiMyo® sensors were placed on the wrists during all the tests. Software designed for use with the device computed several variables to qualify and quantify muscular activity in the non-ambulant subjects. Four variables representative of upper limb activity were studied: the rotation rate, the ratio of the vertical component in the overall acceleration, the hand elevation rate, and an estimate of the power of the upper limb. The correlations between clinical data and physical activity and the ActiMyo® movement parameters were analyzed. The mean of the rotation rate and mean of the elevation rate appeared promising since these variables had the best reliability scores and correlations with task scores. Parameters could be computed even in a patient with a Brooke functional score of 6. The variables chosen are good candidates as potential outcome measures in non-ambulant patients with Duchenne Muscular Dystrophy and use of the ActiMyo® is currently being explored in home environment. TRIAL REGISTRATION:ClinicalTrials.gov NCT01611597

Hierarchical Bayesian modelling of disease progression to inform clinical trial design in centronuclear myopathy.

BACKGROUND: Centronuclear myopathies are severe rare congenital diseases. The clinical variability and genetic heterogeneity of these myopathies result in major challenges in clinical trial design. Alternative strategies to large placebo-controlled trials that have been used in other rare diseases (e.g., the use of surrogate markers or of historical controls) have limitations that Bayesian statistics may address. Here we present a Bayesian model that uses each patient's own natural history study data to predict progression in the absence of treatment. This prospective multicentre natural history evaluated 4-year follow-up data from 59 patients carrying mutations in the MTM1 or DNM2 genes. METHODS: Our approach focused on evaluation of forced expiratory volume in 1 s (FEV1) in 6- to 18-year-old children. A patient was defined as a responder if an improvement was observed after treatment and the predictive probability of such improvement in absence of intervention was less than 0.01. An FEV1 response was considered clinically relevant if it corresponded to an increase of more than 8%. RESULTS: The key endpoint of a clinical trial using this model is the rate of response. The power of the study is based on the posterior probability that the rate of response observed is greater than the rate of response that would be observed in the absence of treatment predicted based on the individual patient's previous natural history. In order to appropriately control for Type 1 error, the threshold probability by which the difference in response rates exceeds zero was adapted to 91%, ensuring a 5% overall Type 1 error rate for the trial. CONCLUSIONS: Bayesian statistical analysis of natural history data allowed us to reliably simulate the evolution of symptoms for individual patients over time and to probabilistically compare these simulated trajectories to actual observed post-treatment outcomes. The proposed model adequately predicted the natural evolution of patients over the duration of the study and will facilitate a sufficiently powerful trial design that can cope with the disease's rarity. Further research and ongoing dialog with regulatory authorities are needed to allow for more applications of Bayesian statistics in orphan disease research

Upper limb disease evolution in exon 53 skipping eligible patients with Duchenne muscular dystrophy.

OBJECTIVE: To understand the natural disease upper limb progression over 3 years of ambulatory and non-ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors. METHODS: Forty boys with DMD (22 non-ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53-skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly. RESULTS: In the whole population, there were strong nonlinear correlations between outcome measures. In non-ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI-based FF, hand grip and key pinch, and MFM. Boys who presented with a FF27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF <10% retained ambulation 3 years later. INTERPRETATION: We demonstrate that continuous decline in upper limb strength, function, and MRI measured muscle structure can be reliably measured in ambulatory and non-ambulatory boys with DMD with high SRM and strong correlations between outcomes. Our results suggest that a combination of grip strength and FF can be used to predict important motor milestones

Reliability between test and retest for all the tasks evaluated for each ActiMyo^® variable.

<p><b>◇</b> MoviPlate; <b>⬜</b> BBT; <b>△</b> Minnesota test; <b>✱</b> Writing;<b>×</b> PC typing.</p

The tools.

<p><b>(A)</b> First version of ActiMyo^®, used in the current study. <b>(B)</b> Box and Block test. <b>(C)</b> Minnesota test with five discs.</p

Patient flow-chart.

<p>Patient flow-chart.</p

Clinical features of the DMD patients ordered by increasing age.

<p>Clinical features of the DMD patients ordered by increasing age.</p