Clinical Trial Readiness for Spinal Muscular Atrophy: Experience of an International Educational-Training Initiative

Several successful clinical trials have been conducted in spinal muscular atrophy (SMA) over recent years which have led to the approval of splicing modifiers and gene transfer therapies. With an increasing number of other agents progressing through pre-clinical and clinical development, increasing worldwide clinical trial readiness is becoming essential.SMA Europe initiated a clinical trial readiness project, which included the development of a pilot face-to-face educational-training initiative for clinical specialists and physiotherapists involved in SMA, with an emphasis on the patient perspective. Participants were selected through two surveys and, ahead of the meeting, a mock protocol with specific questions was provided. The initiative involved a series of presentations, role-play and interactive exercises. We describe here our experience and evaluation of this educational-training initiative, emphasising scientific aspects, psychosocial implications and level of satisfaction.From a participant, patient and industry perspective, such training was considered successful and met the objective, which was to improve clinical trial readiness in emerging sites. Resource planning, ethical considerations and communication with patients were identified as three important topics for future training. This initiative highlights the need to develop a training programme to achieve clinical trial readiness across Europe and showcases a collaborative effort with different stakeholders, clinicians, patient advocacy groups and sponsors to address an important issue

SMA: Des échelles d’évaluation motrice pour le public francophone

À l’heure des nouvelles thérapeutiques chez les personnes présentant une amyotrophie spinale antérieure ou spinal muscular atrophy (SMA), la mesure régulière, précise et fiable des capacités motrices est devenue indispensable. Différents outils ont été développés dans la littérature et peuvent être utilisés pour cela. Le choix d’une échelle/ d’un outil se fait en fonction du type de SMA, de l’âge de la personne et des éléments spécifiques de la motricité que l’on souhaite évaluer. En France, l’échelle MFM est utilisée en pratique clinique dans de nombreux centres de référence de Maladies Neuromusculaires (MNM). Les autres échelles fréquemment utilisées au niveau international ne sont cependant pas disponibles en français rendant leur utilisation plus difficile en pratique clinique courante. Cet article présente le processus de traduction en français des échelles les plus fréquemment utilisées chez la personne avec SMA (CHOP INTEND, HFMSE, RULM, 6-minute walk test et HINE-2). Différentes étapes ont été respectées, notamment les étapes de traduction en français, traduction inversée en anglais, comparaison des versions anglaises, harmonisation et obtention de la version finale en français. Un programme de formation et sensibilisation des différents professionnels des consultations MNM des centres de référence français avec proposition d’ateliers en présence des membres du comité scientifique suivra l’étape de traduction afin de les faire connaître, expliciter leur utilisation et participer à la diffusion de ce travail

Home-Based Monitor for Gait and Activity Analysis.

Current outcomes in neuromuscular disorder clinical trials include motor function scales, timed tests, and strength measures performed by trained clinical evaluators. These measures are slightly subjective and are performed during a visit to a clinic or hospital and constitute therefore a point assessment. Point assessments can be influenced by daily patient condition or factors such as fatigue, motivation, and intercurrent illness. To enable home-based monitoring of gait and activity, a wearable magneto-inertial sensor (WMIS) has been developed. This device is a movement monitor composed of two very light watch-like sensors and a docking station. Each sensor contains a tri-axial accelerometer, gyroscope, magnetometer, and a barometer that record linear acceleration, angular velocity, the magnetic field of the movement in all directions, and barometric altitude, respectively. The sensors can be worn on the wrist, ankle, or wheelchair to record the subject's movements during the day. The docking station enables data uploading and recharging of sensor batteries during the night. Data are analyzed using proprietary algorithms to compute parameters representative of the type and intensity of the performed movement. This WMIS can record a set of digital biomarkers, including cumulative variables, such as total number of meters walked, and descriptive gait variables, such as the percentage of the most rapid or longest stride that represents the top performance of patient over a predefined period of time

Clinical Trial Readiness for Spinal Muscular Atrophy: Experience of an International Educational-Training Initiative.

peer reviewedSeveral successful clinical trials have been conducted in spinal muscular atrophy (SMA) over recent years which have led to the approval of splicing modifiers and gene transfer therapies. With an increasing number of other agents progressing through pre-clinical and clinical development, increasing worldwide clinical trial readiness is becoming essential.SMA Europe initiated a clinical trial readiness project, which included the development of a pilot face-to-face educational-training initiative for clinical specialists and physiotherapists involved in SMA, with an emphasis on the patient perspective. Participants were selected through two surveys and, ahead of the meeting, a mock protocol with specific questions was provided. The initiative involved a series of presentations, role-play and interactive exercises. We describe here our experience and evaluation of this educational-training initiative, emphasising scientific aspects, psychosocial implications and level of satisfaction.From a participant, patient and industry perspective, such training was considered successful and met the objective, which was to improve clinical trial readiness in emerging sites. Resource planning, ethical considerations and communication with patients were identified as three important topics for future training. This initiative highlights the need to develop a training programme to achieve clinical trial readiness across Europe and showcases a collaborative effort with different stakeholders, clinicians, patient advocacy groups and sponsors to address an important issue

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

Longitudinal functional and NMR assessment of upper limbs in Duchenne muscular dystrophy

International audienceObjective:To explore the value of nuclear magnetic resonance (NMR) and functional assessments for follow-up of ambulatory and nonambulatory patients with Duchenne muscular dystrophy (DMD).Methods:Twenty-five 53-skippable patients with DMD were included in this study; 15 were nonambulatory at baseline. All patients underwent clinical and functional assessments every 6 months using the Motor Function Measure (MFM), hand grip and key pinch strength, MoviPlate, and NMR spectroscopy and imaging studies.Results:Upper limb distal strength decreased in nonambulatory patients over the period of 1 year; ambulatory patients showed improvement during the same period. The same applied for several NMRS indices, such as phosphocreatine/adenosine triphosphate, which decreased in older patients but increased in younger ambulatory patients. Fat infiltration in the upper limbs increased linearly with age. Almost all NMR and functional assessment results correlated.Conclusions:Our results underscore complementarity of functional and NMR assessments in patients with DMD. Sensitivity to change of various indices may differ according to disease stage

Use of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-Linked Myotubular Myopathy: Content Validity and Psychometric Performance.

X-linked myotubular myopathy (XLMTM) is a life-threatening, congenital myopathy characterized by extreme hypotonia, weakness, delayed motor milestones, and respiratory failure, often resulting in pediatric mortality. This study evaluated the content validity and psychometric performance of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as a measure of neuromuscular functioning in children with X-linked myotubular myopathy. This study was conducted in two phases. Phase I assessed the content validity of the measure for use in an XLMTM pediatric population through: literature review, clinical expert interviews, caregiver interviews, and a modified-Delphi panel among clinicians. Phase II assessed psychometric performance based on the INCEPTUS observational clinical study and the ASPIRO interventional gene therapy study, including tests of reliability (internal consistency, test-retest, and interrater), validity (construct and criterion), and responsiveness based on observational and interventional clinical trial data analyses. Data established construct validity and reliability of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders among XLMTM patients before administration of resamirigene bilparvovec, and sensitivity to study drug administration as evidenced by the significant post-administration response in ASPIRO. Findings support the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as an appropriate neuromuscular functioning assessment in a pediatric X-linked myotubular myopathy patient population

Natural history of Type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study.

OBJECTIVE: To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials. METHODS: Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease-modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo(®) ), quantitative magnetic resonance imaging (fat fraction [FF(T2) ] mapping and contractile cross-sectional area [C-CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels. RESULTS: MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FF(T2) increased over 12 and 24 months, although not with statistical significance. A significant increase in C-CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months. INTERPRETATION: These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo(®) enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months

Quality of life

Quality of life based on the PROMIS® syste