North Star Ambulatory Assessment Scores Research Articles

Exploring the relationship between North Star Ambulatory Assessment and Health Utilities Index scores in Duchenne muscular dystrophy

BackgroundThe North Star Ambulatory Assessment (NSAA) documents motor performance in ambulatory individuals with Duchenne muscular dystrophy (DMD). Health Utilities Index (HUI) scores, reflecting preferences for health-related quality-of-life (HRQoL) implications of health states, are commonly estimated within trials. This study sought to characterize the relationship between the NSAA score and utility in DMD.MethodsFamily members serving as proxy respondents for placebo-treated ambulatory individuals with DMD (NCT01254019; BioMarin Pharmaceuticals Inc) completed the HUI and the NSAA (score range, 0–34). Mean change over time on these measures was estimated, and the correlation between changes in NSAA score and a) HUI utility; b) HUI3 ambulation and HUI2 mobility attribute scores, over 48 weeks was calculated.ResultsBaseline mean (range) age was 8.0 years (5–16; n = 61) and mean (standard deviation [SD]) scores were 0.87 (0.13; HUI2), 0.82 (0.19; HUI3), and 21.0 (8.1; NSAA). Mean (SD) change over 48 weeks was –0.05 (0.14; HUI2), –0.06 (0.19; HUI3), and –2.9 (4.7; NSAA). Weak positive correlations were observed between baseline NSAA score and HUI utility (HUI2: r = 0.29; HUI3: r = 0.17) and for change over 48 weeks (HUI2: r = 0.16; HUI3: r = 0.15). Stronger correlations were observed between change in NSAA score and the HUI3 ambulation (r = 0.41) and HUI2 mobility (r = 0.41) attributes.ConclusionsAmong ambulatory individuals with DMD, NSAA score is weakly correlated with HUI utility, suggesting that motor performance alone does not fully explain HRQoL. Stronger relationships were observed between HUI ambulation and mobility attributes, and NSAA. Although unidimensional measures like the NSAA are informative for documenting disease-specific health impacts, they may not correlate well with measures of overall health status; requiring use in conjunction with other patient-reported and preference-based outcomes.

Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy.

Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein. Methods: This Phase 2, double-blind, two-part (48weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48). Safety assessments included treatment-related adverse events (TRAEs). Patients were randomized and stratified by age to placebo (n = 21) or delandistrogene moxeparvovec (n = 20) and crossed over for Part 2. Results: SRP-9001 dystrophin expression was achieved in all patients: mean CFBL to Week 12 was 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, CFBL to Week 48 in NSAA score (least-squares mean, LSM [standard error]) was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo; p = 0.37. Disparity in baseline motor function between groups likely confounded these results. In 4- to 5-year-olds with matched baseline motor function, CFBL to Week 48 in NSAA scores was significantly different (+2.5 points; p = 0.0172), but not significantly different in 6-to-7-year-olds with imbalanced baseline motor function (-0.7 points; p = 0.5384). For patients treated with delandistrogene moxeparvovec in Part 2, CFBL to Week 48 in NSAA score was +1.3 (2.7), whereas for those treated in Part 1, NSAA scores were maintained. As all patients in Part 2 were exposed to treatment, results were compared with a propensity-score-weighted external control (EC) cohort. The LSM difference in NSAA score between the Part 2 treated group and EC cohort was statistically significant (+2.0 points; p = 0.0009). The most common TRAEs were vomiting, decreased appetite, and nausea. Most occurred within the first 90days and all resolved. Discussion: Results indicate robust expression of SRP-9001 dystrophin and overall stabilization in NSAA up to 2years post-treatment. Differences in NSAA between groups in Part 1 were not significant for the overall population, likely because cohorts were stratified only by age, and other critical prognostic factors were not well matched at baseline.

Determining minimal clinically important differences in the North Star Ambulatory Assessment (NSAA) for patients with Duchenne muscular dystrophy.

The North Star ambulatory assessment (NSAA) is a functional motor outcome measure in Duchenne muscular dystrophy (DMD), widely used in clinical trials and natural history studies, as well as in clinical practice. However, little has been reported on the minimal clinically important difference (MCID) of the NSAA. The lack of established MCID estimates for NSAA presents challenges in interpreting the significance of the results of this outcome measure in clinical trials, natural history studies and clinical practice. Combining statistical approaches and patient perspectives, this study estimated MCID for NSAA using distribution-based estimates of 1/3 standard deviation (SD) and standard error of measurement (SEM), an anchor-based approach, with six-minute walk distance (6MWD) as the anchor, and evaluation of patient and parent perception using participant-tailored questionnaires. The MCID for NSAA in boys with DMD aged 7 to 10 years based on 1/3 SD ranged from 2.3-2.9 points, and that on SEM ranged from 2.9-3.5 points. Anchored on the 6MWD, the MCID for NSAA was estimated as 3.5 points. When the impact on functional abilities was considered using participant response questionnaires, patients and parent perceived a complete loss of function in a single item or deterioration of function in one to two items of the assessment as an important change. Our study examines MCID estimates for total NSAA scores using multiple approaches, including the impact of patient and parent perspective on within scale changes in items based on complete loss of function and deterioration of function, and provides new insight on evaluation of differences in these widely used outcome measure in DMD.

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

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. 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. 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. 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.

Clinical utilisation of multimodal quantitative magnetic resonance imaging in investigating muscular damage in Duchenne muscular dystrophy: a study on the association between gluteal muscle groups and motor function

BackgroundDuchennemuscular dystrophy (DMD) is a neuromuscular disease characterised by progressive muscular weakness and atrophy. Currently, studies on DMD muscle function mostly focus on individual muscles; little is known regarding the effect of gluteal muscle group damage on motor function.ObjectiveTo explore potential imaging biomarkers of hip and pelvic muscle groups for measuring muscular fat replacement and inflammatory oedema in DMD with multimodal quantitative magnetic resonance imaging (MRI).Materials and methodsOne hundred fifty-nine DMD boys and 32 healthy male controls were prospectively included. All subjects underwent MRI examination of the hip and pelvic muscles with T1 mapping, T2 mapping and Dixon sequences. Quantitatively measured parameters included longitudinal relaxation time (T1), transverse relaxation time (T2) and fat fraction. Investigations were all based on hip and pelvic muscle groups covering flexors, extensors, adductors and abductors. The North Star Ambulatory Assessment and stair climbing tests were used to measure motor function in DMD.ResultsT1 of the extensors (r = 0.720, P < 0.01), flexors (r = 0.558, P < 0.01) and abductors (r = 0.697, P < 0.001) were positively correlated with the North Star Ambulatory Assessment score. In contrast, T2 of the adductors (r = -0.711, P < 0.01) and fat fraction of the extensors (r = -0.753, P < 0.01) were negatively correlated with the North Star Ambulatory Assessment score. Among them, T1 of the abductors (b = 0.013, t = 2.052, P = 0.042), T2 of the adductors (b = -0.234, t = -2.554, P = 0.012) and fat fraction of the extensors (b = -0.637, t = − 4.096, P < 0.001) significantly affected the North Star Ambulatory Assessment score. Moreover, T1 of the abductors was highly predictive for identifying motor dysfunction in DMD, with an area under the curve of 0.925.ConclusionMagnetic resonance biomarkers of hip and pelvic muscle groups (particularly T1 values of the abductor muscles) have the potential to be used as independent risk factors for motor dysfunction in DMD.

Longitudinal study of multi-parameter quantitative magnetic resonance imaging in Duchenne muscular dystrophy: hyperresponsiveness of gluteus maximus and detection of subclinical disease progression in functionally stable patients.

To describe the disease progression of Duchenne muscular dystrophy (DMD) in the pelvic and thigh muscles over 1-year using multiple-parameter quantitative magnetic resonance imaging (qMRI), and to determine the most responsive muscle and predict subclinical disease progression in functionally stable patients. Fifty-four DMD patients (mean age 8.9 ± 2.5, range 5-15years) completed baseline and 1-year follow-up qMRI examinations/biomarkers [3-point Dixon/fat fraction (FF); T1 mapping/T1; T2 mapping/T2]. Meanwhile, clinical assessments [NorthStar ambulatory assessment (NSAA) score] and timed function tests were performed in DMD patients. Twenty-four healthy male controls (range 5-15years) accomplished baseline qMRI examinations. Group differences were compared using the Wilcoxon test. The standardized response mean (SRM) was taken as the responsiveness to the disease progression index. FF, T1, and T2 in all DMD age subgroups changed significantly over 1-year (P < 0.05). Even in functionally stable patients (NSAA score increased, unchanged, or decreased by 1-point) over 1-year, significant increases in FF and T2 and decreases in T1 were observed in gluteus maximus (GMa), gluteus medius, vastus lateralis, and adductor magnus (P < 0.05). Overall, the SRM of FF, T1, and T2 was all the highest in GMa, which were 1.25, - 0.92, and 0.93, respectively. qMRI biomarkers are responsive to disease progression and can also detect subclinical disease progression in functionally stable DMD patients over 1-year. GMa is the most responsive to disease progression of all the muscles analyzed. Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ) ChiCTR1800018340, 09/12/2018, prospectively registered.

P.66 Predicting trajectories of ambulatory function in Duchenne muscular dystrophy (DMD)

The North Star Ambulatory Assessment (NSAA) is a widely used endpoint in DMD clinical trials. Accurately predicting NSAA trajectories is important for understanding effects of novel therapies, via creation of individualized controls for treated patients, especially over longer-term (> 18 month) follow-up, when placebo controls are infeasible. We used longitudinal data for boys with DMD aged 4-10 years and starting with NSAA >12 at baseline to develop prognostic models for trajectories of NSAA total score for up to 4 years of follow-up. Data were drawn from four natural history databases: UZ Leuven, PRO-DMD-01 (provided by CureDuchenne), the North Star Clinical Network, and iMDEX. NSAA trajectories were fit using mixed effects models with age, steroid use, height, weight, and ambulatory function as baseline predictors. Among N=261 boys, mean age at baseline was 6.8 years, mean NSAA score was 25.6; 53% were receiving prednisone, 23% deflazacort, and 24% no steroid. Almost all initiated steroids within the first year of follow-up. The average patient had 6 post-baseline NSAA assessments over 2-4 years of follow-up. Predictors of greater decline in NSAA identified in the training sample (N=208) included older age, longer rise-from-floor times, higher NSAA (more room to decline), greater height, and greater body mass index. The best-fitting model explained 27% of variation in post-baseline NSAA with average prediction errors of ±5.6 units in a held-out sample (N=53). Bias in mean change in NSAA due to missing data was small (0.2, 0.8 and 1.1 units at years 1, 3 and 4 post-baseline, respectively) and in the direction of better-than-actual outcomes in natural history, which would bias against treatment in comparison to long-term natural history controls. Trajectories of ambulatory function in DMD can be well-predicted using baseline characteristics. Extension of this model to include older boys, and additional validation in larger samples is warranted.

A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK.GALGT2

In a phase 1/2, open-label dose escalation trial, we delivered rAAVrh74.MCK.GALGT2 (also B4GALNT2) bilaterally to the legs of two boys with Duchenne muscular dystrophy using intravascular limb infusion. Subject 1 (age 8.9 years at dosing) received 2.5 × 1013 vector genome (vg)/kg per leg (5 × 1013 vg/kg total) and subject 2 (age 6.9 years at dosing) received 5 × 1013 vg/kg per leg (1 × 1014 vg/kg total). No serious adverse events were observed. Muscle biopsy evaluated 3 or 4 months post treatment versus baseline showed evidence of GALGT2 gene expression and GALGT2-induced muscle cell glycosylation. Functionally, subject 1 showed a decline in 6-min walk test (6MWT) distance; an increase in time to run 100 m, and a decline in North Star Ambulatory Assessment (NSAA) score until ambulation was lost at 24 months. Subject 2, treated at a younger age and at a higher dose, demonstrated an improvement over 24 months in NSAA score (from 20 to 23 points), an increase in 6MWT distance (from 405 to 478 m), and only a minimal increase in 100 m time (45.6–48.4 s). These data suggest preliminary safety at a dose of 1 × 1014 vg/kg and functional stabilization in one patient.

Comparison of telerehabilitation versus home-based video exercise in patients with Duchenne muscular dystrophy: a single-blind randomized study

IntroductionPatients with Duchenne muscular dystrophy (DMD) have lost their access to on-site rehabilitation due to the COVID-19 pandemic. Telerehabilitation can be a viable approach for these patients to protect their muscle strength and functional status. The aim of this study is to compare telerehabilitation with home-based video exercises.Patients and methodsMale, ambulatory DMD patients were randomized into telerehabilitation and video-exercise groups. Nineteen patients were included in the final analyses. Telerehabilitation consisted of live online exercises, while video exercise implemented a pre-recorded video as a home-based program. Both programs spanned 8 weeks, three times a week. Patients’ muscle strength with a hand-held dynamometer, Quick Motor Function Test, North-Star Ambulatory Assessment (NSAA), 6-Minute Walk Test (6MWT) and Caregiver Burden were recorded before and after treatment.ResultsThe 6MWT of the telerehabilitation group was391.26 ± 95.08 m before and387.75 ± 210.93 after treatment (p = 0.94) and 327.46 ± 103.88 m before treatment and313.77 ± 114.55 after treatment in video group (p = 0.63). The mean NSAA score of the telerehabilitation group were26.70 ± 8.04 before treatment and 25.20 ± 11.33 after treatment (p = 0.24). In the video group scores were 21.66 ± 6.65 before to 22.00 ± 8.61 after treatment (p = 0.87). There were no significant changes between groups at the end of the treatments. The telerehabilitation group's neck extension, bilateral shoulder abduction, and left shoulder flexion, bilateral knee flexion and extension, bilateral ankle dorsiflexion, and left ankle plantar flexion strength improved significantly and were better than the video group (p < 0.05 for all measurements).ConclusionA telerehabilitation approach is superior in improving muscle strength than a video-based home exercise, but none of the programs improved functional outcomes in ambulatory patients with DMD.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13760-022-01975-4.

Characteristics of disease progression and genetic correlation in ambulatory Iranian boys with Duchenne muscular dystrophy

BackgroundDuchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations of this disease include progressive muscle weakness, gait dysfunction, and motor impairment, leading to a loss of ambulation by the age of 13 years. Molecular diagnosis is the standard diagnostic tool for DMD. This study aimed to investigate disease progression and genetic patterns in Iranian ambulant boys and to find the correlation between genotypes and motor function phenotypes.MethodsThis study was performed on 152 DMD patients. Clinical history, including the disease phenotype, steroid therapy, and the North Star Ambulatory Assessment (NSAA) score, was taken for all the patients. Molecular diagnoses were confirmed by multiplex ligation-dependent probe amplification and next-generation sequencing tests.ResultsA total of 152 Iranian DMD patients were examined in this study. The mean age at the time of disease onset was 4.04 ± 2.00 years, and the mean age at diagnosis was 5.05 ± 2.08 years. The mean age of ambulation loss was 10.9 years. Contracture was reported in 38.9% of cases. In terms of age, the mean total NSAA score showed a peak at 4 years of age, with a mean NSAA score of 24. Annual changes in the NSAA score were determined for all cases, based on the mutation type and exon site. Deletion mutation was found in 79.1% of cases, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon deletion was exon 44 (5.3%), and the most common multiexon deletions were attributed to exons 45–50 and exons 45–52 (4.6%). The results did not indicate any correlation between the mutation type and age at the time of disease onset, loss of ambulation age, and wheelchair dependence; however, a significant association was found between contracture and mutation type. The results showed a significant difference in the NSAA score between the deletion and nonsense groups at the age of 3 years (P = 0.04). No significant correlation was found between the phenotype and exon site. Overall, 91.1% of the study population had a history of corticosteroid use, and 54.1% showed compliance with rehabilitation therapy.ConclusionThis study demonstrated the phenotypes and mutational features of Iranian DMD boys and provided information regarding the natural motor history of the disease, disease progression, diagnosis, and status of DMD management in Iran. The present findings can promote the development of clinical trials and future advanced molecular therapies in Iran.

Investigating the role of dystrophin isoform deficiency in motor function in Duchenne muscular dystrophy.

BackgroundDuchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full‐length Dp427 is the primary dystrophin isoform expressed in muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS comorbidities is well known, relationships between mutations expected to disrupt Dp140 and Dp71 and motor outcomes are not.MethodsFunctional outcome data from 387 DMD boys aged 4–15 years were subdivided by DMD mutation expected effects on dystrophin isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n = 201); Group 2 (Dp427/Dp140 absent, Dp71 present, n = 152); and Group 3 (Dp427/Dp140/Dp71 absent, n = 34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10 m walk/run velocities and rise time velocities were explored using regression analysis.Western blot analysis was used to study Dp427, Dp140 and Dp71 production in myogenic cells (control and DMD human), control skeletal muscle, DMD skeletal muscle from the three isoform groups and cerebral cortex from mice (wild‐type and DMD models). Grip strength and rotarod running test were studied in wild‐type mice and DMD mouse models. DMD mouse models were mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD‐null (lacking all isoforms).ResultsIn DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in Group 3 than Group 1 (P < 0.01) and 4.9 points lower in Group 3 than Group 2 (P = 0.05). Mean peak NSAA scores were 4.0 points lower in Group 3 than Group 1 (P < 0.01) and 1.6 points lower in Group 2 than Group 1 (P = 0.04).Mean four‐limb grip strength was 1.5 g/g lower in mdx52 than mdx mice (P = 0.003) and 1.5 g/g lower in DMD‐null than mdx mice (P = 0.002).Dp71 was produced in myogenic cells (control and DMD human) and skeletal muscle from humans in Groups 1 and 2 and mdx mice, but not skeletal muscle from human controls, myogenic cells and skeletal muscle from humans in Group 3 or skeletal muscle from wild‐type, mdx52 or DMD‐null mice.ConclusionsOur results highlight the importance of considering expected effects of DMD mutations on dystrophin isoform production when considering patterns of DMD motor impairment and the implications for clinical practice and clinical trials. Our results suggest a complex relationship between dystrophin isoforms expressed in the brain and DMD motor function.

Ankle contractures and functional motor decline in Duchenne muscular dystrophy

IntroductionThis prospective, correlational pilot study investigated the relationship between ankle plantar flexion contractures and motor function in boys with Duchenne muscular dystrophy in British Columbia (BC), Canada. ParticipantsAmbulatory boys with Duchenne muscular dystrophy were recruited from BC Children’s Hospital, which follows everyone with Duchenne muscular dystrophy in BC ≤ 18 years of age (n = 14). MethodsSpearman and Pearson correlation coefficients were estimated to examine the association between the degree of ankle dorsiflexion range of motion and North Star Ambulatory Assessment scores and the degree of ankle dorsiflexion range and six-minute walk test distances. ResultsOur analysis showed a moderate correlation between the degree of ankle dorsiflexion range and North Star Ambulatory Assessment scores [rho (14) = 0.50; p = 0.070] and a weak correlation between ankle dorsiflexion range of motion and six-minute walk test distances [rho (13) = 0.08; p = 0.747], however neither result was statistically significant. DiscussionAlthough a significant relationship between ankle dorsiflexion range of motion and motor function was not found, the variability of ankle dorsiflexion range suggests challenges with preventing ankle contracture. This reinforces the importance of assessing ankle range of motion in boys with Duchenne muscular dystrophy with sufficient frequency to identify a need for additional interventions.

DMD & BMD – CLINICAL: P.57 Comparison of North Star Ambulatory Assessment scores in siblings with Duchenne muscular dystrophy

Early diagnosis is important to optimise management and prolong function in patients with Duchenne muscular dystrophy (DMD). There is little research comparing functional outcomes of siblings diagnosed at different ages. This study aims to compare peak North Star Ambulatory Assessment (NSAA) scores in siblings in whom the optimal standards of care were implemented at different ages. NSAA data from 24 siblings (48 patients) were analysed from their first NSAA assessment at Great Ormond Street Hospital, including all scores until January 2020.

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy

Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7). To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD. This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children's Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (≥12 weeks). A single dose of 2.0 × 1014 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion). Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes. Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] years). All adverse events (n = 53) were considered mild (33 [62%]) or moderate (20 [38%]), and no serious adverse events occurred. Eighteen adverse events were considered treatment related, the most common of which was vomiting (9 of 18 events [50%]). Three patients had transiently elevated γ-glutamyltransferase, which resolved with corticosteroids. At 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fibers expressing micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. All patients had confirmed vector transduction and showed functional improvement of NSAA scores and reduced creatine kinase levels (posttreatment vs baseline) that were maintained for 1 year. This trial showed rAAVrh74.MHCK7.micro-dystrophin to be well tolerated and have minimal adverse events; the safe delivery of micro-dystrophin transgene; the robust expression and correct localization of micro-dystrophin protein; and improvements in creatine kinase levels and NSAA scores. These findings suggest that rAAVrh74.MHCK7.micro-dystrophin can provide functional improvement that is greater than that observed under standard of care. ClinicalTrials.gov Identifier: NCT03375164.

Quantitative Muscle MRI Protocol as Possible Biomarker in Becker Muscular Dystrophy.

Aim of this study is to compare Quantitative Magnetic Resonance Imaging (qMRI) measures between Becker Muscular Dystrophy (BMD) and Healthy Subjects (HS) and to correlate these parameters with clinical scores. Ten BMD patients (mean age ±standard deviation: 38.7 ± 15.0 years) and ten age-matched HS, were investigated through magnetic resonance imaging (MRI) at thigh and calf levels, including: 1) a standard axial T1-weighted sequence; 2) a volumetric T2-weighted sequence; 3) a multiecho spin-echo sequence; 4) a 2-point Dixon sequence; 5) a Diffusion Tensor Imaging (DTI) sequence. Mean Fat Fraction (FF), T2-relaxation time and Fractional Anisotropy (FA) DTI at thigh and calf levels were significantly higher in BMD patients than in HS (p-values<0.01). FF at thigh and calf levels significantly correlated with North Star Ambulatory Assessment (NSAA) score (p-values<0.01) and6 Minutes Walking Test (6MWT) (p-values<0.01), whereas only calf muscle FF was significantly associated with time to get up from floor (p-value = 0.01). T2 significantly correlated with NSAA score (p-value<0.01), 6MWT (p-value = 0.02) and time to get up from floor (p-value<0.01) only at calf level. Among DTI values, only FA in thigh and calf muscles significantly correlated with NSAA score, 6MWT and 10-m walk (all p-values<0.05); only FA in calf muscles significantly correlated with time to get up from floor (p = 0.01). Muscle FF, T2-relaxometry and DTI, seem to be a promising biomarker to assess BMD disease severity, although further studies are needed to evaluate changes over the time.

P.203Towards high-resolution clinical digital biomarkers for Duchenne muscular dystrophy

Clinical trials for Duchenne muscular dystrophy (DMD) assess functional performance in artificial set-ups, relying on subjective and motivation-dependant tasks. Furthermore, current outcome measures are subject to intra-rater & inter-rater variability in the patient performance itself. As a consequence, a larger sample size and longer duration of clinical trials are required, often delaying access to novel therapies. In the KineDMD study, we pursue a patient-centric approach to obtain a complete data-driven picture of full-body behavioural capacity in real-life over a 12 month period. Our Ethomics approach (Ethology & Omics) has 2 sides: "At home" & "In clinic". "In clinic" we focus on full-body motion analysis using high-resolution wearable sensors that can track full-skeleton movements of patients during standardised clinical assessments, therefore reducing the subjective assessment of clinical endpoints by data-driven objective analytics. DMD boys and age-matched healthy boys (HC) are assessed in the clinic during 6-monthly visits in conjunction with physio assessments whilst wearing a sensor suit of 17 sensors velcro-attached to normal clothing, capturing full body kinematics of 22 joints. To this end we are developing a number of machine learning algorithms that analyse the behaviour. Our interim analysis of the 15 DMD subjects and 10 HC reveal that motor coordination in HC and DMD show algorithmically identifiable static and dynamic differences. Our Gaussian Process regression approach combining features of individual gait-cycles of the 6-minute walk test was able to estimate from full-body kinematics the North Star Ambulatory Assessment (NSAA) total score of the boys with good accuracy. It is also possible to predict the NSAA scores (both cross-sectional and longitudinal) from the suit data of the NSAA assessment. The predicted and actual scores were highly correlated, supporting the notion that machine learning can accurately predict the results of functional assessments. The ultimate goal of this study is to derive new digital biomarkers, which are independent of artificial set-up and subjective biases and can be assessed in real life/home environment, to capture individual variations in disease progression and benefit to therapies.

Longitudinal natural history in young boys with Duchenne muscular dystrophy

The aim of this prospective multicentric study was to document disease progression in young boys affected by Duchenne muscular dystrophy (DMD) between age 3 and 6 years (±3 months) using the North Star Ambulatory Assessment scale. One hundred fifty-three DMD boys (573 assessments) younger than 6 years (mean: 4.68, SD: 0.84) with a genetically proven DMD diagnoses were included. Our results showed North Star Ambulatory Assessment scores progressively increased with age. The largest increase was observed between age 3 and 4 years but further increase was steadily observed until age of 6 years. Using a multiple linear regression analysis, we found that both the use of corticosteroids and the site of mutation significantly contributed to the North Star Ambulatory Assessment changes (p < 0.001). At each age point, boys on corticosteroid treatment had higher scores than corticosteroid naïve ones (p < 0.001). Similarly, patients with mutations downstream exon 44, had lower baseline scores and lower magnitude of changes compared to those with mutations located at the 5′ end of the gene (p < 0,001). Very few boys achieved the age appropriate maximum score. These results provide useful information for the assessment and counselling of young DMD boys and for the design of clinical trials in this age group.

Categorising trajectories and individual item changes of the North Star Ambulatory Assessment in patients with Duchenne muscular dystrophy.

Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that boys with DMD could be clustered into groups sharing similar trajectories of ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. We also explored associations with other variables such as age, functional abilities, and genotype. Using the NorthStar Clinical Network database, 395 patients with >1 NSAA assessment were identified. We utilised latent class trajectory analysis of longitudinal NSAA scores, which produced evidence for at least four clusters of boys sharing similar trajectories versus age in decreasing order of clinical severity: 25% of the boys were in cluster 1 (NSAA falling to ≤ 5 at age ~10y), 35% were in cluster 2 (NSAA ≤ 5 ~12y), 21% in were cluster 3 (NSAA≤ 5 ~14y), and 19% in cluster 4 (NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters (4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment, a significant (p<0.05) association was observed between earlier declining clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre walk/run times, and younger age of steroid initiation. In order to assess the probability of observing complete loss of function for individual NSAA items, we examined the proportion of patients who shifted from a score of 1 or 2 at baseline to a score of 0. We also assessed the probability of gain of function using the inverse assessment and stratified the probability of deterioration, improvement–or static behavior–by age ranges and using baseline functional status. Using this tool, our study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and, for the first time, describes discrete clusters of disease progression; this will be invaluable for future DMD clinical trial design and interpretation of findings.

Progression of Ankle Plantarflexion Contractures and Functional Decline in Duchenne Muscular Dystrophy: Implications for Physical Therapy Management.

This study characterizes the progressive loss of ankle dorsiflexion range of motion in boys with Duchenne muscular dystrophy (DMD), the relationship to functional decline, and the implications for physical therapy management. Longitudinal data for 332 boys with DMD were extracted from medical records and analyzed. Summary statistics for age, number of visits, ankle dorsiflexion measures, and North Star Ambulatory Assessment (NSAA) scores were computed. Ankle dorsiflexion motion ranged from -32.5 to 25 degrees. Progression of ankle contractures is demonstrated by a trend line: slope -1.43 per year. NSAA score was estimated to decline approximately 0.23 points per 1 degree of ankle dorsiflexion lost. The results of this study describe the progression of ankle contractures and functional decline in DMD. The findings may help inform decisions regarding interventions to support participants with DMD and their families.

Exon skipping for Duchenne muscular dystrophy: a systematic review and meta-analysis

BackgroundExon skipping has been considered a promising therapeutic approach for Duchenne muscular dystrophy (DMD). Eteplirsen received conditional approval in the United States in 2016. To date, no systematic reviews or meta-analyses of randomized controlled trials (RCTs) of exon skipping drugs have been published to determine the pooled estimates for the effect of exon skipping in treating DMD.MethodsA systematic review and meta-analysis of double-blind RCTs comparing exon-skipping drugs with placebo in DMD was performed. Trials were identified by searching published and unpublished studies from electronically available databases and clinical trial registries through October 2017. The primary outcomes were changes in the 6-min walk test (6MWT) distance, North Star Ambulatory Assessment (NSAA) scores, and adverse events. Random-effects meta-analysis and assessment of risk of bias were performed. This systematic review was registered at PROSPERO (CRD42016037504).ResultsFive studies involving 322 participants were included, investigating eteplirsen in one and drisapersen in four studies. There were no changes in 6MWT distance (mean difference [MD] − 9.16, 95% confidence interval [CI] − 21.94 to 3.62) or NSAA scores (MD 1.20, 95% CI − 2.35 to 4.75) after 24 weeks of treatment in the exon-skipping group compared with placebo. Subgroup analysis for a 6 mg/kg weekly injection of drisapersen showed significant changes in the 6MWT, favoring drisapersen after 24 weeks (MD − 20.24; 95% CI − 39.59 to − 0.89). However, drisapersen resulted in a significant increase in injection site reactions (risk ratio [RR] 3.67, 95% CI 1.96 to 6.89, p < 0.0001) and renal toxicity (RR 1.81, 95% CI 1.11 to 2.94, p = 0.02). Risk of bias was high in two of the five studies, including the eteplirsen and one drisapersen study.ConclusionsCurrent available data do not show evidence that exon-skipping drugs are effective in DMD. Despite potential effectiveness when used at a specific dose, significant side effects were reported with drisapersen. The small number of RCTs with relatively small numbers of participants indicate the difficulty in conducting sufficiently powered studies of DMD. Prospectively planned meta-analysis and utilization of the real-world data may provide a more precise estimate of the effect of exon skipping in this disease.