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The Revised Hammersmith Scale (RHS) is an established outcome measure for gross motor function in patients with Spinal Muscular Atrophy (SMA). A description of the minimal detectable change (MDC) is crucial to meaningfully interpret data collected using the RHS. This study aims to identify the MDC on the RHS for disease-modifying treatment (DMT)-naïve patients with SMA. Retrospective data was collected from 2 sites in the UK. Currently, due to data completeness, results are available from a single site (Great Ormond Street Hospital). All DMT-naïve patients reviewed between 2015 and 2019 were included. Patients' ages ranged between 2-18 years (median 8.9 years). Three distribution-based methodologies were used to calculate MDC: ½ standard deviation (SD) of baseline scores, ⅓ SD of baseline scores, and 1 standard error of the mean (SEM) at baseline. The functional groups used were sitters, high-functioning sitters/standers (HFSS), and walkers. Fifty-two patients were included. The MDC for sitters ages 2-4 years (n=5) was 1-1.9 points (pts), 5-7 years (n=8) was 1.2-2.5 pts, 8-13 years (n=8) was 1.4-2.5 pts, and 14-18 (n=3) years was 1.3-2.3 pts. The MDC for HFSS for ages 2-4 years (n=2) was 0.6-1.0 pts, and 5-7 years (n=2) was 1.8-3.2 pts. The MDC for walkers ages 2-4 years (n=2) was 1.2-2.1 pts, 5-7 years (n=5) was 1.4-2.4 pts, and 8-13 years (n=10) was 3.4-6.1 pts. The MDC for type 2 SMA patients ages 2-4 years (n=8) is 1.8-3.1 pts, 5-7 years (n=7) was 1.1-2.0 pts, and 8-13 years (n=10) was 2.2-4.0 pts. The MDC for type 3 SMA patients ages 2-4 years (n=2) was 1.2-2.1 pts, 5-7 years (n=8) was 3.6-6.5 pts, 8-13 years (n=13) was 4.6-8.1 pts, and 14-18 years (n=3) was 1.3-2.3 pts. This study describes the MDC on the RHS for untreated patients across various ages, functional groups, and types of SMA. Results will be presented from the ongoing national data analysis. Future work will focus on treated cohorts and determining a patient-focused minimal clinically important difference. [ABSTRACT FROM AUTHOR]

Disease-modifying treatments, such as nusinersen, have significantly improved the disease trajectory of Spinal Muscular Atrophy (SMA) patients. Treatment response is heterogeneous, and predicting response is crucial for clinicians to give realistic guidance to patients and carers when counselling about treatment options. We collected data on 124 patients from the SMA Reach UK and Italian Network studies. Participants were included if they were treated under 4 years and were non-sitters at nusinersen initiation, were randomly allocated to training (80%) and testing cohorts (20%). Tree and regression-based machine learning for survival outcomes were compared, and oblique random forests were selected, with a testing C-Index of 0.74. The features were selected from items of the CHOP and HINE-2, respiratory symptoms and bulbar interventions using mutual information. In total, 62 (50%) have achieved sitting, at a median age of 2.4 years. The predicted median time-to-sitting in those requiring NG or G-Tubes at treatment was 4-months later on average than those without, and this was the most influential factor. The ability to kick at treatment, (≥1 on the HINE-2 item) was also influential in predicting the likelihood of sitting, as was antigravity shoulder movement in supine and ability to reach in side-lying (4 on items 1 and 8), and neck muscle activation in pull to sit (≥2 on item 14) and rolling fully prone from supine when elicited from arms (≥3 on item 7) on the CHOP at treatment. Most notably, those who could roll fully prone from supine had a median predicted time-to-sit 5.8 months earlier than an identical patient who could not. Nusinersen starting and symptom onset age were less influential, whilst SMN2 copy numbers did not improve the model. This work provides a tool to predict treatment response in nusinersen-treated patients and has the potential to be extended to other treatment options, moving clinicians towards personalised treatment plans for each patient. [ABSTRACT FROM AUTHOR]

Background: Glucocorticosteroids (GC) are standard-of-care treatment for most boys with duchenne muscular dystrophy (DMD). GC use has changed over time with evolving evidence, and we describe GC patterns, dosing and side-effects in the UK over 11 years., Method: NorthStar data from 2012 to 2022 were analysed to understand GC type, regime and starting age. GC dose with age, patterns of GC switching and side-effect profiles by type and regime were also analysed. Participants attributed to 'other' regimes were queried and details were included., Results: Data on GC usage were available for 1117 boys, across 6905 observations, with 74% of boys GC treated. Prednisolone was the most common regime in the period (65% of assessments) but deflazacort prescription has increased (17% in 2012 and 43% in 2022). Daily regimes were more common (66% of assessments), and the incidence of intermittent (10 days on/10 days off) regimes has declined (46% in 2012 and 26% in 2022). Older participants were more commonly on less than recommended doses, and this was more common in those on deflazacort or daily regimes. Gastrointestinal symptoms and cushingoid features were more common in those on deflazacort than prednisolone, while increased appetite, cushingoid features, gastrointestinal symptoms and insomnia were more common in those on daily than intermittent regimes., Conclusions: The use of deflazacort and daily regimes has steadily increased across the UK North Star Network in the last decade. This study provides one of the largest up-to-date real-world set of data of evolution in prescription patterns and the occurrence of side-effects in different groups of GC-treated DMD., Competing Interests: Competing interests: MG has participated in advisory boards for PTC Therapeutics, Capricor, Pfizer and NS Pharma. She has research collaborations with ReveraGen, she is or has been Principal Investigator for clinical trials with Roche, Italfarmaco, Santhera, ReveraGen, Summit, Pfizer, PTC Therapeutics; FM reports participation to Scientific Advisory boards and teaching initiatives for Novartis, Biogen, Roche, he is involved as an investigator in clinical trials from Novartis, Biogen, and Roche, both institutions (UCL and GOSH) receive funding from Biogen and Roche for the SMAREACH SMA registry; GB is PI of clinical trials by Pfizer, NS Pharma, and Reveragen, and has received speaker and/or consulting fees from Sarepta, PTC Therapeutics, Biogen, Novartis Gene Therapies (AveXis), and Roche and has worked as principal investigator of SMA studies sponsored by Novartis Gene Therapies, and Roche; GL, GS, AYM and AS have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background and Purpose: Treatment with glucocorticoids (GCs) is part of the standard of care in Duchenne muscular dystrophy, but excess weight gain and height stunting are common side-effects. It is still unclear how these growth-related side-effects affect motor function., Methods: This retrospective cohort study utilized 2228 observations from 648 participants in the UK NorthStar database who had growth and ambulation data recorded between 2006 and 2020. Joint modelling was used to analyse the effect of longitudinal growth centiles on loss of ambulation with respect to GC type and regimen., Results: Loss of ambulation was observed in 113 patients. National estimates of loss of ambulation age were updated by GC group and showed no significant association between loss of ambulation risk and absolute growth centile. However, yearly drift in weight and/or height centile had an associated risk effect on loss of ambulation. Over a 2-year period, a yearly drift in weight from the 50th to the 75th, 75th to the 90th and 90th to the 95th centile was associated with 138%, 118% and 64% increased risk of loss of ambulation, respectively. Conversely, a 2-year drift in height from the 50th to the 25th, 25th to the 10th and 10th to the 5th centile was associated with 53%, 49% and 35% decreased risk of loss of ambulation, respectively., Conclusions: Our results suggest a complex relationship between growth and loss of ambulation in Duchenne muscular dystrophy boys on chronic GCs, the first step in understanding the effects of drugs which also affect growth patterns., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Spinal muscular atrophy (SMA) is a neuromuscular disorder of mainly early onset and variable severity. Prior to the introduction of disease modifying therapies (DMTs), children with SMA type 1 typically died before 2 years of age and management was primarily palliative. Onasemnogene abeparvovec (OA), nusinersen, and risdiplam are novel DMTs which ameliorate the effects of the underlying genetic defect at least partially making SMA a treatable condition. Survival and achievement of previously unmet developmental milestones result in treated SMA type 1 children spending more time upright than expected based on the natural history of the treatment-naïve condition. Consequently, spinal asymmetry and kyphosis, features not typically seen in untreated SMA type 1 children due to early mortality, are increasingly common complications. Precise data regarding their prevalence, severity, and management are currently limited. This study describes the spinal features and management in 75 children with SMA type 1 who received OA between March 2021 and December 2022. Retrospective analysis from SMA REACH UK data showed that 44/75 (59 %) clinically had spinal asymmetry and 37 (49 %) had kyphosis. This study aims to raise awareness of this important feature as part of the changed natural history of SMA type 1 post OA treatment., Competing Interests: Declaration of competing interest The authors do not have any conflicts of interest to declare in relation to this submission., (Copyright © 2024. Published by Elsevier B.V.)

NorthStar Ambulatory Assessment (NSAA) total score (TS) is an ordinal scale to evaluate disease progression and treatment response in ambulatory Duchenne Muscular Dystrophy individuals. Clinical management according to standard of care could be enhanced by understanding how changes in the TS could inform standards of care. Here we describe the associated item performance patterns in the NorthStar Database for ranges of NSAA TS and its timed tests (10 m walk/run and rise from floor). We then compare these patterns depending on whether a participant is on an improving/stable (≤2-point loss in the prior year) or declining (>2-point loss in the prior year) trend. These TS and trends are subsequently linked and referenced to therapy standards of care. We included 761 participants from the UK NorthStar observational clinical database between 5 and 16 years, who were on steroids. Differences and trends in item ability, compensations, and times can suggest specific disease complications and lead towards anticipatory therapy recommendations. Families and therapists can benefit from using the TS and trend to guide therapy management., Competing Interests: Declaration of competing interest FM reports participation to Scientific Advisory boards and teaching initiatives for Novartis, Biogen, Roche; he is involved as an investigator in clinical trials from Novartis, Biogen, and Roche. Both institutions (UCL and GOSH) receive funding from Biogen and Roche for the SMAREACH SMA registry. GB is PI of clinical trials by Pfizer, NS Pharma, and Reveragen, and has received speaker and/or consulting fees from Sarepta, PTC Therapeutics, Biogen, Novartis Gene Therapies, Inc. (AveXis), and Roche and has worked as principal investigator of SMA studies sponsored by Novartis Gene Therapies, Inc., and Roche. AGM has served on medical/scientific advisory boards for Regenxbio, Sarepta, Biogen and Roche; and has received fees for consulting and training services for Biogen, Roche, Novartis, Biohaven, PTC, Sarepta, Italfarmaco, Dyne, Pfizer, Summit, Catabasis, Capricor, Santhera, Vision, Lysogene, Modis, Amicus, Taysha, Antisense, Analysis Group, MDUK and DUK. MKJ has served on scientific advisory boards for Sarepta, Roche, Pfizer and Genethon; and has received fees for consulting and training services for PTC, Sarepta, Italfarmaco, Dyne, Pfizer, Summit, Catabasis, Capricor, Santhera, Amicus, NSPharma, Antisense, Edgewise, BridgeBio. MG has served on medical/scientific advisory boards for Pzifer, Dyne, NS Pharma, Antisense; has received research grants from PTC Therapeutics, Sarepta, Edgewise and was on the speaker's bureau for Italfarmaco, Sarepta, Pfizer, Novartis, Roche. GS, AM, AS and AW have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS)., Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019)., Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient., Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex., Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

Background Boys with Duchenne Muscular Dystrophy (DMD) display heterogeneous motor function trajectory in clinics, which represents a significant obstacle to monitoring., Objective: In this paper, we present the UK centiles for the North Star Ambulatory Assessment (NSAA), the 10 m walk/run time (10MWR) and velocity (10MWRV), and the rise from floor time (RFF) and velocity (RFFV) created from a cohort of glucocorticoid treated DMD boys between the age of 5 and 16 years., Methods: Participants were included from the UK NorthStar registry if they had initiated steroids (primarily deflazacorts/prednisolone, intermittent/daily) and were not enrolled in an interventional trial. Assessments were included if the participant had a complete NSAA, the timed tests had been completed or the corresponding items were 0, or the participant was recorded as non-ambulant, in which case the NSAA was assumed 0., Results: We analysed 3987 assessments of the NSAA collected from 826 participants. Of these, 1080, 1849 and 1199 were imputed as 0 for the NSAA, RFFV and 10MWRV respectively. The 10th, 25th, 50th, 75th and 90th centiles were presented. The NSAA centiles showed a peak score of 14, 20, 26, 30 and 32 respectively, with loss of ambulation at 10.7, 12.2 and 14.3 years for the 25th, 50th and 75th centiles, respectively. The centiles showed loss of rise from floor at 8.6, 10.1 and 11.9 years and a loss of 10MWR of 0 at 8.9, 10.3 and 13.8 years for the 25th, 50th and 75th centiles, respectively. The centiles were pairwise less correlated than the raw scores, suggesting an increased ability to detect variability in the DMD cohort., Conclusions: The NSAA, 10MWR and RFF centiles may provide insights for clinical monitoring of DMD boys, particularly in late ambulatory participants who are uniformly declining. Future work will validate the centiles in national and international natural history cohorts.

There are multiple avenues for therapeutic development in Duchenne muscular dystrophy (DMD), which are highlighted in the first section of this report for the "10 years of Clinical trials in DMD - What have we learned?" workshop. This report then provides an overview of the presentations made at the workshop grouped into the following core themes: trial outcomes, disease heterogeneity, meaningfulness of outcomes and the utility of real-world data in trials. Finally, we present the consensus that was achieved at the workshop on the learning points from 10 years of clinical trials in DMD, and possible action points from these. This includes further work in expanding the scope and range of trial outcomes and assessing the efficacy of new trial structures for DMD. We also highlight several points which should be addressed during future interactions with regulators, such as clinical meaningfulness and the use of real-world data., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023.)

Background: Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen-an oestrogen receptor regulator-reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks., Methods: We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5-12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed., Findings: Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were included in the intention-to-treat population. The primary efficacy outcome did not differ significantly between tamoxifen (-3·05%, 95% CI -7·02 to 0·91) and placebo (-6·15%, -9·19 to -3·11; 2·90% difference, -3·02 to 8·82, p=0·33). Severe adverse events occurred in two participants: one participant who received tamoxifen had a fall, and one who received placebo suffered a panic attack. No deaths or life-threatening serious adverse events occurred. Viral infections were the most common adverse events., Interpretation: Tamoxifen was safe and well tolerated, but no difference between groups was reported for the primary efficacy endpoint. Slower disease progression, defined by loss of motor function over time, was indicated in the tamoxifen group compared with the placebo group, but differences in outcome measures were neither clinically nor statistically significant. Currently, we cannot recommend the use of tamoxifen in daily clinical practice as a treatment option for boys with Duchenne muscular dystrophy due to insufficient clinical evidence., Funding: Thomi Hopf Foundation, ERA-Net, Swiss National Science Foundation, Duchenne UK, Joining Jack, Duchenne Parent Project, Duchenne Parent Project Spain, Fondation Suisse de Recherche sur les Maladies Musculaires, Association Monegasque contre les Myopathies., Competing Interests: Declaration of interests DF is principal investigator for studies on spinal muscular atrophy sponsored by Hofmann–La Roche. US-S is a consultant for Santhera, PTC Therapeutics, Sarepta, and Pfizer. ND is a consultant for Roche and Novartis and received payment for lectures from Roche. ANO received payment for lectures from Sarepta, Novartis, Biogen, PTC Therapeutics, and Roche and support for attending meetings from PTC Therapeutics, Roche, and Biogen. VL is a consultant for Axelys, Roche, Avexis, and Biogen and received payment for lectures from Biogen, Pfizer, Roche, Novartis, PTC Therapeutics, and Sarepta. VL received support of attending meetings from Novartis, Pfizer, and Biogen and participated in advisory boards for Novartis, Roche, Biogen, and PTC Therapeutics. StS is a consultant for Sarepta, PCT, Roche, WAVE, Pfizer, and Avexis and received payment for lectures from Sarepta. All other authors declare no competing interests. All study sites received payment for study set up and study visits., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Characterise the diagnostic and prognostic value of muscle MRI patterns as biomarkers in a genetically heterogeneous nemaline myopathy (NM) patient cohort., Methods: Modified Mercuri scoring of lower limb MRI in genetically characterised NM patients referred to the highly specialised service for congenital myopathies at Great Ormond Street Hospital. Findings were compared to clinical data and MRI patterns derived from collated published data., Results: Twenty-seven patients with MRI were identified (8 NEB-NM, 13 ACTA1-NM, 6 TPM3-NM). NEB-NM demonstrated sparing of the thigh. ACTA1-NM demonstrated diffuse thigh involvement, notable in the vasti, sartorius and biceps-femoris, with relative adductor and gracilis sparing. TPM3-NM demonstrated diffuse thigh involvement notable in biceps-femoris and adductor magnus with relative rectus femoris, adductor longus and gracilis sparing. In the lower leg, the soleus and tibialis anterior are notably involved in all three genotypes. NEB-NM and ACTA1-NM demonstrated relative gastrocnemii and tibialis posterior sparing, while TPM3-NM showed significantly more tibialis posterior involvement (P =< 0.05). Comparison of involvement patterns with literature datasets highlighted preferential adductor and gracilis sparing in our ACTA1-NM cohort, consistent tibialis posterior involvement in our TPM3-NM cohort and a distinct MRI pattern from those derived from other NM genotypes and congenital myopathies. Greater tibialis anterior involvement correlated with foot drop (P = 0.02). Greater tibialis anterior and extensor hallucis longus involvement correlated with worse mobility (P =< 0.04)., Interpretation: This is the widest NM MRI data set described to date; we describe distinct muscle involvement patterns for NEB-NM, ACTA1-NM and TPM3-NM which may have utility as diagnostic and prognostic biomarkers and aid in genetic variant interpretation., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8-13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items.

Aim: To assess the evolution of bulbar function in nusinersen-treated spinal muscular atrophy type 1 (SMA1)., Method: This single-centre retrospective study identified 24 patients (14 females and 10 males) with SMA1, treated with nusinersen between 2017 and 2020. We adapted and validated the Paediatric Functional Oral Intake Scale (p-FOIS), which is an outcome measure to assess bulbar function. Analysis considered SMA1 subtype, nutritional support, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and p-FOIS scores at initiation of nusinersen treatment (baseline) and at 6, 12, and 24 months after initiation., Results: The median age at baseline was 11 months (range 1 month-7 years 6 months). Median age at initiation of tube feeding was 8 months (range 0-2 years 2 months). Fourteen patients were tube fed at baseline. The median p-FOIS score was 3 at baseline and 2 at 12 and 24 months. Four patients, all with type 1c SMA, remained orally fed at 24 months. Median CHOP INTEND scores increased from 32 at baseline to 42 at 12 and 24 months., Interpretation: Impaired bulbar function persisted as a significant complication in most nusinersen-treated patients with SMA1, in contrast to the improvement in motor abilities demonstrated in the majority. p-FOIS allows for tracking of bulbar function progression and treatment response. Larger, prospective studies investigating the longer-term impacts of nusinersen on bulbar function are warranted., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Objectives: The objective of this study is to analyse retrospective, observational, longitudinal growth (weight, height and BMI) data in ambulatory boys aged 5-12 years with Duchenne muscular dystrophy (DMD)., Background: We considered glucocorticoids (GC) use, dystrophin isoforms and amenability to exon 8, 44, 45, 51 and 53 skipping drug subgroups, and the impact of growth on loss of ambulation. We analysed 598 boys, with 2604 observations. This analysis considered patients from the UK NorthStar database (2003-2020) on one of five regimes: "GC naïve", "deflazacort daily" (DD), "deflazacort intermittent" (DI), "prednisolone daily" (PD) and "prednisolone intermittent" (PI). A random slope model was used to model the weight, height and BMI SD scores (using the UK90)., Results: The daily regime subgroups had significant yearly height stunting compared to the GC naïve subgroup. Notably, the average height change for the DD subgroup was 0.25 SD (95% CI - 0.30, - 0.21) less than reference values. Those with affected expression of Dp427, Dp140 and Dp71 isoforms were 0.77 (95% CI 0.3, 1.24) and 0.82 (95% CI 1.28, 0.36) SD shorter than those with Dp427 and/or Dp140 expression affected respectively. Increased weight was not associated with earlier loss of ambulation, but taller boys still ambulant between the age of 10 and 11 years were more at risk of losing ambulation., Conclusion: These findings may provide further guidance to clinicians when counselling and discussing GCs commencement with patients and their carers and may represent a benchmark set of data to evaluate the effects of new generations of GC., (© 2022. The Author(s).)

Importance: Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups., Objective: To investigate outcomes after 30 months of open-label vamorolone treatment., Design, Setting, and Participants: This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021., Interventions: Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d., Main Outcomes and Measures: Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone., Results: Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time., Conclusions and Relevance: This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD., Trial Registration: ClinicalTrials.gov Identifier: NCT03038399.

Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD), two of the most common, child onset, rare neuromuscular disorders, present a case study for the translation of preclinical research into clinical work. Over the past decade, well-designed clinical trials and innovative methods have led to the approval of several novel therapies for SMA and DMD, with many more in the pipeline. This review discusses several features that must be considered during trial design for neuromuscular diseases, as well as other rare diseases, to maximise the possibility of trial success using historic examples. These features include well-defined inclusion criteria, matching criteria, alternatives to placebo-controlled trials and the selection of trial endpoints. These features will be particularly important in the coming years as the investigation into innovative therapy approaches for neuromuscular diseases continues., Competing Interests: GB has received consultancy honoraria from AveXis, Roche, Biogen, PTC, and Sarepta Therapeutics. GB has received speaker honoraria from AveXis, Roche and PTC. FM is supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre and has received speaker and consultancy honoraria from Sarepta Therapeutics, Avexis, PTC Therapeutics, Roche and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Stimpson, Chesshyre, Baranello and Muntoni.)