Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

Longitudinal Course of Long Finger Flexor Shortening in Males with Duchenne Muscular Dystrophy: A Retrospective Review1.

BACKGROUND: Shortening of the long finger flexors (Flexor Digitorum Profundus, FDPs) in Duchenne Muscular Dystrophy (DMD) causes reduced hand function. Until now, longitudinal studies on the natural course of the shortening of the FDPs are lacking, which impedes recommendations on timing and evaluation of preventive measures. OBJECTIVE: To investigate the longitudinal course of the FDP length during different disease stages focusing on symmetry, timing, and decline of the FDP length. METHODS: A retrospective, longitudinal multicenter study was conducted in the Radboud university medical center and the Leiden university medical center. The FDP outcome was measured using goniometry and gross motor function was assessed using the Brooke score. Longitudinal mixed model analyses were used to describe the course of the FDP outcome, and to investigate symmetry in both hands. RESULTS: Data on 534 visits of 197 males (age ranged 4-48 years) showed that in the ambulatory stages the FDP outcome was within a normal range. The mean decline in FDP outcome is 3.5 degrees per year, the biggest decline was seen in Brooke 5 (>15 degrees per year). In Brooke 4, 41% of the FDP outcome was < 40 degrees. No significant differences were found between right and left. CONCLUSIONS: This study supports the consideration of preventive measures to delay shortening of the FDPs in DMD patients transitioning to a Brooke scale of 4 or higher. Besides, natural history of FDP outcome has been established, which provides a base to evaluate (preventive) interventions.

Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

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.

Using PRPP-Assessment for measuring change in everyday activities by home-based videos: An exploratory case series study in children with multiple disabilities.

BACKGROUND: Currently, paediatric health care aims to use a child-centred tailor-made approach. In order to design tailored occupational therapy, the implementation of personalised occupation-based measurements that guide and evaluate goal setting and are responsive to change is necessary. PURPOSE: Primarily, this study explored the potential of the Perceive, Recall, Plan, and Perform (PRPP) assessment to measure the change in the performance of children with multiple disabilities. As a secondary evaluation, the feasibility of the PRPP-Intervention in a home-based program to enable activities was described. The overall aim is to show the potential of the PRPP-Assessment as an outcome measure to use as a base for designing tailor-made person-centred care. METHODS: An exploratory longitudinal multiple case series mixed-methods design was used. The PRPP-Assessment, scored by multiple raters, was conducted based on parent-provided videos. The assessed activities were chosen by the child and/or parents. Responsiveness was evaluated by hypotheses formulated a priori and by comparing measured change with change on concurrent measures: Goal Attainment Scaling (GAS) and Canadian Occupational Performance Measure (COPM). Over a 6-week period, children and their parents (or caregivers) participated in an online home-based video coaching program where parents were coached in the implementation of the training, based on the PRPP-Intervention, by paediatric occupational therapists on a weekly basis. The feasibility of the intervention was explored using semi-structured interviews with children, parents, and the treating occupational therapists and was analysed by directed content analysis. RESULTS: Three out of 17 eligible children agreed to participate and completed post-intervention measurement, of which two completed the intervention. Quantitative results showed that eight out of nine activities improved on the PRPP-Assessment and the COPM, and nine improved on the GAS. In total, 13 out of 15 hypotheses for responsiveness were accepted. Participants experienced the intervention as successful and acceptable. Facilitators and concerns over demand, implementation, practicality, integration, and adaptation were shared. CONCLUSION: The PRPP-Assessment showed the potential to measure change in a heterogeneous group of children. The results indicated a positive tendency for the intervention and also provide directions for further development.

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.

Ready for handwriting? A reference data study on handwriting readiness assessments.

INTRODUCTION: Early evaluation of writing readiness is essential to predict and prevent handwriting difficulties and its negative influences on school occupations. An occupation-based measurement for kindergarten children has been previously developed: Writing Readiness Inventory Tool In Context (WRITIC). In addition, to assess fine motor coordination two tests are frequently used in children with handwriting difficulties: the modified Timed Test of In-Hand Manipulation (Timed TIHM) and the Nine-Hole Peg Test (9-HPT). However, no Dutch reference data are available. AIM: To provide reference data for (1) WRITIC, (2) Timed-TIHM and (3) 9-HPT for handwriting readiness assessment in kindergarten children. METHODS: Three hundred and seventy-four children from Dutch kindergartens in the age of 5 to 6.5 years (5.6±0.4 years, 190 boys/184 girls) participated in the study. Children were recruited at Dutch kindergartens. Full classes of the last year were tested, children were excluded if there was a medical diagnosis such as a visual, auditory, motor or intellectual impairment that hinder handwriting performance. Descriptive statistics and percentiles scores were calculated. The score of the WRITIC (possible score 0-48 points) and the performance time on the Timed-TIHM and 9-HPT are classified as percentile scores lower than the 15th percentile to distinguish low performance from adequate performance. The percentile scores can be used to identify children that are possibly at risk developing handwriting difficulties in first grade. RESULTS: WRITIC scores ranged from 23 to 48 (41±4.4), Timed-TIHM ranged from 17.9 to 64.5 seconds (31.4± 7.4 seconds) and 9-HPT ranged from 18.2 to 48.3 seconds (28.4± 5.4). A WRITIC score between 0-36, a performance time of more than 39.6 seconds on the Timed-TIHM and more than 33.8 seconds on the 9-HPT were classified as low performance. CONCLUSION: The reference data of the WRITIC allow to assess which children are possibly at risk developing handwriting difficulties.

DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials.

BACKGROUND AND OBJECTIVES: Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients with untreated patients with the same DMD genotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials. METHODS: More than 1,600 patient-years of follow-up (>700 patients) were studied from 6 real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children's Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51, or 53, or other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-m walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors. RESULTS: The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for nongenotypic prognostic factors. DISCUSSION: These findings suggest the viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multigenotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in this study.

The reliability and validity of the perceive, recall, plan and perform assessment in children with a mitochondrial disorder.

PURPOSE: To investigate the reliability and validity of the Perceive, Recall, Plan and Perform System of Task Analysis (PRPP-Assessment) by parent-provided videos of children with mitochondrial disorders. METHODS: Videos of 13 children performing 3-7 activities each were the subject of study, resulting in 65 activities. These were scored using the PRPP-Assessment by 11 raters. Internal consistency was calculated with Cronbach's alpha. Intra-rater reliability was evaluated by Bland-Altman Plots on 44 PRPP-Assessment scores. Inter-rater reliability was calculated with ICCAgreement on 128 PRPP-Assessment scores. Construct validity was assessed by comparing the PRPP-Assessment scores to the Canadian Occupational Performance Measure using Cohen's Kappa. PRPP-Assessments scores were evaluated with a multi-faceted Rasch Analysis. RESULTS: Internal consistency was high (0.92). Intra-rater reliability was sufficient to be good (92-96% within the 95%-Limits of the Agreement). The ICCAgreement for stage 1 Mastery Score showed acceptable inter-rater reliability (0.646). Stage 2 of the PRPP-Assessment showed low ICCs due to a lack of variability within the sample. Four out of six hypotheses on validity were accepted. Rasch's analysis demonstrated sound goodness-of-fit, and supported the validity of the PRPP-Assessment. CONCLUSION: The PRPP-Assessment by parent-provided videos in this heterogenic group showed sufficient to good psychometric properties. In practice, careful task selection and formulating criterion is recommended.Implications for RehabilitationPRPP-Assessment by parent-provided videos is reliable and valid in the complex, heterogenous group of children with mitochondrial disordersThe PRPP-Assessment is suitable for children with mitochondrial disorders as it showed to contain familiar, functional and meaningful tasks and activities that fit with their level of functioningProfessionals should be aware that parents might not be used to the criterium-based frame of reference of the PRPP-AssessmentWhen applying the PRPP-Assessment, it is recommended to be careful in task selection and formulating the criterion.

T Cell Responses to Dystrophin in a Natural History Study of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin, but many patients have rare revertant fibers that express dystrophin. The skeletal muscle pathology of DMD patients includes immune cell infiltration and inflammatory cascades. There are several strategies to restore dystrophin in skeletal muscles of patients, including exon skipping and gene therapy. There is some evidence that dystrophin restoration leads to a reduction in immune cells, but dystrophin epitopes expressed in revertant fibers or following genome editing, cell therapy, or microdystrophin delivery after adeno-associated viral gene therapy may elicit T cell production in patients. This may affect the efficacy of the therapeutic intervention, and potentially lead to serious adverse events. To confirm and extend previous studies, we performed annual enzyme- linked immunospot interferon-gamma assays on peripheral blood mononuclear cells from 77 pediatric boys with DMD recruited into a natural history study, 69 of whom (89.6%) were treated with corticosteroids. T cell responses to dystrophin were quantified using a total of 368 peptides spanning the entire dystrophin protein, organized into nine peptide pools. Peptide mapping pools were used to further localize the immune response in one positive patient. Six (7.8%) patients had a T cell-mediated immune response to dystrophin at at least one time point. All patients who had a positive result had been treated with corticosteroids, either prednisolone or prednisone. Our results show that ∼8% of DMD individuals in our cohort have a pre-existing T cell-mediated immune response to dystrophin, despite steroid treatment. Although these responses are relatively low level, this information should be considered a useful immunological baseline before undertaking clinical trials and future DMD studies. We further highlight the importance for a robust, reproducible standard operating procedure for collecting, storing, and shipping samples from multiple centers to minimize the number of inconclusive data.

Long-term outcomes for females with early-onset dystrophinopathy.

AIM: To study long-term disease course for females with early-onset dystrophinopathy, including common (female) symptoms, challenges in social participation, the need for care, and current healthcare management to support guideline development. METHOD: Twelve females with early-onset dystrophinopathy were followed for a median period of more than 17 years (range 1-36). RESULTS: One patient died owing to end-stage cardiac failure. Cardiac abnormalities were observed in three of the remaining 11 participants. Respiratory function was reduced in seven of 10 participants. Fatigue, myalgia, lower back pain, and arthralgia were reported in more than six of the participants. Functional status varied from exercise intolerance to wheelchair dependency. Most or all of the 10 participants reported restrictions in participation in work (n = 10), household duties (n = 10), sports (n = 9), and education (n = 8). Only a few participants received followed-up pulmonary (n = 2) or rehabilitation (n = 3) care. INTERPRETATION: Females with early-onset dystrophinopathy experience a wide range of impairments, comorbidities, limitations in activities, and restrictions in social participation. The whole spectrum should be acknowledged in the healthcare setting. Neuromuscular and cardiac follow-up are indispensable. Additional respiratory assessment and rehabilitation care are expected to improve health status and support daily activities and participation. WHAT THIS PAPER ADDS: No standard diagnostic procedures seem to exist for female patients suspected for dystrophinopathy. Female participants with early-onset dystrophinopathy experienced a broad scope of burdening symptoms, such as fatigue, myalgia, lower back pain, and arthralgia. None of participants worked full time, all felt restricted in paid work, and most felt restricted in education. Most participants showed decreased lung function, while only one was symptomatic. Availability of rehabilitation care may improve support for daily activities and participation for females with early-onset dystrophinopathy.

Tailored interviewing to uncover the perspectives of children with multiple disabilities on daily activities: A qualitative analyses of interview methods and interviewer skills.

INTRODUCTION: Uncovering the perspective of children with multiple disabilities is important in health care to enable person-centred health care. For occupational therapists, uncovering the child perspective on meaningful activities is necessary to set appropriate goals for treatment. It is not always evident that children with multiple disabilities can express themselves in an interview. The interviewer should adapt his communication to the child. In literature, alternative communication is widely studied, but a clear algorithm for deciding what to use to successfully gain insight into the child perspective is missing. This study aims to identify helpful interview techniques and interviewer skills and how they can be used to effectively uncover the perspective of children. METHODS: Videos of nine interviews with children with a mitochondrial disorder, conducted by an occupational therapist, were analysed by five researchers. The interviews were analysed to see how well the interviewee had obtained the child's perspectives followed by observation of communicative abilities of the child and the types of questions the interviewer asked. A qualitative directed content analysis of the semi-structured interviews followed. FINDINGS: An interview pattern was observed in the children's communication leading to six successful interviews. Children communicated verbally on four different levels and also used non-verbal communication. The interviewer used five types of questions, which varied between and within the children. The content analysis resulted in two themes: parental influences and interviewer skills. CONCLUSION: Results show the importance of matching the type of questions to the verbal communication level of the child and revealed several interviewer skills and techniques. An overview to guide tailor-made interviewing is presented. The interviewer has a major role in successful interviewing and thus in enabling the inclusion of the child perspective in research and care.

Orthopedic Interventions for Foot Deformities in Non-Ambulant People with Duchenne Muscular Dystrophy: A Retrospective Study on Indications, Post-Operative and Long-Term Outcomes.

BACKGROUND: Progressive equinovarus deformities are common in people with Duchenne Muscular Dystrophy (DMD); they may provoke pain, pressure spots, cause problems with wearing footwear, and may lead to an unstable sitting position. OBJECTIVE: Explore indications and compare complications and long-term outcomes after soft tissue and osseous interventions in people with DMD. METHODS: Retrospective, monocenter, longitudinal study. Data on indications, equinus and varus deformity before and after surgery, wound healing problems, 'pain', edema, and long-term outcomes were collected from medical files. Soft tissue interventions were compared with osseous interventions. RESULTS: From a series of 18 patients, data on 32 surgical interventions and 169 follow-up visits were analyzed. 'Footrest placement' was the most frequent surgical indication, followed by pain. Osseous interventions were performed in older patients with rigid deformities. Directly after surgery remaining deformities were reported after soft tissue interventions (18 %), no remaining deformities were reported after osseous interventions. Pain and edema were frequently present, especially after osseous surgery. Longitudinal follow-up showed that surgical interventions could lead to a neutral foot for a for more than 3 years on average years. Relapses of foot deformity occurred, especially the recurrence of varus deformity after osseous interventions. CONCLUSIONS: Surgical interventions can successfully lead to a neutral foot position for for more than 3 years on average. Soft tissue interventions appear to be superior to osseous corrections, considering the varus recurrence period and complications, and may be considered when feet are still (partly) correctable. Pain management and edema prevention should be anticipated before surgery. Future research on patient reported outcomes as well as evaluating the outcome of the initial indication is needed to further identify benefits.

Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.

Importance: Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life. Objective: To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD). Design, Setting, and Participants: Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. Interventions: The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day. Main Outcomes and Measures: Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test. Results: Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo -0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, -1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. Conclusions and Relevance: In this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT03439670.

The Black Box of Technological Outcome Measures: An Example in Duchenne Muscular Dystrophy.

BACKGROUND: Outcome measures for non-ambulant Duchenne muscular dystrophy (DMD) patients are limited, with only the Performance of the Upper Limb (PUL) approved as endpoint for clinical trials. OBJECTIVE: We assessed four outcome measures based on devices developed for the gaming industry, aiming to overcome disadvantages of observer-dependency and motivation. METHODS: Twenty-two non-ambulant DMD patients (range 8.6-24.1 years) and 14 healthy controls (HC; range 9.5-25.4 years) were studied at baseline and 16 patients at 12 months using Leap Motion to quantify wrist/hand active range of motion (aROM) and a Kinect sensor for reached volume with Ability Captured Through Interactive Video Evaluation (ACTIVE), Functional Workspace (FWS) summed distance to seven upper extremity body points, and trunk compensation (KinectTC). PUL 2.0 was performed in patients only. A stepwise approach assessed quality control, construct validity, reliability, concurrent validity, longitudinal change and patient perception. RESULTS: Leap Motion aROM distinguished patients and HCs for supination, radial deviation and wrist flexion (range p = 0.006 to <0.001). Reliability was low and the manufacturer's hand model did not match the sensor's depth images. ACTIVE differed between patients and HCs (p < 0.001), correlated with PUL (rho = 0.76), and decreased over time (p = 0.030) with a standardized response mean (SRM) of -0.61. It was appraised as fun on a 10-point numeric rating scale (median 9/10). PUL decreased over time (p < 0.001) with an SRM of -1.28, and was appraised as fun (median 7/10). FWS summed distance distinguished patients and HCs (p < 0.001), but reliability in patients was insufficient. KinectTC differed between patients and HCs (p < 0.01), but correlated insufficiently with PUL (rho = -0.69). CONCLUSIONS: Only ACTIVE qualified as potential outcome measure in non-ambulant DMD patients, although the SRM was below the commonly used threshold of 0.8. Lack of insight in technological constraints due to intellectual property and software updates made the technology behind these outcome measures a kind of black box that could jeopardize long-term use in clinical development.

Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls.

Using external controls based on real-world or natural history data (RWD/NHD) for drug evaluations in Duchenne muscular dystrophy (DMD) is appealing given the challenges of enrolling placebo-controlled trials, especially for multi-year trials. Comparisons to external controls, however, face risks of bias due to differences in outcomes between trial and RWD/NHD settings. To assess this bias empirically, we conducted a multi-institution study comparing mean 48-week changes in North Star Ambulatory Assessment (NSAA) total score between trial placebo arms and RWD/NHD sources, with and without adjustment for baseline prognostic factors. Analyses used data from three placebo arms (235 48-week intervals, N = 235 patients) and three RWD/NHD sources (348 intervals, N = 202 patients). Differences in mean ΔNSAA between placebo arms and RWD/NHD sources were small before adjustment (-1.2 units, 95% CI: [-2.0 -0.5]) and were attenuated and no longer statistically significant after adjustment (0.1 units (95% CI: [-0.6, 0.8]). Results were similar whether adjusting using multivariable regression or propensity score matching. This consistency in ΔNSAA between trial placebo arms and RWD/NHD sources accords with prior findings for the six-minute walk distance, provides a well-validated framework for baseline adjustment of prognostic factors, and supports the suitability of RWD/NHD external controls for drug evaluations in ambulatory DMD.

Martial Arts Training for Boys With Duchenne Muscular Dystrophy.

PURPOSE: The primary aim of this pilot study was to investigate the safety and feasibility of a 3-month martial arts-based training (MAT) program for patients with Duchenne muscular dystrophy (DMD). The secondary aim was to examine changes in physical and psychosocial abilities after participating in the MAT program. METHODS: Twelve patients with DMD (10 ambulant and 2 nonambulant) were included. The MAT program was evaluated on feasibility and safety. Changes in physical abilities were measured using the Motor Function Measure, Performance of Upper Limb scale, and the North Star Ambulatory Assessment. Changes in psychosocial abilities were measured using the Strength and Difficulties Questionnaire, Personal Adjustment and Role Skills for DMD, and the Self-Perception Profile for Children/Adolescents. RESULTS: Two participants did not complete the MAT program. Attendance rate for the 10 remaining participants was 91%. Eleven falls were reported during the training, but these falls did not result in injuries. Therefore, the MAT program was found feasible and safe. After completing the MAT program, most participants showed an improvement of their psychosocial abilities, and their physical abilities did not show deterioration. CONCLUSION: The MAT program is feasible and safe for boys with DMD.

BMI-z scores of boys with Duchenne muscular dystrophy already begin to increase before losing ambulation: a longitudinal exploration of BMI, corticosteroids and caloric intake.

We aimed to investigate BMI-z course in patients with Duchenne muscular dystrophy (DMD) during transition to loss of ambulation, and to explore the contribution of caloric intake and corticosteroid use. A retrospective multicenter longitudinal study was conducted. First, analyses of characteristics at first visit were carried out. Second, discontinuous change models were fitted to explore associations between BMI-z, loss of ambulation, caloric intake and corticosteroid use. 790 visits of 159 patients were collected. Cross sectional first visit analyses showed the presence of overweight and obesity was 44% in the ambulant group and 51% in the non-ambulant group. In the non-ambulatory group, exceeding the recommended caloric intake was associated with higher BMI-z scores (r 0.36, p = 0.04). Patients who were using corticosteroids had significantly higher BMI-z scores compared with patients not using corticosteroids (1.06 and 0.51 respectively, p = 0.02). Longitudinal analyses on patients ambulant at first visit showed an increase in BMI-z score during transition to the non-ambulatory phase. Caloric intake and corticosteroid use were not associated with BMI-z. Transition to the non-ambulatory phase may be crucial in the development of excessive weight gain. Early measures - starting before this time frame - may contribute to reduce development of obesity.

Genotype-related respiratory progression in Duchenne muscular dystrophy-A multicenter international study.

INTRODUCTION/AIMS: Mutations amenable to skipping of specific exons have been associated with different motor progression in Duchenne muscular dystrophy (DMD). Less is known about their association with long-term respiratory function. In this study we investigated the features of respiratory progression in four DMD genotypes relevant in ongoing exon-skipping therapeutic strategies. METHODS: This was a retrospective longitudinal study including DMD children followed by the UK NorthStar Network and international AFM Network centers (May 2003 to October 2020). We included boys amenable to skip exons 44, 45, 51, or 53, who were older than 5 years of age and ambulant at first recorded visit. Subjects who were corticosteroid-naive or enrolled in interventional clinical trials were excluded. The progression of respiratory function (absolute forced vital capacity [FVC] and calculated as percent predicted [FVC%]) was compared across the four subgroups (skip44, skip45, skip51, skip53). RESULTS: We included 142 boys in the study. Mean (standard deviation) age at first visit was 8.6 (2.5) years. Median follow-up was 3 (range, 0.3-8.3) years. In skip45 and skip51, FVC% declined linearly from the first recorded visit. From the age of 9 years, FVC% declined linearly in all genotypes. Skip44 had the slowest (2.7%/year) and skip51 the fastest (5.9%/year) annual FVC% decline. The absolute FVC increased progressively in skip44, skip45, and skip51. In skip53, FVC started declining from 14 years of age. DISCUSSION: The progression of respiratory dysfunction follows different patterns for specific genotype categories. This information is valuable for prognosis and for the evaluation of exon-skipping therapies.

Natural History of Facioscapulohumeral Dystrophy in Children: A 2-Year Follow-up.

BACKGROUND AND OBJECTIVES: Data on the natural history of facioscapulohumeral dystrophy (FSHD) in childhood are limited and critical for improved patient care and clinical trial readiness. Our objective was to describe the disease course of FSHD in children. METHODS: We performed a nationwide, single-center, prospective cohort study of FSHD in childhood assessing muscle functioning, imaging, and quality of life over 2 years of follow-up. RESULTS: We included 20 children with genetically confirmed FSHD who were 2 to 17 years of age. Overall, symptoms were slowly progressive, and the mean FSHD clinical score increased from 2.1 to 2.8 (p = 0.003). The rate of progression was highly variable. At baseline, 16 of 20 symptomatic children had facial weakness; after 2 years, facial weakness was observed in 19 of 20 children. Muscle strength did not change between baseline and follow-up. The most frequently and most severely affected muscles were the trapezius and deltoid. The functional exercise capacity, measured with the 6-minute walk test, improved. Systemic features were infrequent and nonprogressive. Weakness-associated complications such as lumbar hyperlordosis and dysarthria were common, and their prevalence increased during follow-up. Pain and fatigue were frequent complaints in children, and their prevalence also increased during follow-up. Muscle ultrasonography revealed a progressive increase in echogenicity. DISCUSSION: FSHD in childhood has a slowly progressive but variable course over 2 years of follow-up. The most promising outcome measures to detect progression were the FSHD clinical score and muscle ultrasonography. Despite this disease progression, an improvement on functional capacity may still occur as the child grows up. Pain, fatigue, and a decreased quality of life were common symptoms and need to be addressed in the management of childhood FSHD. Our data can be used to counsel patients and as baseline measures for treatment trials in childhood FSHD.