Background and ObjectivesClinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) tra-ditionally compare treated patients with untreated patients with the same DMD... Show moreBackground and ObjectivesClinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) tra-ditionally 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 eligiblecontrols, increasing challenges for trial enrollment in this already rare disease. To evaluate thesuitability of genotypically unmatched controls in DMD, we quantified effects of genotype classon 1-year changes in motor function endpoints used in clinical trials.MethodsMore 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 inNorth Star Ambulatory Assessment total score (DNSAA) and in 10-m walk/run velocity(D10MWR) were studied in each data source with and without adjustment for baselineprognostic factors.ResultsThe studied genotype classes accounted for approximately 2% of variation in DNSAA outcomesafter 12 months, whereas other prognostic factors explained >30% of variation in large datasources. Based on a meta-analysis across all data sources, pooled effect estimates for the studiedskip-amenable mutation classes were all small in magnitude (<2 units in DNSAA total score in1-year follow up), smaller than clinically important differences in NSAA, and were preciselyestimated with standard errors <1 unit after adjusting for nongenotypic prognostic factors. Show less
Opstal, S.L.S.H.V.; Tak, R.O.; Pelsma, M.; Heuvel, F.M.A. van den; Duyvenvoorde, H.A. van; Cup, E.H.C.; ... ; Willemsen, M.A.A.P. 2022
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... Show moreIMPORTANCE 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 dimb 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), 121were 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. Show less
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... Show moreWe 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. (c) 2022 The Author(s). Published by Elsevier B.V. Show less
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... Show moreBackground: 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 (rangep = 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. Show less
Dijkstra, J.N.; Goselink, R.J.M.; Alfen, N. van; Groot, I.J.M. de; Pelsma, M.; Stoep, N. van der; ... ; Erasmus, C.E. 2021
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... Show moreBackground 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. Show less
Naarding, K.J.; Holst, M. van der; Zwet, E.W. van; Velde, N.M. van de; Groot, I.J.M. de; Verschuuren, J.J.G.M.; ... ; Niks, E.H. 2021
Background and Objectives To study the potential of quantitative MRI (qMRI) fat fraction (FF) as a biomarker in nonambulant patients with Duchenne muscular dystrophy (DMD), we assessed the additive... Show moreBackground and Objectives To study the potential of quantitative MRI (qMRI) fat fraction (FF) as a biomarker in nonambulant patients with Duchenne muscular dystrophy (DMD), we assessed the additive predictive value of elbow flexor FF to age at loss of hand-to-mouth movement. Methods Nonambulant patients with DMD (age >= 8 years) were included. Four-point Dixon MRI scans of the right upper arm were performed at baseline and at the 12-, 18-, or 24-month follow-up. Elbow flexor FFs were determined from 5 central slices. Loss of hand-to-mouth movement was determined at study visits and by phone calls every 4 months. FFs were fitted to a sigmoidal curve by use of a mixed model with random slope to predict individual trajectories. The added predictive value of elbow flexor FF to age at loss of hand-to-mouth movement was calculated from a Cox model with the predicted FF as a time-varying covariate, yielding a hazard ratio. Results Forty-eight MRIs of 20 patients with DMD were included. The hazard ratio of a percent-point increase in elbow flexor FF for the time to loss of hand-to-mouth movement was 1.12 (95% confidence interval 1.04-1.21; p = 0.002). This corresponded to a 3.13-fold increase in the instantaneous risk of loss of hand-to-mouth movement in patients with a 10-percent points higher elbow flexor FF at any age. Discussion In this prospective study, elbow flexor FF predicted loss of hand-to-mouth movement independently of age. qMRI-measured elbow flexor FF can be used as a surrogate endpoint or stratification tool for clinical trials in nonambulant patients with DMD. Classification of Evidence This study provides Class II evidence that qMRI FF of elbow flexor muscles in patients with DMD predicts loss of hand-to-mouth movement independently of age. Show less
Houwen-van Opstal, S.L.S.; Heutinck, L.; Jansen, M.; Krom, Y.D.; Cup, E.H.C.; Hendriksen, J.G.M.; ... ; Groot, I.J.M. de 2021
Introduction/Aims: As life expectancy improves for patients with Duchenne muscular dystrophy (DMD), new symptoms are likely to arise. This aims of this study are: (1) to explore the prevalence of a... Show moreIntroduction/Aims: As life expectancy improves for patients with Duchenne muscular dystrophy (DMD), new symptoms are likely to arise. This aims of this study are: (1) to explore the prevalence of a broad variety of symptoms in the various stages of DMD (with and without steroid use); (2) to explore the prevalence of common secondary diagnoses; and (3) to evaluate the social participation level of patients with DMD older than 16 y of age; and to explore correlations between social participation and symptoms.Methods A cross-sectional self-report questionnaire, including questions on functional level and health status, as well as a standardized participation scale was distributed among Dutch patients with DMD.Results Eighty-four male patients with a mean age of 22.0 (SD = 10.0) y were enrolled. The most prevalent and limiting symptoms were difficulty coughing (58%), coldness of hands (57%), contractures (51%), stiffness (49%), fatigue (40%), myalgia (38%), and low speech volume (33%). Prevalent secondary diagnoses included cardiac disease (14%), neurobehavioral diagnosis (13%), low blood pressure (13%), and arthrosis (5%). Social participation correlated negatively with coldness of hands (r = - .29; P < .03), decreased intelligibility (r = - .40; P < .003), and chewing problems (r = - .33; P < .02).Discussion The prevalence of a broad spectrum of symptoms and secondary diagnoses is high in patients with DMD, and some of these symptoms are correlated with social participation. Growing awareness of new symptoms and secondary diagnoses among patients, caregivers, and professionals can enhance their recognition, possibly facilitating prevention and early treatment. Show less
Introduction: Lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems are common in Duchenne muscular dystrophy (DMD), but not systematically assessed in regular care. We aimed to... Show moreIntroduction: Lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems are common in Duchenne muscular dystrophy (DMD), but not systematically assessed in regular care. We aimed to determine the prevalence of bladder and bowel dysfunction (BBD) in DMD patients compared with healthy controls (HC). Methods: The Childhood Bladder and Bowel Dysfunction Questionnaire (CBBDQ) based on the International Rome III criteria and the International Children's Continence Society was filled out by 57 DMD patients and 56 HC. Additionally, possible associations of BBD with, for example, medication use or quality of life were evaluated in an additional questionnaire developed by experts. Results: In 74% of patients versus 56% of HC >= 1 LUTS (n.s.) were reported, 68% of patients versus 39% of HC reported >= 1 bowel symptom (p = 0.002) and 53% of patients versus 30% of HC reported combined LUTS and bowel symptoms (p = 0.019). A negative impact of BBD on daily life functioning was reported by 42% of patients. Conclusions: These data underscore that standard screening for BBD is needed and that the CBBDQ could be of added value to optimize DMD care. Show less
Heutinck, L.; Gameren, M. van; Verschuuren, J.J.G.M.; Geurts, A.C.H.; Jansen, M.; Groot, I.J.M. de 2021
Background: In order to successfully implement the international clinical care guidelines for Duchenne muscular dystrophy (DMD) in the Netherlands, it is essential to know what barriers are... Show moreBackground: In order to successfully implement the international clinical care guidelines for Duchenne muscular dystrophy (DMD) in the Netherlands, it is essential to know what barriers are experienced by healthcare practitioners regarding guideline adherence and organization of care. In the Netherlands, academic medical centers provide follow up visits and work together with peripheral hospitals, rehabilitation centers, centers for home ventilation and primary care centers for treatment.Objective: To investigate perceived barriers to international clinical DMD guideline adherence and identify potential areas of improvement for implementation in the Dutch 'shared care' organization.Methods: Semi-structured in-depth interviews with healthcare practitioners of academic medical hospitals and questionnaires for healthcare practitioners of rehabilitation centers, based on the framework of Cabana.Results: The analyses identified 4 barriers for non-adherence to the DMD guideline: (i) lack of familiarity/awareness, (ii) lack of agreement with specific guideline, (iii) lack of outcome expectancy, (iv) external barriers.Conclusions: A heterogeneous set of barriers is present. Therefore, a multifaceted intervention strategy is proposed to overcome these barriers, including a clear division of roles, allowing for local (Dutch) adaptations per specialism by local consensus groups, and the facilitation of easy communication with experts/opinion leaders as well as between care professionals. Show less
Heutinck, L.; Houwen-van Opstal, S.L.S.; Krom, Y.D.; Niks, E.H.; Verschuuren, J.J.G.M.; Jansen, M.; Groot, I.J.M. de 2021
Background and objective: To optimize care for patients with DMD, it is essential to know to what extent current care complies with the recommended monitoring frequencies suggested by the DMD care... Show moreBackground and objective: To optimize care for patients with DMD, it is essential to know to what extent current care complies with the recommended monitoring frequencies suggested by the DMD care considerations. The objective of this study was to investigate the current care for patients with DMD in the Netherlands and to what extent the care complies with the international care considerations.Methods: A cross-sectional questionnaire was carried out among the Dutch DMD patients and caregivers about the patients' functional and health status, visits to healthcare professionals, clinical tests and assessments, therapy, medication use and access to medical aids and devices. Compliance to guidelines was defined by comparing the frequency of visits to health care providers and clinical tests with the recommended frequencies derived from the care considerations of 2010.Results: Eighty-four participants completed the questionnaire. The majority of participants met the recommended visit frequencies to a neuromuscular specialist and cardiologist. Compliance was suboptimal for respiratory assessments in the non-ambulatory phase, monitoring of side effects of corticosteroid use and neuromuscular assessments. Disease specific information supply was perceived as sufficient and participants were satisfied with the received care.Conclusions: This study identifies areas in which compliance is lacking. Countries, such as the Netherlands, working according to a shared care system require easy and low-threshold communication between health care centers and a clear division of roles and responsibilities to reach optimal compliance. In the Netherlands the Duchenne Center Netherlands has the coordinating role. Show less
Background: Natural history data are essential for trial design in Duchenne (DMD) and Becker muscular dystrophy (BMD), but recruitment for observational studies can be challenging.Objective: We... Show moreBackground: Natural history data are essential for trial design in Duchenne (DMD) and Becker muscular dystrophy (BMD), but recruitment for observational studies can be challenging.Objective: We reviewed reasons why patients or caregivers declined participation, and compared characteristics of participants and non-participants to assess possible selection bias in four observational studies, three on DMD and one on BMD.Methods: Three pediatric DMD studies focused on cross-sectional cognitive function and brain MRI (DMDbrain, n=35 and DMDperfusion, n = 12), and on longitudinal upper extremity function and muscle MRI (DMDarm, n = 22). One adult BMD study assessed longitudinal functioning (n = 36). Considerations for non-participation were retrospectively reviewed from screening logs. Age, travel-time, DMD gene mutations and age at loss of ambulation (DMDarm and BMD study only), of participants and non-participants were derived from the Dutch Dystrophinopathy Database and compared using nonparametric tests (p < 0.05).Results: The perceived burden of the protocol (38.2%), use of MRI (30.4%), and travel-time to the study site (19.1%) were the most frequently reported considerations for non-participation. Only few patients reported lack of personal gain (0.0–5.9%). Overall, participating patients were representative for the studied sub-populations, except for a younger age of DMDarm study participants and a complete lack of participants with a mutation beyond exon 63.Conclusion: Optimizing patient involvement in protocol design, improving MRI experiences, and integrating research into clinics are important factors to decrease burden and facilitate participation. Nationwide registries are essential to compare participants and non-participants and ensure representative observational research. Specific effort is needed to include patients with distal mutations in cognitive studies. Show less
Background: Natural history data are essential for trial design in Duchenne (DMD) and Becker muscular dystrophy (BMD), but recruitment for observational studies can be challenging.Objective: We... Show moreBackground: Natural history data are essential for trial design in Duchenne (DMD) and Becker muscular dystrophy (BMD), but recruitment for observational studies can be challenging.Objective: We reviewed reasons why patients or caregivers declined participation, and compared characteristics of participants and non-participants to assess possible selection bias in four observational studies, three on DMD and one on BMD.Methods: Three pediatric DMD studies focused on cross-sectional cognitive function and brain MRI (DMDbrain, n = 35 and DMDperfusion, n = 12), and on longitudinal upper extremity function and muscle MRI (DMDarm, n= 22). One adult BMD study assessed longitudinal functioning (n = 36). Considerations for non-participation were retrospectively reviewed from screening logs. Age, travel-time, DMD gene mutations and age at loss of ambulation (DMDarm and BMD study only), of participants and non-participants were derived from the Dutch Dystrophinopathy Database and compared using nonparametric tests (p < 0.05).Results: The perceived burden of the protocol (38.2%), use of MRI (30.4%), and travel-time to the study site (19.1%) were the most frequently reported considerations for non-participation. Only few patients reported lack of personal gain (0.0-5.9%). Overall, participating patients were representative for the studied sub-populations, except for a younger age of DMDarm study participants and a complete lack of participants with a mutation beyond exon 63.Conclusion: Optimizing patient involvement in protocol design, improving MRI experiences, and integrating research into clinics are important factors to decrease burden and facilitate participation. Nationwide registries are essential to compare participants and non-participants and ensure representative observational research. Specific effort is needed to include patients with distal mutations in cognitive studies. Show less
