Millions of people worldwide currently suffer from serious neurological diseases and injuries for which there are few, and often no, effective treatments. The paucity of effective interventions is, ...no doubt, due in large part to the complexity of the disorders, as well as our currently limited understanding of their pathophysiology. The bleak picture for patients, however, is also attributable to avoidable impediments stemming from quality concerns in preclinical research that often escape detection by research regulation efforts. In our essay, we connect the dots between these concerns about the quality of preclinical research and their potential ethical impact on the patients who volunteer for early trials of interventions informed by it. We do so in hopes that a greater appreciation among preclinical researchers of these serious ethical consequences can lead to a greater commitment within the research community to adopt widely available tools and measures that can help to improve the quality of research.
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Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term ...effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy.
For this prospective cohort study, we enrolled male patients aged 2–28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832.
440 patients were enrolled during two recruitment periods (2006–09 and 2012–16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1–4·4 years and upper limb milestones by 2·8–8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1–2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22–1·00; p=0·0501).
In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death.
US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.
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ABSTRACT
Introduction: More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence‐based treatments have not been available. Methods: A multicenter, double‐blind, ...placebo‐controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps. Results: Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P < 0.05). The average reduction, based on t tests, was 1.8 cramps per day (a reduction from 5.3 with placebo to 3.5 with mexiletine). The estimated reduction of cramp severity was 15 units on a 100‐unit scale (P = 0.01) from a baseline average of 46. No effect on fasciculations was noted. One patient discontinued the study because of dizziness, and another patient discontinued the study to start open‐label mexiletine therapy. No serious adverse event occurred. Discussion: Mexiletine is a well tolerated and effective medication for controlling the symptom of muscle cramps in ALS. Muscle Nerve 58: 42–48, 2018
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction/Aims
Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE‐083 could ...safely increase muscle volume and improve functional outcomes in adults with FSHD.
Methods
Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double‐blind for 6 months, evaluating ACE‐083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6‐minute walk test, 10‐meter walk/run, and 4‐stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient‐reported outcomes (PROs), and safety were also evaluated.
Results
Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least‐squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%‐23.0%) in the BB group (P < .0001) and 9.5% (3.2%‐15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection‐site reactions.
Discussion
Significant increases in TMV with ACE‐083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.
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Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess ...the safety, efficacy, and tolerability of bimagrumab—a fully human monoclonal antibody—in individuals with inclusion body myositis.
We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36–85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis.
Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI –19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, –18·2 to 55·4; p=0·19; and for 1 mg/kg group, –1·3 m, 14·1, –38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 76% in the bimagrumab 10 mg/kg group, 55 87% in the 3 mg/kg group, 54 86% in the 1 mg/kg group, and 52 84% in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 51% in the bimagrumab 10 mg/kg group, 43 68% in the 3 mg/kg group, 25 40% in the 1 mg/kg group, and 13 21% in the placebo group) and diarrhoea (33 52%, 28 44%, 20 32%, and 11 18%, respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab.
Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months.
Novartis Pharma.
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Muscle biopsy evaluation in neuromuscular disorders Joyce, Nanette C; Oskarsson, Björn; Jin, Lee-Way
Physical medicine and rehabilitation clinics of North America,
08/2012, Volume:
23, Issue:
3
Journal Article
Peer reviewed
Open access
This article reviews the indications for a muscle biopsy, and then gives a step-by-step description of the processes of muscle selection through to interpreting the biopsy report. The article aims to ...aid the clinician in preparing for a muscle biopsy procedure to avoid common pitfalls and obtain optimal results from this minimally invasive procedure. The basic anatomic structure of normal muscle is reviewed to provide a foundation for understanding common patterns of pathologic change observed in muscle disease and common and disease-specific histopathologic findings are presented, focusing on a select group of neuromuscular diseases.
ABSTRACT
Introduction: Reachable workspace is a measure that provides clinically meaningful information regarding arm function. In this study, a Kinect sensor was used to determine the spectrum of ...3‐dimensional reachable workspace encountered in a cross‐sectional cohort of individuals with amyotrophic lateral sclerosis (ALS). Methods: Bilateral 3D reachable workspace was recorded from 10 subjects with ALS and 17 healthy controls. The data were normalized by each individual's arm length to obtain a reachable workspace relative surface area (RSA). Concurrent validity was assessed by correlation with scoring on the ALS Functional Rating Score—revised (ALSFRSr). Results: The Kinect‐measured reachable workspace RSA differed significantly between the ALS and control subjects (0.579 ± 0.226 vs. 0.786 ± 0.069; P < 0.001). The RSA demonstrated correlation with ALSFRSr upper extremity items (Spearman correlation ρ = 0.569; P = 0.009). With worsening upper extremity function, as categorized by the ALSFRSr, the reachable workspace also decreased progressively. Conclusions: This study demonstrates the feasibility and potential of using a novel Kinect‐based reachable workspace outcome measure in ALS. Muscle Nerve 53: 234–241, 2016
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Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of ...sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy.
In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA. Patients were randomly assigned (1:1) using stratified permuted blocks to receive CAP-1002 (1·5 × 108 CDCs) or placebo intravenously every 3 months for a total of four infusions. Clinicians, caregivers, patients, and clinical operations personnel were fully masked to treatment groups. The primary outcome was the change in mid-level elbow Performance of Upper Limb version 1.2 (PUL 1.2) score at 12 months, assessed in the intention-to-treat population. Safety was assessed in all individuals who received an investigational product. This trial is registered with ClinicalTrials.gov, NCT03406780.
Between March 1, 2018, and March 31, 2020, 26 male patients with Duchenne muscular dystrophy were enrolled, of whom eight were randomly assigned to the CAP-1002 group and 12 to the placebo group (six were not randomised due to screening failure). In patients who had a post-treatment PUL 1.2 assessment (eight in the CAP-1002 group and 11 in the placebo group), the mean 12-month change from baseline in mid-level elbow PUL1.2 favoured CAP-1002 over placebo (percentile difference 36·2, 95% CI 12·7–59·7; difference of 2·6 points; p=0·014). Infusion-related hypersensitivity reactions without long-term sequelae were observed in three patients, with one patient discontinuing therapy due to a severe allergic reaction. No other major adverse reactions were noted, and no deaths occurred.
CAP-1002 cell therapy appears to be safe and effective in reducing deterioration of upper limb function in patients with late-stage Duchenne muscular dystrophy. Various measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. Longer-term extension studies are needed to confirm the therapeutic durability and safety of CAP-1002 beyond 12 months for the treatment of skeletal myopathy and cardiomyopathy in Duchenne muscular dystrophy.
Capricor Therapeutics.
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•Natural history changes in pulmonary function tests across time in Duchenne muscular dystrophy.•Treatment with glucocorticoids (steroids) > 1 year was compared to steroid naïve treatment.•Steroid ...treatment slowed the rate of pulmonary decline as measured by FVC%p in 7–9.9 year olds;•Steroid treatment resulted in higher peak absolute FVC and PEFr values with later onset of decline.•Time to FVC < 1 liter was delayed by steroid treatment; FVC < 1 liter increased risk of death 4-fold.
We describe changes in pulmonary function measures across time in Duchenne muscular dystrophy patients treated with glucocorticoids (GCs) > 1 year compared to GC naïve patients in the Cooperative International Research Group Duchenne Natural History Study, a multicenter prospective cohort study. 397 participants underwent 2799 pulmonary function assessments over a period up to 10 years. Fifty-three GC naïve participants (< 1 month exposure) were compared to 322 subjects with > 1 year cumulative GC treatment. Forced vital capacity (FVC), peak expiratory flow rate (PEFr), maximal inspiratory and expiratory pressures were performed and calculated as a percent predicted (%p). GC treatment slowed the rate of pulmonary decline as measured by FVC%p, in patients aged 7–9.9 years. GC treatment slowed 12 and 24-month progression of percent predicted spirometry to a greater degree in those with baseline FVC%p from < 80–34%. GC treatment resulted in higher peak absolute FVC and PEFr values with later onset of decline. Progression to an absolute FVC < 1 liter was delayed by GC treatment. Patients who reached a FVC below 1 L were 4.1 times more likely to die (p = 0.017). Long-term glucocorticoid treatment slows pulmonary disease progression in Duchenne dystrophy throughout the lifespan.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
National Study of Muscle Cramps in ALS in the USA Stephens, Helen E.; Joyce, Nanette C.; Oskarsson, Björn
Amyotrophic lateral sclerosis and frontotemporal degeneration,
02/2017, Volume:
18, Issue:
1-2
Journal Article
Peer reviewed
Open access
The objective of this study was to describe muscle cramps in an US sample of amyotrophic lateral sclerosis (ALS) patients. Utilizing an anonymous web based questionnaire we queried ALS patients ...regarding the severity, frequency, time-course, treatment of muscle cramps and their relationship to pain. The survey had 282 respondents with 92% reporting that they had cramps. For 20% of the sample, cramps were stated to be the presenting ALS symptom. Cramp severity was rated at a mean of 5.2/10 and the mean cramp frequency was 5.3 cramps per day. Cramp intensity and frequency did not correlate with duration or severity of ALS. Pain as measured with the Patient Reported Outcome Measurement Information System (PROMIS) pain scales was not statistically different from the US general population. Cramp severity and frequency significantly and positively correlated with the PROMIS pain scales. Patients with more severe cramps were more likely to use prescription medications for their cramps compared to patients with milder symptoms. Treatments directed at cramps were tried by 57%. In conclusion, cramps are a common symptom in ALS and it does not correlate with disease duration or severity. The severity of cramps is on average moderate and many patients try treatments.
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