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- Dijkstra, Jildou N., et al.
(författare)
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Natural History of Facioscapulohumeral Dystrophy in Children A 2-Year Follow-up
- 2021
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Ingår i: Neurology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0028-3878 .- 1526-632X. ; 97:21, s. E2103-E2113
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Tawil, Rabi, et al.
(författare)
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Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial
- 2024
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Ingår i: Lancet Neurology. - : ELSEVIER SCIENCE INC. - 1474-4422 .- 1474-4465. ; 23:5, s. 477-486
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Tidskriftsartikel (refereegranskat)abstract
- Background Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38 alpha MAPK, a regulator of DUX4 expression, and p38 beta MAPK) for the treatment of facioscapulohumeral muscular dystrophy. Methods We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. Findings Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45<middle dot>7 (SD 12<middle dot>5) years. Least squares mean changes from baseline in DUX4driven gene expression did not differ significantly between the losmapimod (0<middle dot>83 [SE 0<middle dot>61]) and placebo (0<middle dot>40 [0<middle dot>65]) groups (difference 0<middle dot>43 [SE 0<middle dot>56; 95% CI -1<middle dot>04 to 1<middle dot>89]; p=0<middle dot>56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drugrelated) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. Interpretation Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy.
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- Widholm, Per, et al.
(författare)
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Quantitative muscle analysis in facioscapulohumeral muscular dystrophy using whole-body fat-referenced MRI: Protocol development, multicenter feasibility, and repeatability
- 2022
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Ingår i: Muscle and Nerve. - : WILEY. - 0148-639X .- 1097-4598. ; 66:2, s. 183-192
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Tidskriftsartikel (refereegranskat)abstract
- Introduction/Aims Functional performance tests are the gold standard to assess disease progression and treatment effects in neuromuscular disorders. These tests can be confounded by motivation, pain, fatigue, and learning effects, increasing variability and decreasing sensitivity to disease progression, limiting efficacy assessment in clinical trials with small sample sizes. We aimed to develop and validate a quantitative and objective method to measure skeletal muscle volume and fat content based on whole-body fat-referenced magnetic resonance imaging (MRI) for use in multisite clinical trials. Methods Subjects aged 18 to 65 years, genetically confirmed facioscapulohumeral muscular dystrophy 1 (FSHD1), clinical severity 2 to 4 (Riccis scale, range 0-5), were enrolled at six sites and imaged twice 4-12 weeks apart with T1-weighted two-point Dixon MRI covering the torso and upper and lower extremities. Thirty-six muscles were volumetrically segmented using semi-automatic multi-atlas-based segmentation. Muscle fat fraction (MFF), muscle fat infiltration (MFI), and lean muscle volume (LMV) were quantified for each muscle using fat-referenced quantification. Results Seventeen patients (mean age +/- SD, 49.4 years +/- 13.02; 12 men) were enrolled. Within-patient SD ranged from 1.00% to 3.51% for MFF and 0.40% to 1.48% for MFI in individual muscles. For LMV, coefficients of variation ranged from 2.7% to 11.7%. For the composite score average of all muscles, observed SDs were 0.70% and 0.32% for MFF and MFI, respectively; composite LMV coefficient of variation was 2.0%. Discussion We developed and validated a method for measuring skeletal muscle volume and fat content for use in multisite clinical trials of neuromuscular disorders.
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- Mellion, Michelle L., et al.
(författare)
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Quantitative Muscle Analysis in FSHD Using Whole-Body Fat-Referenced MRI Composite Scores for Longitudinal and Cross-sectional Analysis
- 2022
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Ingår i: Neurology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0028-3878 .- 1526-632X. ; 99:9, s. E877-E889
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Facioscapulohumeral muscular dystrophy (FSHD) is a rare, debilitating disease characterized by progressive muscle weakness. MRI is a sensitive assessment of disease severity and progression. We developed a quantitative whole-body (WB) musculoskeletal MRI (WB-MSK-MRI) protocol analyzing muscles in their entirety. This study aimed to assess WB-MSK-MRI as a potential imaging biomarker providing reliable measurements of muscle health that capture disease heterogeneity and clinically meaningful composite assessments correlating with severity and more responsive to change in clinical trials. Methods Participants aged 18-65 years, with genetically confirmed FSHD1, clinical severity 2 to 4 (Ricci scale, range 0-5), and >= 1 short tau inversion recovery-positive lower extremity muscle eligible for needle biopsy, enrolled at 6 sites and were imaged twice 4-12 weeks apart. Volumetric analysis of muscle fat infiltration (MFI), muscle fat fraction (MFF), and lean muscle volume (LMV) in 18 (36 total) muscles from bilateral shoulder, proximal arm, trunk, and legs was performed after automated atlas-based segmentation, followed by manual verification. A WB composite score, including muscles at highest risk for progression, and functional cross-sectional composites for correlation with relevant functional outcomes including timed up and go (TUG), FSHD-TUG, and reachable workspace (RWS), were developed. Results Seventeen participants enrolled in this study; 16 follow-up MRIs were performed at 52 days (range 36-85 days). Functional cross-sectional composites (MFF and MFI) showed moderate to strong correlations: TUG (rho = 0.71, rho = 0.83), FSHD-TUG (rho = 0.73, rho = 0.73), and RWS (left arm: rho = -0.71, rho = -0.53; right arm: rho = -0.61, rho = -0.65). WB composite variability: LMVtot, coefficient of variation (CV) 1.9% and 3.4%; MFFtot, within-subject SD (S-w) 0.5% and 1.5%; and MFItot (S-w), 0.3% and 0.4% for normal and intermediate muscles, respectively. CV and S-w were higher in intermediate (MFI >= 0.10; MFF <0.50) than in normal (MFI <0.10, MFF <0.50) muscles. Discussion We developed a WB-MSK-MRI protocol and composite measures that capture disease heterogeneity and assess muscle involvement as it correlates with FSHD-relevant clinical endpoints. Functional composites robustly correlate with functional assessments. Stability of the WB composite shows that it could be an assessment of change in therapeutic clinical trials. Classification of Evidence This study provides Class II evidence that quantitative WB-MSK-MRI findings associate with FSHD1 severity measured using established functional assessments.
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