Introduction
The North Star Ambulatory Assessment (NSAA) tool is a key instrument for measuring clinical outcomes in patients with Duchenne muscular dystrophy (DMD). To gain a better understanding of ...the longitudinal utility of the NSAA, we evaluated NSAA data from a phase II trial of 120 patients with DMD treated with domagrozumab or placebo.
Methods
The NSAA exploratory analyses included assessment of individual skills gained/lost, total skills gained/lost, cumulative loss of function, and the impact of transient loss of function due to a temporary disability on NSAA total score (temporary zero score).
Results
There was no significant difference in the total number of NSAA skills gained (mean 1.41 and 1.04, respectively; p = 0.3314) or lost (3.90 vs. 5.0; p = 0.0998) between domagrozumab- vs. placebo-treated patients at week 49. However, domagrozumab-treated patients were less likely to lose the ability to perform a NSAA item (hazard ratio 0.80, 95% confidence interval CI: 0.65–0.98, p = 0.029) over 48-weeks vs. placebo-treated patients. When temporary zero scores were changed to “not obtainable” (8 values from 7 patients), domagrozumab-treated patients scored higher on the NSAA total score versus placebo-treated patients (difference at week 49: 2.0, 95% CI: 0.1–3.9, p = 0.0359).
Conclusions
These exploratory analyses reveal additional approaches to interpreting the NSAA data beyond just change in NSAA total score. These observations also highlight the importance of reporting items as “not obtainable” for a patient with a temporary/transient physical disability that impacts their ability to perform the NSAA test.
ClinicalTrials.gov identifier
NCT02310763
.
Aim
To report the differences between Performance of Upper Limb (PUL) versions 1.2 and 2.0, compare the measurement ability of the two versions, and compare their longitudinal performance in Duchenne ...muscular dystrophy.
Method
Rasch analysis was performed on the dual data from three centres to confirm whether the two scales measure the same construct. Change scores in natural history for the different domains were compared for the two versions.
Results
Rasch analysis demonstrated that both versions measure the same construct and that the PUL 2.0 was a better fit to the construct of motor performance and better able to detect change at 12 months in all levels of ability than the PUL 1.2. This was also true when change scores were reviewed over 2 years.
Interpretation
Our results confirm that the PUL 1.2 and 2.0 versions detect change in all domains over 2 years. They also demonstrate that simplifying the original scoring of the PUL 1.2 for the revised PUL 2.0 maintains the validity of the construct and enhances the scale measurement qualities.
What this paper adds
The original and revised Performance of Upper Limb (PUL) scales measure the same construct.
Both scales detected change in all domains over 2 years.
The PUL 2.0 enhances the measurement qualities of the scale.
What this paper adds
The original and revised Performance of Upper Limb (PUL) scales measure the same construct.
Both scales detected change in all domains over 2 years.
The PUL 2.0 enhances the measurement qualities of the scale.
Video Podcast: https://youtu.be/AhSjB9aEQuo
ABSTRACT
Introduction
There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the ...extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients.
Methods
An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale.
Results
Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups.
Conclusions
The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi‐center clinical research. Muscle Nerve 55: 869–874, 2017
Aim
An international Clinical Outcomes Group consisting of clinicians, scientists, patient advocacy groups, and industries identified a need for a scale to measure motor performance of the upper ...limb. We report the steps leading to the development of the Performance of the Upper Limb (PUL), a tool specifically designed for assessing upper limb function in ambulant and non‐ambulant patients with Duchenne muscular dystrophy (DMD).
Method
The development of the PUL followed a number of steps, from the systematic review and a preliminary study exploring the suitability of the existing measures, to the application of a pilot version in a multicentric setting, with Rasch analysis of the preliminary results, leading to a revised pro forma.
Results
The PUL was specifically designed for DMD, with a conceptual framework reflecting the progression of weakness and natural history of functional decline in DMD. Modern psychometric methods were used to create a scale with robust internal reliability, validity, and hierarchical scalability; males with DMD and their families were involved iteratively throughout the process of the clinician‐reported outcome assessment tool development to establish clinical meaningfulness and relevance of individual PUL items to activities of daily living.
Interpretation
The module was developed using innovative approaches and will be useful for designing clinical trials.
Clinical trials in Duchenne muscular dystrophy (DMD) require 3-6 months of stable glucocorticoids, and the primary outcome is explored at 48-52 weeks. The factors that influence the clinical outcome ...assessment (COA) trajectories soon after glucocorticoid initiation are relevant for the design and analysis of clinical trials of novel drugs. We describe early COA trajectories, associated factors, and the time from glucocorticoid initiation to COA peak.
This was a prospective 18-month analysis of the Finding the Optimum Corticosteroid Regimen for Duchenne Muscular Dystrophy study. Four COAs were investigated: rise from supine velocity (RFV), 10-meter walk/run velocity (10MWRV), North Star Ambulatory Assessment (NSAA) total score, and 6-minute walk test distance (6MWT). The relationships of baseline age (4-5 vs 6-7 years), COA baseline performance, genotype, and glucocorticoid regimen (daily vs intermittent) with the COA trajectories were evaluated using linear mixed-effects models.
One hundred ninety-six glucocorticoid-naïve boys with DMD aged 4-7 years were enrolled. The mean age at baseline was 5.9 ± 1.0 years, 66% (n = 130) were on daily regimens, 55% (n = 107) showed a 6MWT distance >330 metres; 41% (n = 78) showed RFV >0.2 rise/s; 76% (n = 149) showed 10MWRV >0.142 10m/s, and 41.0% (n = 79) showed NSAA total score >22 points. Mean COA trajectories differed by age at glucocorticoid initiation (
< 0.01 for RFV, 10MWRV, and NSAA;
< 0.05 for 6MWT) and regimen (
< 0.01 for RFV, 10MWRV, and NSAA). Boys younger than 6 years reached their peak performance 12-18 months after glucocorticoid initiation. Boys aged 6 years or older on a daily regimen peaked between months 9 and 12 and those on an intermittent regimen by 9 months. The baseline COA performance was associated with the NSAA (
< 0.01) and the 6MWT trajectory in boys younger than 6 years on a daily regimen (
< 0.01). Differences in the mean trajectories by genotype were not significant.
Glucocorticoid regimen, age, duration of glucocorticoid exposure, and baseline COA performance need to be considered in the design and analysis of clinical trials in young boys with DMD.
Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that boys with DMD could be clustered ...into groups sharing similar trajectories of ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. We also explored associations with other variables such as age, functional abilities, and genotype. Using the NorthStar Clinical Network database, 395 patients with >1 NSAA assessment were identified. We utilised latent class trajectory analysis of longitudinal NSAA scores, which produced evidence for at least four clusters of boys sharing similar trajectories versus age in decreasing order of clinical severity: 25% of the boys were in cluster 1 (NSAA falling to ≤ 5 at age ~10y), 35% were in cluster 2 (NSAA ≤ 5 ~12y), 21% in were cluster 3 (NSAA≤ 5 ~14y), and 19% in cluster 4 (NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters (4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment, a significant (p<0.05) association was observed between earlier declining clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre walk/run times, and younger age of steroid initiation. In order to assess the probability of observing complete loss of function for individual NSAA items, we examined the proportion of patients who shifted from a score of 1 or 2 at baseline to a score of 0. We also assessed the probability of gain of function using the inverse assessment and stratified the probability of deterioration, improvement-or static behavior-by age ranges and using baseline functional status. Using this tool, our study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and, for the first time, describes discrete clusters of disease progression; this will be invaluable for future DMD clinical trial design and interpretation of findings.
Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and ...may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups.
To determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period.
32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C>A mutation in the fukutin-related protein gene (FKRP) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale.
There was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T₁w images.
Quantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.
To describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA).
...This was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy.
There were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8-16.6) and 15.1 (13.8-16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes.
In SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.
Aim
Clinician‐reported outcome instruments such as the North Star Ambulatory Assessment (NSAA) need to be able to detect clinically important change to be suitable for clinical trials. However, in ...Duchenne muscular dystrophy (DMD), identifying changes in function is not straightforward. In this study, we use Rasch‐transformed data to examine the responsiveness and minimal important difference (MID) of the NSAA in males with DMD receiving different corticosteroid regimes.
Method
NSAA data were examined from 198 males (mean age at assessment was 8y 6mo SD 2y 6mo range 4y–18y; 805 assessments). Responsiveness was assessed using mean score changes (using Rasch‐transformed data) between adjacent pairs of age groups, pairwise squared t‐values from paired samples t‐tests, and an effect size calculation. The MID was assessed using the effect size calculation and 0.5 standard deviation (SD) of mean score differences.
Results
Our findings revealed a difference in change scores over time between the two corticosteroid regimes. Mean NSAA person estimates were higher in the daily prednisolone group. The mean MID (0.5 SD) was 8.8 and 6.9 for the daily group and intermittent group respectively.
Interpretation
This study, based on Rasch‐transformed NSAA data, provides an initial basis for the interpretation of clinical change in DMD over time and between corticosteroid regimes. Our proposed MIDs can be mapped back to differences in specific item content across the range of the NSAA.
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