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Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool.

ABSTRACT: Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.

SUBMITTER: Ramsey D

PROVIDER: S-EPMC5319655 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool.

Ramsey Danielle D Scoto Mariacristina M Mayhew Anna A Main Marion M Mazzone Elena S ES Montes Jacqueline J de Sanctis Roberto R Dunaway Young Sally S Salazar Rachel R Glanzman Allan M AM Pasternak Amy A Quigley Janet J Mirek Elizabeth E Duong Tina T Gee Richard R Civitello Matthew M Tennekoon Gihan G Pane Marika M Pera Maria Carmela MC Bushby Kate K Day John J Darras Basil T BT De Vivo Darryl D Finkel Richard R Mercuri Eugenio E Muntoni Francesco F

PloS one 20170221 2

Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psyc ...[more]

PMID: 28222119

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Project description:ObjectivesSpinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS).MethodsBforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores.Results12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13(th) analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures.ConclusionsDiscovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

Project description:BackgroundSpinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease that affects individuals with a broad age range. SMA is typically characterised by symmetrical muscle weakness but is also associated with cardiac defects, life-limiting impairments in respiratory function and bulbar function defects that affect swallowing and speech. Despite the advent of three innovative disease-modifying therapies (DMTs) for SMA, the cost of DMTs in addition to the costs of standard of care can be a barrier to treatment access for patients. Health Technology Assessment (HTA) decision makers evaluate the cost effectiveness of a new treatment before making a reimbursement decision.ObjectiveThe primary objective was to conduct a systematic literature review (SLR) to identify the modelling approaches used in economic evaluations that assess current approved treatments in SMA, with a secondary objective to widen the scope and identify economic evaluations assessing other (non-SMA) neuromuscular disorders.MethodsAn SLR was performed to identify available economic evaluations associated with any type of SMA (Type 1, 2, 3 and/or 4). Economic evaluations associated with other (non-SMA) neuromuscular disorders were identified but not further analysed. Electronic searches were conducted in Embase, MEDLINE, Evidence-Based Medicine Reviews and EconLit via the Ovid platform in August 2019, and were supplemented by searches of the grey literature (reference lists, conference proceedings, global HTA body websites and other relevant sources). Eligibility criteria were based on the population, interventions, comparators and outcomes (PICO) framework. Quality assessment of full publications was conducted with reference to a published checklist.ResultsNine publications covering eight unique studies met all eligibility criteria for inclusion in the SLR, including four conference abstracts, two peer-reviewed original research articles and three HTA submissions (conducted in Canada, the US and the UK). Evaluations considered patients with early infantile-onset (most likely to develop Type 1 or Type 2 SMA), later-onset SMA and both infantile- and later-onset SMA. Data for the identified economic models were collected from literature reviews and relatively short-term clinical trials. Several intent-to-treat clinical trial populations were used in the studies, which resulted in variation in cycle length and different outcome measures to determine clinical efficacy. The results of the quality assessment on the five full-text, peer-reviewed publications found that they generally provided clear descriptions of objectives, modelling methods and results. However, key decisions, such as choice of economic evaluation, model type and choice of variables for sensitivity analysis, were often not adequately justified.ConclusionsThis SLR highlights the need for economic evaluations in SMA to better align in modelling approaches with respect to (i) consistency in model structure and use of motor function milestones as health states; (ii) consensus on measuring quality of life to estimate utilities; (iii) consistency in data collection by registries; and (iv) consensus on SMA-type classification and endpoints that determine intervention efficacy. Future economic evaluations should also incorporate the review group critiques of previous HTA submissions relating to data inputs and approaches to modelling and should include patient data reflective of the SMA population being modelled. Economic evaluations would also be improved with inclusion of long-term efficacy and safety data from clinical trials and valid patient and caregiver utility data.

Dataset Information

Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool.

Publications

Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool.

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