A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer's disease and Parkinson's disease.

BACKGROUND: Disease-modification clinical trials in neurodegenerative disorders have struggled to separate symptomatic effects of putative agents from disease-modification. In response, a variety of clinical trial designs have been developed. A systematic review was undertaken to examine which trial designs have been used in Alzheimer's disease (AD) and Parkinson's disease (PD) to detect disease-modifying, as opposed to symptomatic, drug effects. In addition we aimed to identify novel clinical trial designs used in the past or planned for use in the future. We aimed to critique whether the methods used would have identified true disease-modification. METHODS: MEDLINE, Embase and CENTRAL (1980-2015) were searched to identify papers meriting review in full. ClinicalTrials.gov was searched to identify unpublished or planned randomised controlled trials (RCTs). We included RCTs in PD or AD which aimed to demonstrate the disease-modifying properties of drug therapy and differentiate that benefit from any symptomatic effect. RESULTS: 128 RCTs were finally included: 84 in AD (59 published, 25 unpublished); 44 in PD (36 published, 8 unpublished). A variety of clinical trial designs were applied including long-term follow-up, wash-in and wash-out analyses, randomised delayed-start, the use of time-to-event outcome measures and surrogate disease progression biomarkers. Deficiencies in each of these design strategies, the quantity of missing data in included RCTs and the methods used to deal with missing data, meant that none of the included studies convincingly demonstrated disease-modification. No truly novel clinical trial designs were identified. CONCLUSION: We currently believe that the best clinical trial design available to demonstrate disease-modification is a long-term follow-up study, in which an examination is made for sustained divergence in outcome measures between treatment arms over the study period.

Using 'dead or dependent' as an outcome measure in clinical trials in Parkinson's disease.

BACKGROUND: Simple, robust, sensitive and clinically meaningful outcome measures are required for neuroprotective trials in Parkinson's disease (PD). We explored the feasibility of a composite binary outcome measure, 'dead or dependent', in such trials using data from a prospective follow-up study of an incident cohort of PD patients. METHODS: Two hundred incident patients had an annual follow-up, including assessment of the Hoehn-Yahr stage (H-Y) and Schwab and England Activities of Daily Living Scale (S&E). Annual scores were converted into binary variables (H-Y <3 vs H-Y ≥3, and S&E ≥80% vs S&E <80%). A new outcome of 'dead or dependent' was also created, with dependence in activities of daily living defined as S&E <80%. Using these data, sample sizes were calculated for a hypothetical three-year randomised trial in which the trial outcome was defined by a binary clinical variable, all-cause mortality, or PD-related mortality. RESULTS: At 3 years, 18.0% of patients were dead and 38.4% were dead or dependent. At 80% power, large sample sizes were required if PD-related mortality (n=1938 per study arm) or all-cause mortality (n=734) were used as the outcome, even for large treatment effects (30% reduction in relative risk). The new outcome of 'death or dependency' required the smallest sample sizes of all the outcome measures (n=277 for 30% reduction in relative risk, 627 for a 20% reduction). CONCLUSIONS: 'Death or dependency' is a feasible and potentially useful outcome measure in PD trials of neuroprotective agents, but further work is required to validate its use and define dependency.

Lending a hand: can DASH items help ABILHAND improve manual ability measurement in multiple sclerosis?

BACKGROUND: Our examination in multiple sclerosis (MS) of the ABILHAND, a patient-reported outcome (PRO) instrument measuring manual ability, identified limited measurement range and precision. These deficiencies could lead to type II errors in clinical trials. OBJECTIVES: This paper aims to determine if ABILHAND's measurement performance in MS can be improved by adding relevant items from the Disabilities of the Arm, Shoulder and Hand scale (DASH). METHODS: The 23-item ABILHAND and 30-item DASH were administered to 461 people with MS. Data from the ABILHAND were combined with 16 DASH items to create a 39-item scale (AD-39). Using Rasch Measurement Theory methods, we compared the psychometric properties of AD-39 with ABILHAND. RESULTS: Data were analysed from 300 people. AD-39 performed robustly as a measure and had greater measurement range, lower floor and ceiling effects, and higher reliability (person separation index 0.97) than ABILHAND. Surprisingly, AD-39 appeared no better than ABILHAND at detecting group differences in self-reported hand function. CONCLUSION: Despite improving some psychometric properties, adding 16 DASH items to the ABILHAND did not improve its measurement performance to the degree expected. Our explanations for this anomaly emphasise the importance of evidence-based, conceptually driven scale modifications guided by hypothesis testing psychometric methods.

Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of Parkinson's disease.

Parkinson's disease primarily affects the central nervous system, but autopsy and small patient studies have revealed autonomic nervous system pathology in most cases. We looked for α-synuclein pathology in routinely acquired biopsies from patients and matched controls. Immunocytochemistry was performed and assessed blind to the clinical diagnoses. One hundred and seventeen gastrointestinal tissue samples from 62 patients, and 161 samples from 161 controls, were examined. Twelve biopsies from seven patients showed accumulation of α-synuclein within mucosal and submucosal nerve fibres, and ganglia, which was more extensive with an antibody to phosphorylated, than with an antibody to non-phosphorylated, α-synuclein. These included gastric, duodenal and colonic biopsies, and were taken up to 8 years prior to the onset of motor symptoms. All patients with positive biopsies had early autonomic symptoms and all controls were negative. This large scale study demonstrates that accumulation of α-synuclein in the gastrointestinal tract is a highly specific finding that could be used to confirm a clinical diagnosis of Parkinson's disease. We have shown that α-synuclein accumulation occurs prior to the onset of motor symptoms in the upper, as well as the lower gastrointestinal tract, remains present in serial biopsies until the onset of motor symptoms and is predominantly composed of phosphorylated α-synuclein. Accumulation of α-synuclein in the bowel therefore offers an accessible biomarker which allows further study of the early stages of the disease and could be of value in the assessment of disease modifying treatments.

Evaluating change in mobility in people with multiple sclerosis: relative responsiveness of four clinical measures.

BACKGROUND AND OBJECTIVES: Determining responsiveness of measures across different samples and settings is important for selecting measures of mobility and understanding multiple sclerosis (MS) study results. Currently such information is limited. METHODS: This exploratory study examined the relative responsiveness of four mobility measures (walking velocity, 6-minute walk distance, Rivermead Mobility Index and MS Walking Scale) in a community sample (n = 70), after three annual assessments. Distribution based estimates and anchor-based methods (comparison against transition questions) determined responsiveness. A head-to-head comparison was made. RESULTS: While variations in individuals occurred, the group mean change scores for all measures was small, suggesting that there was minimal deterioration in the total sample. Consistent with this, total sample Effect Size (ES) was negligible to small (ES -0.32 to +0.03) for all measures. Differentiation between sub-groups, defined by the participants' perception of change in mobility over the past year (transition questions), showed that some instruments could detect clinically significant changes (small sample sizes limited this interpretation). Correlation analyses between change scores demonstrated that these measures captured related, but different information (r < 0.364). CONCLUSIONS: The measures were broadly comparable in detecting mobility changes in this community sample. These correlations highlight that in selection of measures, one should also consider the discrete mobility dimension that the intervention intends to impact.

Achieving valid patient-reported outcomes measurement: a lesson from fatigue in multiple sclerosis.

BACKGROUND: The increasing influence of patient-reported outcome (PRO) measurement instruments indicates their scrutiny has never been more crucial. Above all, PRO instruments should be valid: shown to assess what they purport to assess. OBJECTIVES: To evaluate a widely used fatigue PRO instrument, highlight key issues in understanding PRO instrument validity, demonstrate limitations of those approaches and justify notable changes in the validation process. METHODS: A two-phase evaluation of the 40-item Fatigue Impact scale (FIS): a qualitative evaluation of content and face validity using expert opinion (n=30) and a modified Delphi technique; a quantitative psychometric evaluation of internal and external construct validity of data from 333 people with multiple sclerosis using traditional and modern methods. RESULTS: Qualitative evaluation did not support content or face validity of the FIS. Expert opinion agreed with the subscale placement of 23 items (58%), and classified all 40 items as being non-specific to fatigue impact. Nevertheless, standard quantitative psychometric evaluations implied, largely, FIS subscales were reliable and valid. CONCLUSIONS: Standard quantitative 'psychometric' evaluations of PRO instrument validity can be misleading. Evaluation of existing PRO instruments requires both qualitative and statistical methods. Development of new PRO instruments requires stronger conceptual underpinning, clearer definitions of the substantive variables for measurement and hypothesis-testing experimental designs.

A systematic review of biomarkers for disease progression in Parkinson's disease.

BACKGROUND: Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true disease-modifying effects. A systematic review was undertaken to determine what biomarkers for disease progression in Parkinson's disease (PD) exist. METHODS: MEDLINE and EMBASE (1950-2010) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with idiopathic PD diagnosed by formal criteria or clearly described clinical means were included. We made no restriction on age, disease duration, drug treatment, or study design. We included studies which attempted to draw associations between any tests used to investigate disease progression and any clinical measures of disease progression. The electronic search was validated by hand-searching the two journals from which most included articles came. RESULTS: 183 studies were included: 163 (89%) cross-sectional, 20 (11%) longitudinal. The electronic search strategy had a sensitivity of 71.4% (95% CI 51.1-86.0) and a specificity of 97.1% (95% CI 96.5-97.7). In longitudinal studies median follow-up was 2.0 years (IQR 1.1-3.5). Included studies were generally poor quality--cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and simplistic statistical analyses. CONCLUSION: We found insufficient evidence to recommend the use of any biomarker for disease progression in PD clinical trials, which may simply reflect the poor quality of research in this area. We therefore present a provisional 'roadmap' for conducting future disease progression biomarker studies, and recommend new quality criteria by which future studies may be judged.

Putting the Alzheimer's cognitive test to the test I: traditional psychometric methods.

BACKGROUND: The Alzheimer's Disease Assessment Scale-Cognitive Behavior section (ADAS-Cog) is the most commonly used cognitive test in AD clinical trials. However, there are concerns about its use in early-stage disease. Herein we examine those concerns using traditional psychometric methods. METHODS: We analyzed ADAS-Cog data (n = 675) based on six psychometric properties: data completeness; scaling assumptions; targeting; reliability; validity; and responsiveness. RESULTS: At the scale-level, criteria tested for data completeness, scaling assumptions (item total correlations 0.33-0.59), targeting (no floor/ceiling effects), reliability (Cronbach's α = 0.74), and validity (correlation with MMSE = -0.70) were satisfied. Responsiveness (baseline to 12 months; n = 145) was moderate to high (effect size = -0.73). However, 8 of 11 ADAS-Cog components had substantial ceiling effects (range 32%-83%), and decreased responsiveness associated with low to moderate effect sizes (0.14-0.65). CONCLUSION: In our study, many patients with AD found large portions of the ADAS-Cog too easy. Future research should consider modifying the ADAS-Cog or developing a new test.

Putting the Alzheimer's cognitive test to the test II: Rasch Measurement Theory.

BACKGROUND: The Alzheimer's Disease Assessment Scale-Cognitive Behavior section (ADAS-Cog) is the most widely used measure of cognitive performance in AD clinical trials. This key role has rightly brought its performance under increased scrutiny with recent research using traditional psychometric methods, questioning the ADAS-Cog's ability to adequately measure early-stage disease. However, given the limitations of traditional psychometric approaches, herein we use the more sophisticated Rasch Measurement Theory (RMT) methods to fully examine the strengths and weaknesses of the ADAS-Cog, and identify potential paths toward its improvement. METHODS: We analyzed AD Neuroimaging Initiative (ADNI) ADAS-Cog data (675 measurements across four time-points over 2 years) from the AD participants. RMT analysis was undertaken to examine three broad areas: adequacy of scale-to-sample targeting; degree to which, taken together, the ADAS-Cog items adequately perform as a measuring instrument; and how well the scale measured the subjects in the current sample. RESULTS: The 11 ADAS-Cog components mapped-out a measurement continuum, worked together adequately, and were stable across different time-points and samples. However, the scale did not prove to be a good match to the patient sample supporting previous research. RMT analysis also identified problematic "gaps" and "bunching" of the components across the continuum. CONCLUSION: Although the ADAS-Cog has the building blocks of a good measurement instrument, this sophisticated analysis confirms limitations with potentially serious implications for clinical trials. Importantly, and unlike traditional psychometric methods, our RMT analysis has provided important clues aimed at solving the measurement problems of the ADAS-Cog.

Establishing the psychometric underpinning of cognition measures for clinical trials of Alzheimer's disease and its precursors: a new approach.

The Alzheimer's disease (AD) Cognitive Behavior Section (ADAS-Cog) is the most commonly used cognitive test in clinical trials of AD. Recent trials have focused on people earlier in the course of disease; however, there are concerns about using the ADAS-Cog at this crucial stage. Using data from the Alzheimer's disease Neuroimaging Initiative study, we used a range of traditional psychometric tests to evaluate those concerns. This issue of Alzheimer's & Dementia includes two articles that evaluate the ADAS-Cog. These articles report evaluations using two psychometric approaches: traditional methods and new methods. In this review, we provide accompanying background information to this program of research.

Multiple sclerosis and extract of cannabis: results of the MUSEC trial.

OBJECTIVE: Multiple sclerosis (MS) is associated with chronic symptoms, including muscle stiffness, spasms, pain and insomnia. Here we report the results of the Multiple Sclerosis and Extract of Cannabis (MUSEC) study that aimed to substantiate the patient based findings of previous studies. PATIENTS AND METHODS: Patients with stable MS at 22 UK centres were randomised to oral cannabis extract (CE) (N=144) or placebo (N=135), stratified by centre, walking ability and use of antispastic medication. This double blind, placebo controlled, phase III study had a screening period, a 2 week dose titration phase from 5 mg to a maximum of 25 mg of tetrahydrocannabinol daily and a 10 week maintenance phase. The primary outcome measure was a category rating scale (CRS) measuring patient reported change in muscle stiffness from baseline. Further CRSs assessed body pain, spasms and sleep quality. Three validated MS specific patient reported outcome measures assessed aspects of spasticity, physical and psychological impact, and walking ability. RESULTS: The rate of relief from muscle stiffness after 12 weeks was almost twice as high with CE than with placebo (29.4% vs. 15.7%; OR 2.26; 95% CI 1.24 to 4.13; p=0.004, one sided). Similar results were found after 4 weeks and 8 weeks, and also for all further CRSs. Results from the MS scales supported these findings. CONCLUSION: The study met its primary objective to demonstrate the superiority of CE over placebo in the treatment of muscle stiffness in MS. This was supported by results for secondary efficacy variables. Adverse events in participants treated with CE were consistent with the known side effects of cannabinoids. No new safety concerns were observed. TRIAL REGISTRATION NUMBER: NCT00552604.

Using the Multiple Sclerosis Impact Scale to estimate health state utility values: mapping from the MSIS-29, version 2, to the EQ-5D and the SF-6D.

OBJECTIVES: The 29-item Multiple Sclerosis Impact Scale (MSIS-29) is a psychometrically validated patient-reported outcome measure increasingly used in trials of treatments for multiple sclerosis. However, it is non-preference-based and not amenable for use across policy decision-making contexts. Our objective was to statistically map from the MSIS-29, version 2, to the EuroQol five-dimension (EQ-5D) and the six-dimension health state short form (derived from short form 36 health survey) (SF-6D) to estimate algorithms for use in cost-effectiveness analyses. METHODS: The relationships between MSIS-29, version 2, and EQ-5D and SF-6D scores were estimated by using data from a cohort of people with multiple sclerosis in South West England (n=672). Six ordinary least squares (OLS), Tobit, and censored least adjusted deviation (CLAD) regression analyses were conducted on estimation samples, including the use of subscale and item scores, squared and interaction terms, and demographics. Algorithms from models with the smallest estimation errors (mean absolute error [MAE], root mean square error [RMSE], normalized RMSE) were then assessed by using separate validation samples. RESULTS: Tobit and CLAD. For the EQ-5D, the OLS models including subscale squared terms, and item scores and demographics performed comparably (MAE 0.147, RMSE 0.202 and MAE 0.147, RMSE 0.203, respectively), and estimated scores well up to 3 years post-baseline. Estimation errors for the SF-6D were smaller (OLS model including squared terms: MAE 0.058, RMSE 0.073; OLS model using item scores and demographics: MAE 0.059, RMSE 0.08), and the errors for poorer health states found with the EQ-5D were less pronounced. CONCLUSIONS: We have provided algorithms for the estimation of health state utility values, both the EQ-5D and SF-6D, from scores on the MSIS-29, version 2. Further research is now needed to determine how these algorithms perform in practical decision-making contexts, when compared with observed EQ-5D and SF-6D values.

Analysis and validation of a Parkinson's disease register as a recruitment tool for clinical studies.

Promotion of research is a key strategy of the National Health Service (NHS). Currently, many patients are not afforded the opportunity to participate in clinical studies. A register of research-interested patients has the potential to maximise inclusivity. We have established a register of research-interested patients with Parkinson's disease within the South West of England, with pragmatic inclusion criteria and multiple recruitment routes. We undertook an analysis of the register, investigation of its utility as a recruitment tool and a survey of recruiters. There were 529 active participants; 30% were self-referred and 70% were recruited by a healthcare practitioner. Response rate to annual questionnaires was 86.5%. Staff time required for pack preparation, recruitment and data entry was 15 min per new recruit and 5 min per follow-up questionnaire. In total, 85% of recruiters viewed the register positively. A single mailing to participants resulted in a recruitment rate that significantly exceeded that achieved by traditional recruitment methods.

Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy. Objective: To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD. Design, Setting, and Participants: This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021. Interventions: Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period. Main Outcomes and Measures: The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event. Results: Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE. Conclusions and Relevance: In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. Trial Registration: ISRCTN Identifier: 16108482.

Model-based economic evaluation in Alzheimer's disease: a review of the methods available to model Alzheimer's disease progression.

OBJECTIVE: To consider the methods available to model Alzheimer's disease (AD) progression over time to inform on the structure and development of model-based evaluations, and the future direction of modelling methods in AD. METHODS: A systematic search of the health care literature was undertaken to identify methods to model disease progression in AD. Modelling methods are presented in a descriptive review. RESULTS: The literature search identified 42 studies presenting methods or applications of methods to model AD progression over time. The review identified 10 general modelling frameworks available to empirically model the progression of AD as part of a model-based evaluation. Seven of these general models are statistical models predicting progression of AD using a measure of cognitive function. The main concerns with models are on model structure, around the limited characterization of disease progression, and on the use of a limited number of health states to capture events related to disease progression over time. None of the available models have been able to present a comprehensive model of the natural history of AD. CONCLUSIONS: Although helpful, there are serious limitations in the methods available to model progression of AD over time. Advances are needed to better model the progression of AD and the effects of the disease on peoples' lives. Recent evidence supports the need for a multivariable approach to the modelling of AD progression, and indicates that a latent variable analytic approach to characterising AD progression is a promising avenue for advances in the statistical development of modelling methods.

Patient-orientated longitudinal study of multiple sclerosis in south west England (The South West Impact of Multiple Sclerosis Project, SWIMS) 1: protocol and baseline characteristics of cohort.

BACKGROUND: There is a need for greater understanding of the impact of multiple sclerosis (MS) from the perspective of individuals with the condition. The South West Impact of MS Project (SWIMS) has been designed to improve understanding of disease impact using a patient-centred approach. The purpose is to (1) develop improved measurement instruments for clinical trials, (2) evaluate longitudinal performance of a variety of patient-reported outcome measures, (3) develop prognostic predictors for use in individualising drug treatment for patients, particularly early on in the disease course. METHODS: This is a patient-centred, prospective, longitudinal study of multiple sclerosis and clinically isolated syndrome (CIS) in south west England. The study area comprises two counties with a population of approximately 1.7 million and an estimated 1,800 cases of MS. Self-completion questionnaires are administered to participants every six months (for people with MS) or 12 months (CIS). Here we present descriptive statistics of the baseline data provided by 967 participants with MS. RESULTS: Seventy-five percent of those approached consented to participate. The male:female ratio was 1.00:3.01 (n = 967). Average (standard deviation) age at time of entry to SWIMS was 51.6 (11.5) years (n = 961) and median (interquartile range) time since first symptom was 13.3 (6.8 to 24.5) years (n = 934). Fatigue was the most commonly reported symptom, with 80% of participants experiencing fatigue at baseline. Although medication use for symptom control was common, there was little evidence of effectiveness, particularly for fatigue. Nineteen percent of participants were unable to classify their subtype of MS. When patient-reported subtype was compared to neurologist assessment for a sample of participants (n = 396), agreement in disease sub-type was achieved in 63% of cases. There were 836 relapses, reported by 931 participants, in the twelve months prior to baseline. Twenty-three percent of the relapsing-remitting group and 12% of the total sample were receiving disease-modifying therapy at baseline. CONCLUSIONS: Demographics of this sample were similar to published data for the UK. Overall, the results broadly reflect clinical experience in confirming high symptom prevalence, with relatively little complete symptom relief. Participants often had difficulty in defining MS relapses and their own MS type.

Assessment of a home-based standing frame programme in people with progressive multiple sclerosis (SUMS): a pragmatic, multi-centre, randomised, controlled trial and cost-effectiveness analysis.

BACKGROUND: People severely impaired with progressive multiple sclerosis spend much of their day sitting, with very few options to improve motor function. As a result, secondary physical and psychosocial complications can occur. Effective and feasible self-management strategies are needed to reduce sedentary behaviour and enhance motor function. In this study, we aimed to assess the clinical and cost effectiveness of a home-based, self-managed, standing frame programme. METHODS: SUMS was a pragmatic, multicentre, randomised controlled superiority trial of people with progressive multiple sclerosis and severe mobility impairment, undertaken in eight centres from two regions in the UK. The study had assessor-blinded outcome assessments with use of clinician-rated and patient-rated measures at baseline, 20 weeks, and 36 weeks. After baseline assessment, participants were randomised (1:1) by computer-generated assignment to either a standing frame programme plus usual care or usual care alone. The intervention consisted of two home-based physiotherapy sessions (60 min each) to set up the standing frame programme, supported by six follow-up telephone calls (15 min per call). Participants were asked to stand for 30 min, three times per week over 20 weeks, and encouraged to continue in the longer term, although no further physiotherapy support was provided. The primary clinical outcome was motor function measured by the Amended Motor Club Assessment (AMCA) score at week 36, analysed in the modified intention-to-treat population (excluding only patients who were deemed ineligible after randomisation, those who withdrew from the trial and were unwilling for their previously collected data to be used, or those who did not provide baseline and week 36 measurements). A 9-point AMCA score change was considered clinically meaningful a priori. Adverse events were collected through a daily preformatted patient diary throughout the 36 weeks and analysed in the modified intention-to-treat population. An economic assessment established the resources required to provide the standing frame programme, estimated intervention costs, and estimate cost effectiveness. This trial is registered with the International Standard Randomised Controlled Trials, number ISRCTN69614598. FINDINGS: Between Sept 16, 2015, and April 28, 2017, 285 people with progressive multiple sclerosis were screened for eligibility, and 140 were randomly assigned to either the standing frame group (n=71) or the usual care group (n=69). Of these, 122 completed the primary outcome assessment (61 participants in both groups) for the modified intention-to-treat analysis. The use of the standing frame resulted in a significant increase in AMCA score compared with that for usual care alone, with a fully adjusted between-group difference in AMCA score at 36 weeks of 4·7 points (95% CI 1·9-7·5; p=0·0014). For adverse events collected through patient diaries, we observed a disparity between the two groups in the frequency of short-term musculoskeletal pain (486 [41%] of 1188 adverse events in the standing frame group vs 160 [22%] of 736 adverse events in the usual care group), which was potentially related to the intervention. The musculoskeletal pain lasted longer than 7 days in five participants (two in the standing frame group and three in the usual care group). No serious adverse events related to the study occurred. The standing frame group had a mean 0·018 (95% CI -0·014 to 0·051) additional quality-adjusted life-years (QALYs) compared with those of the usual care group, and the estimated incremental cost-per-QALY was approximately £14 700. INTERPRETATION: The standing frame programme significantly increased motor function in people with severe progressive multiple sclerosis, although not to the degree that was considered a priori as clinically meaningful. The standing frame is one of the first physiotherapy interventions to be effective in this population. We suggest that the programme is feasible as a home-based, self-managed intervention that could be routinely implemented in clinical practice in the UK. FUNDING: UK National Institute of Health Research.

A self-management programme to reduce falls and improve safe mobility in people with secondary progressive MS: the BRiMS feasibility RCT.

BACKGROUND: Balance, mobility impairments and falls are common problems for people with multiple sclerosis (MS). Our ongoing research has led to the development of Balance Right in MS (BRiMS), a 13-week home- and group-based exercise and education programme intended to improve balance and encourage safer mobility. OBJECTIVE: This feasibility trial aimed to obtain the necessary data and operational experience to finalise the planning of a future definitive multicentre randomised controlled trial. DESIGN: Randomised controlled feasibility trial. Participants were block randomised 1 : 1. Researcher-blinded assessments were scheduled at baseline and at 15 and 27 weeks post randomisation. As is appropriate in a feasibility trial, statistical analyses were descriptive rather than involving formal/inferential comparisons. The qualitative elements utilised template analysis as the chosen analytical framework. SETTING: Four sites across the UK. PARTICIPANTS: Eligibility criteria included having a diagnosis of secondary progressive MS, an Expanded Disability Status Scale (EDSS) score of between ≥ 4.0 and ≤ 7.0 points and a self-report of two or more falls in the preceding 6 months. INTERVENTIONS: Intervention - manualised 13-week education and exercise programme (BRiMS) plus usual care. Comparator - usual care alone. MAIN OUTCOME MEASURES: Trial feasibility, proposed outcomes for the definitive trial (including impact of MS, mobility, quality of life and falls), feasibility of the BRiMS programme (via process evaluation) and economic data. RESULTS: A total of 56 participants (mean age 59.7 years, standard deviation 9.7 years; 66% female; median EDSS score of 6.0 points, interquartile range 6.0-6.5 points) were recruited in 5 months; 30 were block randomised to the intervention group. The demographic and clinical data were broadly comparable at baseline; however, the intervention group scored worse on the majority of baseline outcome measures. Eleven participants (19.6%) withdrew or were lost to follow-up. Worsening of MS-related symptoms unrelated to the trial was the most common reason (n = 5) for withdrawal. Potential primary and secondary outcomes and economic data had completion rates of > 98% for all those assessed. However, the overall return rate for the patient-reported falls diary was 62%. After adjusting for baseline score, the differences between the groups (intervention compared with usual care) at week 27 for the potential primary outcomes were MS Walking Scale (12-item) version 2 -7.7 [95% confidence interval (CI) -17.2 to 1.8], MS Impact Scale (29-item) version 2 (MSIS-29vs2) physical 0.6 (95% CI -7.8 to 9) and MSIS-29vs2 psychological -0.4 (95% CI -9.9 to 9) (negative score indicates improvement). After the removal of one outlier, a total of 715 falls were self-reported over the 27-week trial period, with substantial variation between individuals (range 0-93 falls). Of these 715 falls, 101 (14%) were reported as injurious. Qualitative feedback indicated that trial processes and participant burden were acceptable, and participants highlighted physical and behavioural changes that they perceived to result from undertaking BRiMS. Engagement varied, influenced by a range of condition- and context-related factors. Suggestions to improve the utility and accessibility of BRiMS were highlighted. CONCLUSIONS: The results suggest that the trial procedures are feasible and acceptable, and retention, programme engagement and outcome completion rates were sufficient to satisfy the a priori progression criteria. Challenges were experienced in some areas of data collection, such as completion of daily diaries. FUTURE WORK: Further development of BRiMS is required to address logistical issues and enhance user-satisfaction and adherence. Following this, a definitive trial to assess the clinical effectiveness and cost-effectiveness of the BRiMS intervention is warranted. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13587999. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 27. See the NIHR Journals Library website for further project information.

People with secondary progressive multiple sclerosis (SPMS) often have problems with walking and balance, which lead them to fall. Undertaking exercise and learning about falls prevention could help reduce injury risk and improve mobility. We developed a mobility, balance and falls programme called Balance Right in MS (BRiMS). Before testing its effectiveness in a large-scale trial, we needed to conduct a small-scale version of the trial. We asked people with SPMS who had balance and mobility problems to be assigned by chance to undertake the BRiMS programme plus their usual care, or to continue with usual care only. Questionnaires were used to ask people about their mobility, falls and quality of life, and we measured their balance and activity levels. We interviewed participants about BRiMS and being in the trial, and collected information about costs. Fifty-six people entered the trial from three areas of the south-west and from Ayrshire. At completion of the study we were able to review 44 people. The key measures were completed by 98% of those we assessed, but only around half (62%) of the diaries detailing falls were returned. As this was a feasibility trial, the numbers were too small for us to look at differences between the groups. Participants liked the BRiMS programme; some did a lot of exercise and learning activities, but most did not manage the amount we asked them to do. People reported feeling a little overwhelmed by the educational content of BRiMS, and that this should be reduced in future. They told us that they felt that their balance had improved and that they fell less frequently after the BRiMS programme. Our assessment of the trial methods we used showed that it would be possible to conduct a full-scale trial using this design, but that we need to adapt the BRiMS programme further to make it more user-friendly.