Trial design
This is a pragmatic multi-centre randomised controlled trial with blinded outcome assessment and full economic evaluation. Figure 1 shows the participant pathway.
Study Setting
Eight healthcare sites will be involved in this multi-centred RCT which is based in two geographical regions of England: Devon/Cornwall and East Anglia. Each site consists of up to seven individual community based therapy teams.
Participants
Sample size
Our primary outcome is the Amended Motor Club Assessment (AMCA) at 16 weeks follow-up. Our primary analysis will utilise analysis of covariance (ANCOVA), comparing AMCA scores at week 36 between allocated groups, adjusting for baseline AMCA score. The trial is powered to detect a between-group difference of nine points which is both plausible and considered clinically relevant [17, 20]. In people with severe MS a score change of 9 points is considered clinically significant, reflecting changes such as allowing a person to balance and lean forwards in sitting to dress themselves or to stand in the shower and wash their hair with two hands.
Estimates of final SD and baseline/follow-up correlation for AMCA are subject to uncertainty and thus we have used conservative 80 % upper confidence limits for both parameters in our calculations. To detect a between-group difference of nine points, with 80 % power and at the 5 % significance level, requires data from 55 participants per group [21].
Allowance is required for people not completing the programme, and for participants not attending the final follow-up assessment. Based on our previous experiences, we have allowed for 20 % loss to follow-up. Therefore the sample size required is 69 participants per group, rounded to a total of 140. An estimated 380 people will need to be screened to achieve the required sample size.
Inclusion criteria
The study population will comprise individuals diagnosed with primary or secondary progressive MS according to McDonald’s criteria [22].
These participants will:
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be aged >18 years
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be willing and able to consent to participate
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score 6.5–8.0 on the Expanded Disability Status Scale (EDSS), i.e. people who “require bilateral assistance to walk 20 metres or less” to those “restricted to bed or wheelchair”
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be able to get into a standing frame independently or with assistance from one person
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have the agreement of another person (e.g. carer) should assistance be necessary for the standing programme
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be able and willing to accommodate the standing frame in their home
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be willing and able to travel to local assessment centres for blinded outcomes assessment
Exclusion criteria
Participants will be excluded if they:
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have had any recent changes in disease modifying therapies. More specifically they will be excluded if: they have ever had Alemtuzumab, are within past six months of ceasing Nataluzimab, or are within three months of ceasing any other MS disease modifying drug
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have relapsed/received steroid treatment within the last month
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are currently undertaking a regular standing frame programme (>x1/week), or have done so during the past six months
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have a history of osteoporotic-related fractures
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have co-morbidities which contraindicate standing in the frame (e.g. foot ulceration, uncontrolled epilepsy) or likely to impact on the trial (e.g. chronic jaundice, heart disease, age related multiple co-morbidities)
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currently participating in another clinical trial (rehabilitation or pharmacological)
Identification and recruitment of participants will be via a number of routes which include screening MS databases, identification by healthcare professionals, and advertising via MS support groups and newsletters.
Randomisation
Participants will be randomised immediately after the baseline assessment. Randomisation, using random sized permuted blocks, will be on a 1:1 basis to receive the intervention plus usual care or usual care only. It will be stratified by region and baseline EDSS (≤7.0 or ≥7.5). The allocation sequence is computer-generated by the local United Kingdom Clinical Research Collaboration Registered Peninsula Clinical Trials Unit (UKCRC PenCTU) (Registration Number 31) in conjunction with an independent statistician who will have no involvement with the final analysis. Following assessment, the blinded assessor will input the details of the participants directly into the randomisation web-site. This will generate an e-mail stating the participant’s allocated treatment group to the regional study co-ordinators and study administrator to notify them of the treatment allocation.
Blinding
The trial participants and carers are unable to be blinded in this trial due to the nature of the intervention. Similarly, the treating physiotherapists and health care providers are unable to be blinded. However, the outcome assessors will be blinded to participants’ allocated group. All assessments will be undertaken in separate visits independently of delivery of treatment/usual care and away from the participant’s home. Every effort will be made throughout the trial to ensure these assessments are blinded. Upon any interaction with the participant, the blinded assessors will remind participants not to discuss their allocated group, and this will be re-iterated within any written and telephone correspondence.
At each assessment time point, the blinded assessor will be asked to record on a standardised form whether or not they were un-blinded to the group allocation, and if so the reasons for this.
Interventions
Participants in the intervention group will be asked to stand in an Oswestry standing frame [17] for 30 min three times per week for a total of 16 weeks during a 20 week period. The Oswestry standing frame is a wooden frame, used in clinical practice, which provides support in standing whilst allowing for exercise and controlled movement.
The treating physiotherapist will teach the participant and carer safe and effective use of the standing frame over two face-to-face sessions in the participant’s home (~60 min/session). Participants will also be taught exercises and stretches to undertake in the frame. A detailed user-friendly information leaflet and digital versatile disc (DVD) will be provided to support these sessions. Further support will be provided by weekly telephone contact for four weeks, and then monthly for two months. Telephone calls will focus on facilitating individuals to set and achieve personal targets.
Standardisation and fidelity of the intervention
Treating physiotherapists from each of the eight healthcare sites will perform the interventions as part of their NHS role; all physiotherapists will implement the intervention in a similar manner.
Use of standing frames is incorporated within undergraduate physiotherapy training and is a recognised core skill for neurological physiotherapists. To standardise and optimise implementation of the intervention, treating therapists, participants and carers will be provided with an information pack. This includes a written template of what is required to be undertaken within each session and a link to the study web-site, which houses a range of resources including a detailed booklet, instructional video with suggested exercise/stretches/balance activities, and evidence based articles on this topic.
All treating therapists will be required to complete a pre-formatted checklist to self-assess their fidelity with the content of the sessions. They will be asked to record any deviations from the protocol on a Protocol Deviations form. In addition, 10 % of the intervention sessions will be assessed in each region by the unblinded regional Principal Investigator who will observe the home-based treatment sessions and independently complete the same fidelity checklist.
Usual care
This trial will use a usual clinical care control group. A recent MS Society national survey demonstrated that access to physiotherapy services varies throughout the UK/England [14]. Although usual care varies between individuals [1], it rarely involves regular physiotherapy intervention either within the community or hospital [13]. Any intervention is generally limited to a few visits, typically reacting to presenting problems (e.g. practising transfer skills, providing mobility aids) rather than promoting long-term preventative self-management [13]. This national picture reflects the care provided in our study regions. The usual care received (including frequency of physiotherapy intervention as well as any other health/social service interventions and medications) will be recorded within the economic cost effectiveness assessments.
Data collection and outcome measurements
Standardised, validated clinician-rated and patient self-reported clinical outcomes will be measured at baseline, immediately post intervention (20 weeks) and follow-up (week 36). Any deviations from this will be recorded on a Protocol Deviations form. The longer term follow-up is important to assess maintenance of any observed effect, and determine whether long-term engagement is sustained once support from the treating physiotherapist is withdrawn.
Measures have been selected on the basis of demonstrated reliability and validity in assessing physical impairments, clinical outcomes, quality of life, and economic costs in people with MS.
Primary outcome measures
The primary clinical outcome is motor function, assessed using the Amended Motor Club Assessment (AMCA) [23]. This rates motor impairment of the lower limb and trunk and key functional movements such as sit-to-stand and standing balance. It was developed specifically for people with MS and has demonstrated validity, reliability and responsiveness [20, 23, 24]
The primary economic endpoint is the quality-adjusted life year (QALY), assessed using the EuroQol five dimensional descriptive system, the EQ-5D-5 L self report measure [25].
Secondary outcome measures
A. Key clinical outcomes:
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1.
Bowel and bladder control using the self-report Bladder and Bowel Control Scales [26]
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Sitting balance using the single item Modified Functional Reach in Sitting [27]
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Falls frequency through a single yes/no question “Did you fall today?”, recorded on the daily diary
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4.
Health-related quality-of-life (HRQoL), using the 29 item Multiple Sclerosis Impact Scale (MSIS-29 version 2.0) [28], a disease specific patient-reported outcome measure with a preference-based tariff [29] for use in sensitivity analyses for the Quality Adjusted Life Year (QALY) outcome.
B. Explanatory physical impairments:
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1.
Knee extensor strength using a portable hand-held dynamometer [30]
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Length of hip flexors, hamstrings and ankle plantarflexors using manual goniometry [16]
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3.
Spasm frequency using the Penn Spasm Frequency Scale [31]
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Respiratory capacity using a hand-held spirometer to record forced expiratory volume at one second [32]
Measures of intervention adherence
A simple pre-formatted daily diary will be completed by those allocated to the standing frame programme. Either the participant or carer will record adherence with the intervention (frequency, duration, reasons for not standing), and will also have the opportunity to comment on why standing was continued or stopped. Adverse events (including new symptoms and falls) will also be recorded in the diary.
The usual care group will also be asked to complete a daily diary to capture adverse events (including new symptoms and falls).
Safety monitoring
Participants will be monitored for adverse events via completion of their study daily diaries and during follow-up assessments. The group receiving the intervention will also be monitored during the scheduled telephone calls with their treating physiotherapist. Physiotherapists will be asked to report all adverse events to the research team, whether or not they are thought to be related to the intervention.
Economic evaluation
The economic evaluation will estimate the cost effectiveness of the standing frame programme plus usual care, versus usual care alone. The primary perspective of the analyses will be that of the NHS and Personal Social Services (i.e. Third Party Payer), with a broader perspective to be considered in sensitivity analyses. Cost effectiveness analyses (CEA) will present an estimate of the incremental cost per unit change in the primary outcome measure (AMCA), but the primary economic analyses will be the incremental cost per QALY gained (over 36 week follow-up). The EQ-5D-5 L will be the primary economic endpoint used to estimate QALYs, applying a UK tariff [33], at final follow-up, with the MSIS-8D [29] used to estimate QALYS based on the MSIS-29, a condition specific measure. Economic analyses will estimate the resource use (e.g. standing frames, physiotherapy sessions, travel, telephone calls, social care assistance) and related cost associated with delivery of the standing frame programme, in addition to usual care, via data collected within the trial.
Data will be collected, via a self-report Resource Use Questionnaire, on participant use of health and social care services (primary, secondary and social care), and on broader aspects of participant and carer-related resource use.
Regression methods will be used to estimate incremental costs and QALYs, adjusting for baseline (cost, QALY) values, with covariates for baseline ACMA and stratification variables (baseline EDSS, geographic regions), and economic analyses will be consistent with the primary statistical analysis plan. The CEA will synthesise cost and outcome data, and explore uncertainty, to present results of the economic evaluation in a policy relevant way.
Qualitative assessment
A qualitative approach will be used to capture and explore the “real-life” experiences of people’s participation in the standing frame programme. Purposive sampling to achieve maximum variation will be used to request 10 participants and 10 carers to keep audio diaries of their experiences of standing and using the frame. They will be asked to use an audio recorder to record their reflections and experiences on how it feels to stand, changes they are experiencing, plus any comments they wish to make throughout the intervention period. To ensure contemporaneous collection of data they will be asked to record these reflections, if possible, during each stand or as near to the completed standing period as possible.
Statistical analysis
A full statistical analysis plan will be developed and approved by an independent statistician, prior to final database-lock. The primary statistical analysis will utilise analysis of covariance (ANCOVA), comparing AMCA scores at week 36 between allocated groups, adjusting for baseline AMCA score and the two stratification variables (baseline EDSS category and geographical region). The primary comparative analyses of all outcome measures will be on the basis of intention-to-treat (adverse events will be presented per protocol if different). Between-group differences will be presented with 95 % confidence intervals wherever possible, with the significance level for hypothesis testing set at 5 %, unless otherwise stated.
Secondary outcomes will be compared between groups in a similar way to that for the primary outcome. Comparisons of interest will be presented with 95 % confidence intervals for both unadjusted and adjusted between-group comparisons.
Subgroup analyses
Exploratory analyses of the possible interaction between baseline EDSS and allocated group will be undertaken, to explore whether any difference between the allocated groups is modified by baseline EDSS category (≤7.0 vs ≥7.5).
Qualitative analysis
Participants’ stories will be gathered, analysed and reported using narrative methodology [34]. The texts from audio recordings will be left whole, crafted into a story, and not fractured into themes, as an attempt to capture the immediate impact of standing, and to form a chronological record of the person’s experience. This promotes a contextual and holistic account; providing stories that are intended to resonate with people with MS, their families and professionals. By reading these stories the aim is to encourage the reader to reflect on their own situation gaining insight into their own experience as a person standing and living with MS, assisting a person to stand or as a professional.
Data management, audit and monitoring
Data will be recorded on study specific data collection forms by the research therapists. Completed forms will be entered onto a password-protected customised database, developed by the Peninsula CTU. All data will be double entered and compared for discrepancies. Discrepant data will be verified using the original paper data sheets.
Participants’ anonymity will be maintained on all documents. Data will be collected and stored in accordance with the Data Protection Act 1998, and will be accessible for the purposes of monitoring, auditing, or at the request of the regulatory agency.
Trial management committees
There are two trial management groups involved in the set up and management of this trial: the Trial Management Group (TMG) and the Trial Steering Committee (TCS).
The TMG comprises 10 individuals involved in the study design and protocol development. The group will meet approximately monthly to oversee the general management of the day to day running of the trial and release the trial results and publications. Closely involved with the sponsors, most members are co-investigators on this study. In contrast the decisions made by the TSC are independent of the sponsors and investigators. The TSC, which meets annually, comprises eight individuals, with majority independent representation (chair, external statistician, member of MS Society and two independent lay members. In addition the chair of the TSC will receive a quarterly update of the adverse events, and a telephone conference / additional face-to-face meeting will be instigated by the Chair or the Chief Investigator should any issues need to be discussed.
The role of the TSC is to oversee the conduct of the trial, including for instance monitoring adverse events, recruitment and attrition rates, the project timeline and finances.
Ethics
The trial will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, 1996; the principles of Good Clinical Practice, and the Department of Health Research Governance Framework for Health and Social Care, 2005. The study protocol, participant information and enrolment procedures were assessed and approved through the National Research Ethics Scheme (NRES Committee South West – Frenchay, REC ref no. 15/SW/0088) and management permissions gained from the Research and Development Departments of the eight participating centres in accordance with NHS research governance arrangements. Any amendments to the protocol will be reported to, and approved via NRES.
Dissemination plan
We will target users, clinicians, researchers, organisations developing clinical guidelines and NHS decision makers. On completion of the trial, the full study report will be accessible on the study web-site page, as will the full protocol. This protocol (Version 3.0, dated 5.2.2015) has been published in line with SPRIT Guidelines [35]. Similarly CONSORT (Consolidated Standards of Reporting Trials) [36] and The Template for Intervention Description and Replication (TiDIER) Guidelines [37] will be reviewed prior to submitting future publications of the trial results to high quality journals. Authorship of intended articles will be by the study team; professional writers will not be used. Results will be presented at national and international conferences to ensure dissemination to academics and those responsible for service delivery. In addition results will be disseminated through the newsletters of MS organisations and via talks to their local support groups. If proven effective, the training materials (treatment manual, instructional video recordings, case scenarios) will be made freely available via the study website, with the aim of optimising roll out. Extracts from the audio recordings will also be used as educational and decision making tools for use by both people with MS and therapists involved in their care. All participants, who consent to receiving notifications, will be notified in writing of trial outcomes.