Clinical effectiveness and cost-effectiveness of physiotherapy and occupational therapy versus no therapy in mild to moderate Parkinson's disease: a large pragmatic randomised controlled trial(PD REHAB)

Parkinson’s disease

Parkinson’s disease (PD) affects over 1% of people older than 60 years and the prevalence is set to rise with the ageing population. 1 PD causes significant problems with activities of daily living (ADL) that are only partially treated by medication and occasionally surgery. Despite treatment, patients go on to develop intractable motor problems (e.g. imbalance and falls), along with mental-health problems and other non-motor symptoms.

Physiotherapy and occupational therapy

Physiotherapy (PT) and occupational therapy (OT) are traditionally used later in the course of PD. 2 PT aims to promote and maintain mobility and activity by treating motor impairments with task-related practice and exercise. Core work areas are motor practice and exercise prescription for gait, balance, posture and transfers. 3 A recent summary of the role of PT included the prevention of inactivity and falls. 4

Occupational therapists work in partnership with patients to address personal rehabilitation goals through activity and participation, helping them to remain as independent as possible and to reduce carer strain. When delivered in a domiciliary setting, OT includes equipment provision and environmental adaptations to facilitate independence in the home. Therapists provide task-related training and educate patients and carers. 5,6

Evidence for physiotherapy and occupational therapy in Parkinson’s disease

Cochrane reviews of PT and OT for PD found insufficient evidence of their individual effectiveness, but the trials included in the reviews were methodologically flawed with small size and short-term follow-up. 7–9 Despite this lack of evidence, the UK National Institute for Health and Care Excellence guidelines, although recognising these shortcomings and recommending further trials, stated that all patients should have access to both therapies. 2

Physiotherapy versus no or placebo intervention

This review was published by the trial team in The Cochrane Library8 and subsequently in the British Medical Journal9 © 2016 BMJ Publishing Group Ltd. All rights reserved.

Physiotherapy versus alternative physiotherapy intervention

This review was published by the trial team in The Cochrane Library. 11

Occupational therapy versus no or placebo intervention

This Cochrane review was published by collaborators of the trial team. 7

Method

This pilot study was a RCT with masked assessment of standard community-based individual OT targeting functional independence and mobility versus usual NHS care with OT deferred until the end of the trial.

We aimed to recruit 50 patients with idiopathic PD, defined by the UPDRS,12 with Hoehn and Yahr stages 3–4. We excluded patients with dementia, since they would be unable to complete trial forms, and those who had received OT in the last 2 years or PT in the last year, to avoid carry-over effects.

Patients were recruited from four neurology and elderly care PD clinics in the West Midlands. After patients were identified and informed about the study, written consent was taken and baseline information was collected. Patients were randomised by the therapist between the two trial groups (1 : 1) using a computer-generated random number list via a telephone call to the University of Birmingham Clinical Trials Unit. Patients were informed of their treatment allocation. The trial manager and chief investigator were masked to treatment allocation.

The intervention was developed by combining existing evidence from our surveys of current and best-practice OT in PD5,6 and the consensus of a group of expert occupational therapists. 13 The intervention was provided by an experienced occupational therapist and was delivered at the level of the individual. Primary interventions were targeted towards limitations in ADL (self-care and instrumental); mobility (indoor and outdoor); and home safety. Six sessions of 45 minutes each were administered over 2 months. Content was dependent on the patient’s and therapist’s agreed goals. OT followed a routine process using a ‘client-centred approach’,14 with a continuous process of assessment, treatment and re-evaluation.

The content of the OT intervention addressed specific tasks (e.g. eating, mobilising) within the participant’s home. Techniques employed by the therapist included task-specific practice (e.g. dressing, transfers, mobility training), reducing the complexity or demands of tasks and/or altering the environment through provision of aids and adaptations. The therapist also provided advice and information to patients and carers and referral to other health-care workers when appropriate. When time allowed, secondary interventions addressed fatigue management, leisure therapy, continence, speech and communication interventions, and relaxation techniques.

Since the intervention was targeted towards improving functional ability, we assessed instrumental ADL with the Nottingham Extended Activity of Daily Living Scale (NEADL). This has been validated in stroke15 and has been shown in other community OT trials to be relevant and sensitive to change. 16 We also explored the use of the Rivermead Mobility Index (RMI); the patient-completion UPDRS ADL scale; PDQ-39; European Quality of Life-5 Dimensions (EQ-5D); and Hospital Anxiety and Depression Scale (HADS).

For economic analysis, resource-use data were collected in a patient-completed questionnaire at the end of the trial to estimate the costs associated with treatment and management over the previous 6 months.

At baseline (before randomisation), patients completed assessments by interview. At 2 and 8 months after randomisation, assessments were posted to all patients for self-completion.

As this was a pilot study, definitive answers to the randomised comparison were not expected, so formal statistical hypothesis testing was not performed. Differences between the two arms in change from baseline at 2 and 8 months were calculated with 95% CI. Pearson correlation coefficients were calculated to correlate outcome measures. Statistical analysis was performed using SAS version 9.1 (SAS Institute Inc., Cary, NC, USA).

The PD OT trial was approved by Sandwell and West Birmingham Local Research Ethics Committee, funded by the Parkinson’s Disease Society and sponsored by the University of Birmingham. Professor Sackley was funded by a National Primary Care Career Scientist award.

Results

Over 16 months (July 2005 to October 2006), 39 patients were recruited from four centres (25 male; mean age 73 years). Patient eligibility was assessed in one centre’s movement disorders clinics (City Hospital, Birmingham) over 9 months. Only 11 patients (6%) attending 196 PD patient visits (some patients attended more than once) were eligible for the trial. The reasons for exclusion were early PD without significant difficulties with ADL (61%), recent OT or PT (21%), dementia (7%), advanced PD (1%) and other (10%).

In the treatment group (11 male; mean age 73 years), 15 were living with someone, three were living alone and one was living in a care home. The mean number of treatment visits was 5.7 (range 3–9). The interval between visits varied from 3 to 63 days. The total time spent by the therapist with patients was 103.1 hours (mean 5.4 hours per patient).

The differences between the OT and no OT arms at 2 and 8 months for the main outcome measures are shown in Table 3. There were strong correlations between the mobility, ADL and emotional well-being domains of PDQ-39 and RMI, UPDRS ADL subscale and anxiety and depression subscores of the HADS.

The health economics questionnaire piloted in the trial adequately captured data on health service utilisation.

Conclusions

Method

The development of the PD OT intervention followed a three-step approach:

1. Published trial evidence was gathered (until recruitment commenced in July 2005) to ensure that the PD OT intervention was evidence-based where possible; the evidence considered included OT-specific PD studies, multidisciplinary PD interventions which incorporated OT, studies from the wider PD rehabilitation literature and clinical guidelines.

2. Current UK practice was examined through two published surveys. 25,26

3. The expert steering group met to evaluate and synthesise the findings of the first two steps with expert opinion consensus, formalising the PD OT intervention.

The aim was to provide treatment that was informed by best practice but could be delivered within the structure and format of the NHS: an enhanced current practice intervention.

Results

All 19 participants completed both their initial assessments and the treatment sessions required to address the goals identified. Treatment was delivered by one occupational therapist. The mean number of visits was 5.7 (range 3–9). A total of 108 therapist visits were carried out. The interval between visits varied from 3 days to 63 days. The initial assessment took a median of 60 minutes (range 45–90 minutes). Subsequent visits lasted a median of 50 minutes (range 5–180 minutes). On average, the occupational therapist spent a mean of 5.4 hours in total with each patient. The mean duration of the complete intervention (from first to last visit inclusive) was 60.3 days.

The content of the intervention for each patient was categorised and recorded as time (minutes) spent under the appropriate headings by the treating therapist. Two hundred and seventy-four interventions were delivered in total. The most common types of intervention were adaptive equipment (n = 56), transfers/mobility training (n = 46), environmental adaptations (n = 38), daily living activities training (n = 35), techniques/education (n = 25) and goal setting (n = 15).

Following completion of the trial, the treating therapist provided feedback on the intervention log. The log was reported as easy to use and was seen to contain categories that were relevant to the treatment being delivered. Difficulties in using the tool were also noted; overlap between categories and issues in identifying the primary aim of an intervention both led to problems with accurate categorisation.

Data collection

The PD REHAB trial prospectively collected resource-use data as an integral part of the clinical trial using a collection instrument adapted from the PD MED35 and PD SURG trials. 36 The resources monitored include use of therapy services, primary care consultations including GP and practice nurse appointments, hospital inpatient stays, outpatient visits and accident and emergency attendances. For patients admitted to hospital, the length of stay and reason for admission were noted. All resource use relevant to PD was collected. The use of OT and PT services were recorded in detail by the therapists using the data acquisition forms; use of other primary and secondary care services was collected after randomisation using a postal resource-utilisation questionnaire for patient completion. All resource-use data were collected at 3, 9 and 15 months. PD-related medication was recorded by the clinician at baseline and at 15 months. Health-related QoL was measured by the EQ-5D at baseline and at 3, 9 and 15 months.

Estimating the costs

Analysis

The analysis followed that specified in the health-economic analysis plan in the protocol. The economic analysis was based on patient-specific resource use and costs, and patient-specific outcome and QoL data. The base-case analysis was framed in terms of costs and consequences, reporting the incremental costs and consequences in a disaggregated manner. As stated in the protocol, if this convincingly identified a situation of dominance (i.e. one arm is associated with both better outcomes and a lower cost), then further analysis would not be required. If no dominance was found, then cost–utility analysis [i.e. cost per quality-adjusted life-year (QALY)] would be employed.

Accumulated total costs per patient were calculated by the sum of the products of resources used and the associated unit costs, aggregated over the study period. The mean costs associated with the therapy and control group were evaluated and the differences in costs were compared according to the intention-to-treat allocation. No discounting rate was applied, as the follow-up period was 15 months.

Quality-of-life data were measured using EQ-5D questionnaires, which were collected at baseline and at 3, 9 and 15 months. The UK Tariff was used to produce utility scores. QALYs for each patient were calculated based on the utility scores at different points using area-under-the-curve. We assumed linear interpolation between two points of measurements.

Missing data because of non-completion in the resource use and EQ-5D questionnaires were imputed by substituting the mean adjusted by treatment groups. We did not employ multiple imputation, as there were few missing values. The costs and QALYs for the cases of death and withdrawals were assumed to cease at the time points when such event occurs.

The bias-corrected bootstrap method was used to estimate mean costs, QALYs and the incremental cost-effectiveness ratio (ICER) with the associated 95% CI. Uncertainty around the costs and effectiveness estimates was illustrated using scatterplots with confidence ellipses and addressed by plotting cost-effectiveness acceptability curves (CEACs).

All analyses were based on the principle of intention to treat. The analyses were conducted in SAS 9.2.

Effectiveness analysis

The PD REHAB trial showed that NHS PT and OT produced no immediate beneficial effects on ADL or QoL in patients with mild to moderate PD. At 3 months, there was no difference in NEADL total score (difference 0.5 points, 95% CI –0.7 to 1.7; p = 0.4) or PDQ-39 summary index (difference 0.007 points, 95% CI –1.5 to 1.5 points; p = 1.0) between groups. EQ-5D quotient was of borderline significance in favour of therapy (–0.03, 95% CI –0.07 to –0.002; p = 0.04).

Using repeated measures analysis, the NEADL primary outcome measure failed to show any effect 9 and 15 months after randomisation (NEADL total score 0.07 higher in the therapy arm, 95% CI –0.64 to 0.77; p = 0.9). In contrast, the PDQ-39 summary index (curves diverging at 1.55 points per annum, 95% CI 0.47 to 2.62 points; p = 0.005) and EQ-5D quotient (0.02, 95% CI 0.00007 to 0.03; p = 0.04) showed significant differences in favour of the therapy arm with long-term follow-up. Crucially, however, the absolute size of the long-term difference in PDQ-39 summary index was small (15-month difference 2.2 points, 95% CI 0.5 to 3.9 points; p = 0.01) and not at a clinically significant level, which we had previously set at twice the MCIC value (1.6 × 2 points),23 so it is unlikely to be clinically significant to patients. The small difference in PDQ-39 summary index was driven by differences in the PDQ-39 domains of ADL (curves diverging at 2.29 points per annum, 95% CI 0.58 to 4.01; p = 0.009), emotional well-being (curves diverging at 2.66 points per annum, 95% CI 1.0 to 4.31; p = 0.002) and social support (curves diverging at 1.92 points per annum, 95% CI 0.33 to 3.51 points; p = 0.02) in favour of therapy. Importantly, these differences do not reach the individual MCIC levels for these domains either (4.4, 4.2 and 11.4, respectively). 23

The PD REHAB trial clearly shows that PT and OT, as currently practised in the NHS, do not produce immediate or long-term clinically meaningful improvements in ADL or QoL in patients with mild to moderate PD.

Health economics analysis

The PD REHAB trial found no statistically significant differences in its primary outcome. While PT/OT was associated with a small gain in QALYs at a small incremental cost, the difference was not statistically significant. These QALY and cost results are unsurprising given that any difference was premised on a change in the primary outcome.

The protocol required expressing these results in terms of a CEAC. This approach employs differences in both cost and QALYs regardless of statistical significance. The intervention led to a small incremental QALY gain at a small incremental cost. The incremental cost per QALY was just under £4000 but had wide CIs (Table 16).

The CEAC put the probability of the intervention being cost-effective for a willingness-to-pay threshold of both £20,000 and £30,000 at 50.5%.

More robust findings might be expected from a meta-analysis of other relevant studies. However, as reported previously, only one other trial that included evidence on cost-effectiveness was identified. 27 It, too, showed no statistically significant difference in either costs or outcomes, so its inclusion would make little difference to the overall outcome.

The cost-effectiveness analysis depended on the assumption that change in PD medication in the short term was unlikely. There was a possibility that the effect of PT/OT could be beneficial, leading to a reduction in medication in the intervention group. However, there was no difference in levodopa dose equivalents in either arm between baseline and 15-month follow-up, so this will not have affected the cost-effectiveness analysis.

On reflection, we consider that CEAC analysis should proceed only if the results show a difference in outcome that is considered clinically meaningful. This seems unlikely in the case of PD rehabilitation.

Adverse events

Following a risk assessment, only targeted adverse events were recorded in PD REHAB. These included therapy-related adverse events and serious adverse events, such as falls or equipment failure leading to injury requiring a hospital, GP or ambulance visit. Falls occurred in a similar number of patients in the therapy and control arms over the first 3 months and the whole 15 months of the trial. Injuries using a rollator or frame were reported by one patient in each arm of the trial.

Subgroup analyses

Planned subgroup analyses were performed to examine whether the NEADL score response at 3 months was dependent on initial disability with the NEADL total score (severe, 0–21; moderate, 22–43; and mild, 44–66), age (< 60 years, 60–69 years, 70–79 years and ≥ 80 years), or disease severity using the Hoehn and Yahr stage (≤ 2, 2.5, 3 and ≥ 4). As detailed in Figure 3, no trends in response were found with any of these variables.

We hypothesised that patients with more severe disease would show a better response, but the subgroup analyses examining the response according to the baseline NEADL score and Hoehn and Yahr stage do not support this. Similarly, older patients might respond better to the therapies because of greater levels of frailty and comorbidities, but there was no evidence of this in the subgroup analysis.

Trial population

Traditionally, PT and OT have been used in the more advanced stages of PD, often once balance problems and falls have developed (Hoehn and Yahr stage 3 and above). 2 Most patients in PD REHAB had Hoehn and Yahr scores less than 3 at randomisation, so less severe disease may not respond to therapies as delivered in the NHS, whereas more severe disease may respond, although this remains to be established.

Therapy dose

The median therapy dose was four sessions of 58 minutes over 8 weeks for both therapies combined, including assessments. This is low in comparison with the previous five PT trials in the Cochrane review (5–52 weeks’ therapy). 8 A recent Dutch trial of PT in Parkinson’s disease (ParkNet)29 also showed no evidence in favour of therapy. 40 Total contact time between patients and physiotherapists over 6 months in ParkNet was 15 sessions of 30 minutes, nearly double that in PD REHAB. 29 Importantly, however, the dose delivered in PD REHAB reflects what therapists routinely deliver in NHS practice.

Lack of consistency in therapy assessment and intervention approaches

Therapy expert groups recommended an individual goal-setting approach for the PD REHAB interventions, as this is recognised as gold standard practice and addresses the personalised needs and wishes of the individual receiving rehabilitation. The content of both types of therapy (see Tables 9 and 10) was in keeping with UK NHS PT and OT and European guidelines. 3–6 However, an individualised goal-setting approach with this content may not be directly transferable to patients with mild disease, particularly when no treatment protocol exists for early PD. Expert groups were very supportive of early referral. Indeed, we were unable to run the study in some sites as all patients were automatically referred at their first PD clinic appointment, so the team was not in equipoise about the value of the therapies.

The lack of task-related practice was also of particular concern, as this activity is a logical ‘practice makes perfect’ intervention when struggling with specific ADL and, more importantly, has been shown to be a significant factor in functional recovery in stroke rehabilitation trials. 41

We were also very concerned by the low and unstructured prescription of exercise in the PD REHAB trial, in addition to the low dose of exercise, which we would have expected to see administered as routine practice in the early stages of the disease.

Size and duration

The PD REHAB (n = 762), the Dutch ParkFit42 (n = 540) and the ParkNet29 (n = 699) trials show that large pragmatic rehabilitation trials are feasible in PD and that long-term follow-up is mandatory and achievable. Previous PT trials in PD have been relatively small (range 6–153) and with follow-up of less than 3 months. 8 It is now clear that larger and longer trials can be done in PD, and these will provide more reliable answers.

The successful pragmatic design of PD REHAB shows that patients will complete questionnaires and post them back long after therapy has been completed. This positive experience is in keeping with our previous pragmatic trials of medical interventions (PD MED) and surgery (PD SURG) in PD. 36,43,44

Therapy content

The PD REHAB trial adopted an individualised goal setting approach to PT and OT which may not be directly transferable to patients with mild PD. This resulted in a relatively low dose of therapy intervention, with a lack of task-related practice and surprisingly low levels of exercise prescribed. The content of OT was as expected in terms of provision of equipment (e.g. bed levers, etc.) and onward referral to other services. However, we would have expected to have observed evidence of more practice of specific ADL tasks. In future trials of physical therapies in PD, more formalised and intensive intervention programmes should be adopted with more task-related practice, as this may be more effective.

Trial design

A representative from Parkinson’s UK (Mrs Ramilla Patel, Regional Manager, Parkinson’s UK) was a co-applicant on the grant. She was involved in the design of the study and was a member of the trial management group. Specific participant-oriented responsibilities were also discussed in the Patient Advisory Group, namely participant and carer information sheets.

Improved communication

One of the main roles of the Patient Advisory Group was to ensure that the language used in all trial documentation, newsletters and other communications with participants were comprehensible by a non-expert audience. Specifically, the group:

1. reviewed and edited the participant information sheets and consent forms

2. wrote articles in the newsletters reflecting their experiences of PD. These newsletters were sent to our whole trial community including doctors, nurses, therapists, participants and carers

3. were involved in the dissemination of results to participants and carers mainly through the Parkinson’s UK newsletter.

The patient as the expert

Throughout the PD REHAB trial, annual meetings were held to provide support and education, and to share best practice for physiotherapists and occupational therapists. A key part of the ongoing training was the inclusion of panel sessions where the patient was the expert. The three annual patient panel sessions were a popular and insightful opportunity for patients to describe and reflect on their experiences of PT or OT. This reversal of the usual patient/therapist roles provided a forum for the patients to candidly discuss their view of therapy and answer therapists’ questions in a neutral environment.

Oversight

In line with the HTA guidelines, two members of the Patient Advisory Group were also members of the trial steering committee.

Patient Advisory Group support

Members of the Patient Advisory Group were supported by Mrs Ramilla Patel and the person leading the group. The latter changed over the course of the trial, commencing with Dr Sandy Herron-Marx, then Sunil Shah and finally Dr Caroline Rick. Patient Advisory Group communication was primarily by e-mail. This reduced travel burden on people with a movement disorder and enabled people who lived further from Birmingham to participate. It also allowed people to review documents at their own convenience. The group membership was flexible, so people could opt out of reviewing/writing documents or leave the group if they were no longer able or willing to participate.

Non-viable objectives

Part of the Patient Advisory Group’s remit was to develop recommendations for practice and patient information leaflets (top-tip leaflet) about therapy choices based on the results of the trial. However, the null result of the trial precluded any such involvement.

Dissemination

Members of the Patient Advisory Group were invited to the final Collaborators’ Meeting to hear the first trial results at the same time as the other collaborators. The group were involved in writing the lay summary of the trial findings for the participants, which was disseminated at the same time as the results were published in a peer-reviewed journal.

Lessons learned from Patient Advisory Group

The role of patient and public involvement in clinical research is a constantly evolving process. Since the completion of the PD REHAB trial, we have developed a generic Parkinson’s Patient Advisory Group with the support of Parkinson’s UK. This group will work across all of the PD trials in the BCTU portfolio. This will include the design of new trials and the interpretation and dissemination of the long-term results of the older trials. Individual members have the option to opt in or out of any project depending on their personal experience and interest. Feedback from the PD REHAB Patient Advisory Group has informed this new group’s objectives and code of conduct.

What the study found

The NHS-provided PT and OT did not produce immediate or long-term clinically meaningful improvements in ADL or QoL in mild to moderate PD. This evidence does not support the use of low-dose, patient-centred, goal-directed PT and OT in patients in the early stages of PD.

Implications for research

More formalised and intensive physical therapy programmes should be developed for different stages of PD. These should then be tested in large-scale RCTs at all stages of PD. Such trials should include QoL measures and follow-up should continue for at least 1 year after the therapy to look for any long-term or carry-over effects of therapy.

University of Birmingham Clinical Trials Unit

P Au, V Cheed, F Dowling, N Hilken, N Ives, C Meek, R Ottridge, S Patel, C Rick, E Tyler, K Wheatley, A Wilcockson and R Woolley.

University of Birmingham, Birmingham

CE Clarke (Chief Investigator, Neurologist).

University of East Anglia, Norwich

CM Sackley (PT Lead).

University of Nottingham, Nottingham

MF Walker (OT Lead).

University of Southampton, Southampton

G Yao (Health Economics).

Aberdeen Royal Infirmary, Aberdeen (5)

S Armour, C Counsell,* C Harris, C Knight, V Leslie and M Ord.

Central Middlesex Hospital, London (24)

R Bharmal, N Idris, A Lacey, S Molloy,* C Mummery, M Patel, C Sequeira, G Sharma and E White.

City Hospital, Birmingham (38)

A Billingham, K Blachford, C Clarke,* C Coley, T Doxsey, C Holdsworth, C Kanakaratna, F Kinney, D Nicholl, S Purkis, F Siddiqui and C Street.

Cumberland Infirmary, Carlisle (13)

B Bishop, J Bowyer, J George,* A Hampson and V Marshall.

Darlington Memorial Hospital, Darlington (21)

L Alderton, S Ayirookuzhi, S Carney, P Carr, L Cochrane, M Corr, L Curran, C Deacon, S Hilton, A Martin, M Omole, R Prescott,* A Rose and H Watson.

Dorset County Hospital, Dorchester (21)

M Baker, S Breakspear, B Burgess, S Caddy, S Carr, S Chaplin, C Coleman, R Gregory,* A Jones, L O’Shea, H Read, S Richardson and L Villanueva.

Eryri Hospital, Caernarfon (9)

J Hindle, P Ohri,* A Owen, C Pritchard, E Roberts and F Williams.

Fairfield General Hospital, Bury (24)

A Ansari, K Birtwell, J Brooke, L Craven, A Drogan, E Hill, E Johnson, E Oughton, J Raw,* C Thistlewaite and T Wijethunge.

Gloucestershire Royal Hospital, Gloucester (27)

K Bird, P Brown, F Clayton-Smith, F Davis, H Dix, P Fletcher,* E Folkes, V Hardwick, K Harrison, K Keene, P Medcalf, P Morrish, M Silva, G Thistlewood and H Wilson.

Lincolnshire Hospitals, Lincoln and Grantham (52)

D Boyer, L Crisp, A Kirjazovas, H Lister, A Macedonska, E Munyonga, R Norton, C Rees, B Sharrack, J Sharma,* K Shelbourn, S Strickland and E Ward.

Harrogate District Hospital, Harrogate (11)

P Bagot, G Burton, A Gillespie, E Jackson, S Smith, G Wihl,* R Worton and J Young.

Hereford County Hospital, Hereford (4)

M Cottrell, J Dalziel, C Evans, D Kent, P Matheson and E Wales.*

Hull Royal Infirmary, Hull (5)

J Cook, J Curran, A Ming* and D Parker.

Leicester General Hospital, Leicester (9)

D Bovington, C Brownson, K Castle, N Clague, S Forrest, N Lavin, J Lindsay, N Lo,* J Lokat, R MacDonald, K MacSwiney, S Seaman and J Taylor.

Macclesfield District General Hospital, Macclesfield (25)

K Bullivant, A Crosby, R Graba, E Oughton, S Raybould, D Rowarth, H Rooney, M Silverdale,* C Vandor, H Vanek and T Wright.

Mount Gould Hospital, Plymouth (19)

H Brookes, S Edwards, B Dingle, M Holme, K Jones, G Kendall, S Mahadik,* F Murphy, K Stocker, M-J Trimmer and M Visick.

Musgrove Park Hospital, Taunton (31)

R Chorley, S Cooper,* A Dawton, C Henley, J Homan, D Sharratt and J Vassalli.

Newmarket Community Hospital, Newmarket (8)

G Calderon, L Canovas, M Glass, S Hooley, W Houghton, A Jackson, G Lennox,* A South and T Ward.

Norfolk & Norwich University Hospital, Norwich (30)

A Clark, P Crosby, C Herrington, A Hursey, C Garrett, K Goddard, L Reynolds, J Taylor, J West and P Worth.*

North Devon District Hospital, Barnstaple (10)

G Harper,* S Hilsdon, T Harrower, S Pike and N Vernon.

Peterborough City Hospital, Peterborough (6)

G Calderon, L Canovas, E Davies, C Farrar, S Guptha,* A Jackson, C Noble and J Sheldrake.

Poole General Hospital, Poole (15)

L Chohra, C Cooper, M Goddard, R Gregory,* G King and V Stone.

Princess of Wales Hospital, Bridgend (20)

L Ebenezer, R Gdesis, C Muller, S Raha,* P Sloan, S Thomson and R Turner.

Queen Alexandra Hospital, Portsmouth (23)

M Chawner, C Delves, C Edwards, C Francis, W Gibb, Z Hemsley,* J Hewitt, E Hoysted, K Lapicki, T Jepp, S Marsh, A McBride, E McNaughton, S Pearce, C Rayner, C Saunders, A Stephenson, B Uwe, J Walker and L Wimshurst.

Royal Blackburn Hospital, Blackburn (24)

J Birt, S Crane, M Hare, C Kenyon, L McToal, P Tidswell,* N Verstraelen and K Ward.

Royal Bournemouth General Hospital, Bournemouth (40)

K Amar,* S Atkins, C Cooper, L du Preez, G Hodges, G King, K Kuhr, T Senyard, C Thompson and B Utting.

Royal Devon & Exeter Hospital, Exeter (65)

C Askham, B Bailey, W Blour, L Butler, F Chanton, C Davies, R Elliott, G Fenwick, D Gladman, K Gormley, F Havlin, T Harrower, J Holman, S Irvine, R James, A-M Jones, D Kendrick, R Lane, T Malone,* V Matthews, T Morris, L Morley, V Pearce, A Potter, K Priestner, A Quthue-Jones, F Robotham, R Sheridan, C Smith, K Smith, A Souster, V Wilkins and A Woodger.

Royal Hampshire County Hospital, Winchester (9)

C Barlow, E Carroll, E Ghazaros, C Gordon,* T McElwaine and H Slater.

Royal Preston Hospital, Preston (24)

J Bimson, J Birt, S Cornall, M Hare, T Majeed,* J Pearson, D Stephenson, R Turner, N Verstraelen and K Ward.

St Helens and Knowsley Hospitals, St Helen (25)

J Abrams,* C Andrew, S Ashley, D Dufay, D Gandecha, A Howman, L Molloy, E Oughton, H Rayner and N Smith.

Salisbury District Hospital, Salisbury (3)

K Grainger, J Lee and J Marigold.*

Southampton General Hospital, Southampton (26)

V Agarwal, L Ashdown, C Carden-Noad, C Dean, C Edwards, G Howard and H Roberts.*

Torbay District General Hospital, Torbay (10)

L Halfhide, A Hall, G Kendall,* P McConkey, P Mercer and K Roberts.

Walton Centre for Neurology & Neurosurgery, Liverpool (41)

S Burns, D Davies, A Deaves, N Hallissey, L Hughes, H McGuinn, AP Moore,* I O’Brien, H O’Heary, N Porter, M Steiger, D Watling, L Webb and L Wyatt.

Weston General Hospital, Weston-super-Mare (18)

S Barber, S Bedford, H Dymond, P Easton, F Henchie, K Powell, R Roberts,* G Saunders, D Simmons and S Whitford.

William Harvey Hospital, Ashford (11)

J Hawkins, A Heller, L Hills, M Jenkinson, M McHenry, N Munro, M Sakel, M Samuel,* N Scoble, K Turner, R Vahid and A Vincent.

Yeovil District Hospital, Yeovil (17)

K Baker, H Brunt, C Buckley, M Jones, K Randall, C Redman, R Rowland-Axe, R Sophia* and R Tonkin.

Data Monitoring Committee

Professor G Kwakkel (Chairperson), Professor J Gladman, Dr N Bajaj and Dr L Hiller.

Trial Steering Committee

Professor D Burn (Chairperson), Dr K Breen, Mr H Bridge, Professor H Dawes, Dr D MacMahon, Dr P Ohri, Dr H Roberts and Mrs E Wolstenholme.

Therapy experts group

A Aragon, A Birleson, P Chapman, V Goodwin, A Keene, V Kelly, F Lindop, E Morgan, B Ramaswamy and L Rochester.

Service users group

H Bridge, R Coelho, K Gordon, S Herron-Marx, J Morgan, D Muir Wood, R Norton, R Patel, A Peet, C Sanders, S Shah, J Taylor, G Thorpe and EWK Young,