Multiple sclerosis. National Clinical Guideline Centre. Management of multiple sclerosis in primary and secondary care. Clinical Guideline 186

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1 National Clinical Guideline Centre. Multiple sclerosis Management of multiple sclerosis in primary and secondary care Clinical Guideline 186 Appendices H-M October 2014 Final Commissioned by the National Institute for Health and Care Excellence

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3 Contents Disclaimer Healthcare professionals are expected to take NICE clinical guidelines fully into account when exercising their clinical judgement. However, the guidance does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of each patient, in consultation with the patient and/or their guardian or carer. Copyright National Clinical Guideline Centre, 2014 Funding National Institute for Health and Care Excellence National Clinical Guideline Centre, 2014

4 Contents Contents Appendices... 5 Appendix H: Economic evidence tables... 6 Appendix I: Forest plots Appendix J: Excluded clinical studies Appendix K: Excluded economic studies Appendix L: Research recommendations Appendix M: Unit costs National Clinical Guideline Centre,

5 Appendices National Clinical Guideline Centre,

6 Economic evidence tables Appendix H: Economic evidence tables H.1 Coordination of care Table 1: Pozzilli ,123 C. Pozzilli, M. Brunetti, A. M. Amicosante, C. Gasperini, G. Ristori, L. Palmisano, and M. Battaglia. Home based management in multiple sclerosis: results of a randomised controlled trial. J Neurol Neurosurg Psychiatry 73 (3): , Study details Population & interventions Costs Health outcomes Cost effectiveness Economic analysis: CUA (health outcome = QALY). Study analysis was CCA (health outcome = QoL), QALYs were calculated by NCGC. Study design: Within trial analysis (RCT) Pozzilli ,123 Approach to analysis: Analysis of individual level data for SF-36 (using regression to account for baseline differences) and resource use. Unit costs applied. Perspective: Italian third party payer Population: Clinically definite multiple sclerosis Patient characteristics: Start age = 46.7 (Intvn 1); 47 (Intvn 2) M =69% (Intvn 1); 65% (Intvn 2) Intervention 1: Usual care in MS referral centres Intervention 2: Multidisciplinary home-based care (see clinical review Appendix G for more information on costs (mean per patient): Intvn 1: 1,806 Intvn 2: 1,151 Incremental (2-1): -655 (CI NR; p = NR) Currency & cost year: 1999 Euros (presented here as 1999 UK pounds ) Cost components incorporated: Inpatient care; medical outpatient, home care and telephone service (provided by neurologist, urologist and rehabilitation physician); non-medical outpatient, home care and telephone service (provided by QALYs (mean per patient): Intvn 1: Intvn 2: Incremental (2-1): (CI NR; p = NR) ICER (Intvn 2 vs Intvn 1): Intvn 2 dominant (da) CI: NR Probability Intvn 2 cost-effective ( 20K/30K threshold): NR Analysis of uncertainty: Multivariate analysis conducted for costs in order to generate a best/worst case scenario. For the best case scenario an increase of 10% in reimbursement for admissions, a decrease of 10% for home based management costs, and upper limit of 95% CI was applied. For the worst case scenario, a decrease of 10% in reimbursement for admissions, an increase of 10% for home based management costs, and lower limit of 95% CI was applied. NCGC used the best/worst case scenario costs to analyse impact on ICER. Using the best case scenario Intvn 2 remained

7 Economic evidence tables Follow-up: 1 year Treatment effect duration: 1 year Discounting: Costs = n/a ; Outcomes = n/a Data sources interventions) psychologist, social worker, physical therapist and nurses); home care programme for Intvn 2 (including personnel and overheads). dominant. Using the worst case scenario the ICER was 9,015 per QALY, therefore Intvn 2 was cost-effective at the NICE threshold of 20,000 per QALY. Health outcomes: Within trial data on QoL presented as differences between mean changes in SF-36 scores of patients who were allocated to Intvn 1 or 2. See clinical review Appendix G. Baseline SF-36 scores taken from UK study of people with multiple sclerosis. Quality-of-life weights: SF-36 scores collected at baseline and at 12 month follow-up. Cost sources: Resource use: within trial data 123,123. Unit costs from national Italian published sources (third party reimbursement for DRGs and Italian national health service). Comments Source of funding: Fondazione Italiana Sclerosi Multipla, the Instituto Superiore di Santa and Dompe Biotec. Limitations: Cost of pharmaceuticals and aids for daily life activities excluded. SF-36 used as opposed to EQ-5D. Other: The study comparators make it difficult to distinguish if the incremental effects and cost savings observed are a result of the setting (home vs. outpatient) or the multidisciplinary approach. Overall applicability (a) : Partially applicable Overall quality (b) : Minor limitations Abbreviations: CCA = cost-consequence analysis; CI = 95% confidence interval; CUA = cost-utility analysis; da = deterministic analysis; DRGs = diagnosis-related groups; EQ-5D = Euroqol five dimensions (scale: 0.0 [death] to 1.0 [full health]; <0.0 = worse than death); ICER = incremental cost-effectiveness ratio; NR = not reported; pa = probabilistic analysis; QALYs = qualityadjusted life years; QoL = quality of life; SF-36 = 36 item short-form health survey questionnaire (scale: 0 to 100). Converted using 1999 purchasing power parities 114. QALYs calculated by NCGC by mapping SF-36 mean difference in scores to EQ-5D using the Ara and Brazier 2008 algorithm 3,3. NCGC were informed by study authors that baseline SF-36 data for study participants was no longer available. As a substitute, baseline data from a study measuring SF-36 scores in people with multiple sclerosis in the UK 126,126 were used. (a) Directly applicable / Partially applicable / Not applicable (b) Minor limitations /Potentially serious limitations / Very serious limitations

8 Economic evidence tables H.2 Acute relapse with steroids Table 2: Chataway ,23 Chataway J, Porter B, Riazi A, Heaney D, Watt H, Hobart J et al. Home versus outpatient administration of intravenous steroids for multiple-sclerosis relapses: a randomised controlled trial. Lancet Neurology. United Kingdom 2006; 5(7): Study details Population & interventions Costs Health outcomes Cost effectiveness Economic analysis: CCA Study design: Within-RCT analysis Approach to analysis: Analysis of individual level resource use where possible, with unit costs applied. Perspective: UK NHS Time horizon: 6 weeks Treatment effect duration: 3 days Population: Patients older than 18 yrs, had clinically definite MS and had a sustained definite relapse of more than 24 hrs but less than 4 wks in duration. N=138 M =22% Median age: 40.4 Intervention 1: Outpatients administration of 1g methylprednisolone over 1 hr, daily, for 3 days in a dedicated suite N=69 Intervention 2: Home administration of intravenous methylprednisolone. Patients left hospital with a 3-day supply. N=69 M=26% costs (mean per patient): Intvn 1: 499 Intvn 2: 354 Incremental (2-1): 145 Currency & cost year: 2006 UK pounds Cost components incorporated: Direct medical costs (salaries, equipment, drugs, hospital overheads and investigations). QALYs (mean per patient): Intvn 1: NR Intvn 2: NR Other outcomes See Appendix G in the clinical review section for full list of outcomes. ICER (Intvn 2 vs Intvn 1): NA Home administration costs less than hospital administration. The results suggest there is no significant difference in effect of treatment setting on disease impact and health status. Analysis of uncertainty: Univariate sensitivity analysis was conducted which showed that if the charge for health at home increased by 51% or more or if NHS salaries were reduced by 50%, it would become cheaper to treat patients in the hospital. When direct non-medical costs (transport, childcare costs) were included, outpatient treatment was even more costly than home treatment ( 560 vs 355; difference 205).

9 Economic evidence tables Discounting: NA Median age: 36.8 Data sources Health outcomes: Within trial analysis; study included in clinical review. Quality-of-life weights: SF-36, obtained directly from patients enrolled in study Cost sources: PSSRU, hospital tariff. Comments Source of funding: Multiple Sclerosis Trust Limitations: Not in line with NICE reference case which states a preference for health effects expressed in terms of QALYs. Overall applicability (a) : Partially applicable Overall quality (b) : Minor limitations Abbreviations: CCA = cost-consequence analysis; ICER = incremental cost-effectiveness ratio; NR = not reported; QALYs = quality-adjusted life years (a) Directly applicable / Partially applicable / Not applicable (b) Minor limitations /Potentially serious limitations / Very serious limitations H.3 Pharmacological treatment H.3.1 Spasticity Table 3: Rushton ,128 Rushton DN, Lloyd AC, Anderson PM. Cost-effectiveness comparison of tizanidine and baclofen in the management of spasticity Pharmacoeconomics. 20(12): Study details Population & interventions Costs Health outcomes Cost effectiveness Economic analysis: CEA, health outcome = successfully treated days (STD) Study design: Deterministic decision analytic model. Approach to analysis: Decision tree of first, second and third-line management of Population: Patients with spasticity caused by MS or spinal injury whose symptoms have not been resolved by physiotherapy alone Cohort settings: Start age = NR M = NR costs (mean per patient) for comparison 1): Intvn 1: 181,545 Intvn 2: 211,930 Incremental (2-1): 30,385 (CI NR; p = NR) costs (mean per patient) for comparison 2): Intvn 1: 177,486 Intvn 2: 212,459 STDs per patient per year for comparison 1): Intvn 1: 17,289 Intvn 2: 20,192 Incremental (2-1): 2,903 (CI NR; p = NR) STDs per patient per year for comparison 2): Intvn 1: 16,806 ICER (Intvn 2 vs Intvn 1) in comparison 1) per STD gained (da) ICER (Intvn 2 vs Intvn 1) in comparison 2) 8.46 per STD gained (da) Probability Intvn 2 cost-effective ( 20K/30K threshold): NR Analysis of uncertainty: One way sensitivity analysis of effectiveness of tizanidine compared with baclofen, rate of muscle

10 Economic evidence tables spasticity. Outcomes were lack of efficacy; muscle weakness; another adverse event and adequate relief. Perspective: UK NHS Time horizon: one year Treatment effect duration: until discontinuation Discounting: n/a Data sources Intervention 1: Baclofen 40mg/day Intervention 2: Tizanidine 16mg/day Two comparisons: 1) tizanidine vs baclofen as first line therapy. 2) tizanidine vs lower dose baclofen (20mg/day) as second line therapy in patients initially treated with baclofen and who experienced muscle weakness. Incremental (2-1): 34,973 Currency & cost year: 2000 UK pounds Cost components: Daily costs ( ): gen. mgt. of spasticity (2.45), baclofen (0.20), baclofen low dose (0.10), tizanidine (2.99), tizanidine low dose (2.39), third line therapies (6.41). Consultations: LFT (15), GP visit (18), neurologist (84), physio (28) and specialist nurse (13). Intvn 2: 20,938 Incremental (2-1): 4,132 (CI NR; p = NR) weakness, time horizon of analysis, main cost parameters, definition of STDs, and duration of dose-titration process. The key determinants of the results at first line (comparison 1) were: the effectiveness of tizanidine and baclofen, the rate of muscle weakness with tizanidine and baclofen, and the non-drug cost of managing spasticity. The key determinants of the results at second line (comparison 2) were the same as those for first line and in addition, the time horizon of the study and the definition of treatment success used. Health outcomes: STDs (successfully treated days) were calculated for the model using pooled results of eight studies comparing baclofen and tizanidine. All eight studies were included in a review of tizanidine. STD was defined as a day when the patient experienced improvement and when patient reported no adverse event or muscle weakness. STDs were calculated from pooled data as follows: percentage of patients reporting improvement multiplied by percentage of patients reporting no muscle weakness. The results were referred to as number of patients experiencing adequate relief. The study notes The figures for adequate relief were lower than success rates reported in clinical trials as we have assumed that some patients who experience improvement may also experience muscle weakness. Quality-of-life weights: n/a. Cost sources: Resource use based on published survey of patients with spasticity. 122,122 Unit costs form PSSRU, BNF, published and unpublished literature. Comments Source of funding: Elan Pharmaceuticals Ltd (manufacturer of tizanidine). Limitations: Value of health effects not expressed in terms of QALYs. Does not include all relevant health outcomes. Specifically the study focuses on adverse events related to the comparator drug baclofen. There are serious concerns about how the measure of effectiveness for the model is calculated and the impact this might have on introducing bias into the results. Other: Results from each of the eight trials showed no statistically significant differences in effectiveness between baclofen and tizanidine treatment groups regardless of measure of effectiveness used. However, because of the way STDs were calculated, the model resulted in a substantial difference between treatment groups in favour of tizanidine. This is due to several factors. Muscle weakness is an adverse event mainly experienced by patients using baclofen. The model made the assumption that the likelihood of muscle weakness was independent of whether or not a patient s spasticity was perceived to have improved. This assumption had the effect of consistently lowering estimates of effectiveness of baclofen used in the model (STDs) compared to tizanimide and this conflicts with success rates reported in clinical trials. Overall applicability (a) : Partially applicable. Overall quality (b) : Potentially serious limitations. See comments.

11 Economic evidence tables Abbreviations: BNF = British National Formulary; CCA = cost-consequence analysis; CEA = cost-effectiveness analysis; CI = 95% confidence interval; da = deterministic analysis; ICER = incremental cost-effectiveness ratio; LFT=liver function test; n/a not applicable; MS = multiple sclerosis; NR = not reported; pa = probabilistic analysis; PSSRU=Personal and Social Services Research Unit; STD=successfully treated days. (a) Directly applicable / Partially applicable / Not applicable (b) Minor limitations /Potentially serious limitations / Very serious limitations

12 Economic evidence tables Table 4: Lu ,91 Lu L, Pearce H, Roome C, Shearer J, Lang IA, and Stein K. Cost Effectiveness of Oromucosal Cannabis-Based Medicine (Sativex ) for Spasticity in Multiple Sclerosis. Pharmacoeconomics 30 (12): , Study details Population & interventions Costs Health outcomes Cost effectiveness Economic analysis: CUA (health outcome = QALY) Study design: Probabilistic decision analytic model Approach to analysis: Markov model. Health states x 3: responders on treatment, withdrawn from treatment, and dead. Cycle length 4 weeks. Perspective: UK NHS Time horizon: Five years Treatment effect duration: until discontinuation Discounting: Costs = 3.5%; Outcomes = 3.5% Population: The population modelled was adults with moderate to severe spasticity due to MS who did not respond adequately to oral antispasticity medication. Cohort settings: Start age = 50 years M = 40% Intervention 1: Oral anti-spasticity agents alone. Intervention 2: Sativex plus oral antispasticity agents. Sativex dosage: 6.9 spays/day for first cycle; 8.3 sprays/day for cycle 2 onwards. costs (mean cost per patient): Intvn 1: 1,298 Intvn 2: 8,925 Incremental (2-1): 7,627 (CI NR; p = NR) Currency & cost year: 2009 UK pounds Cost components: Cost of Sativex (average 4,207 per year), clinic visits ( 201 for first and 131 for subsequent 6 monthly visits). QALYs (mean per patient): Intvn 1: Intvn 2: Incremental (2-1): (CI NR; p = NR) ICER (Intvn 2 vs Intvn 1): 49,238 per QALY gained (pa) Probability Intvn 2 cost-effective ( 30K threshold): 10.2%. Analysis of uncertainty: Threshold analyses were conducted to identify what changes in costs and effects would be required for the ICER to be below 20,000 per QALY. The analyses found that the cost of Sativex would need to reduce by 61% or the difference in utilities would need to be above 0.23 (difference in the base case was 0.09). A scenario analysis was also conducted. When it was assumed that patients were to gain benefits with 4 sprays per day that are similar to those gained with 8 sprays per day the ICER would be 25,324 per QALY. Finally, a scenario analysis indicated that the ICER would reduce to 23,888 per QALY if 40% of all patients who withdrew from the two interventions received botulinum toxin ( 2 vials per injection) and another 40% received intrathecal baclofen. Data sources Health outcomes: Sativex efficacy data (cycle 1-4) was based on results of the European RCT by Novotna 2011 which is included in the clinical review. 113,113 Quality-oflife weights: Average QALYs gained for the cohort treated with Sativex plus oral medicines and the cohort receiving oral medicines alone were estimated from the EQ- 5D data collected from a clinical trial of Sativex 102,102 ), tariff not stated. Cost sources: Resource use from Novotna 2011 and Sativex SPC. 113,113 Unit costs from Medicines and Healthcare products Regulatory Agency 2011 (Sativex) and NHS reference costs 2009 for NHS (clinic visits).

13 Economic evidence tables Comments Source of funding: National Institute for Health Research (NIHR). Limitations: The study extrapolated effectiveness data from a 16 week trial over 5 years. The model assumed that there were no discontinuations from Sativex after 16 weeks (cycle 5). EQ-5D tariff not stated. Costs and disutilities associated with side-effects of drugs not included in analysis. Other: Study reports the incremental QALYs as and ICER as 49,257, there is an error in their incremental analysis table, the incremental QALY should be and ICER 49,238 per QALY gained. Overall applicability (a) : Directly applicable. Overall quality (b) : Minor limitations. Abbreviations: CEA=cost effectiveness analysis; CI = 95% confidence interval; da = deterministic analysis; HRQoL = health-related quality of life; ICER = incremental cost-effectiveness ratio; MS = multiple sclerosis; NR = not reported; pa = probabilistic analysis; SPC = summary of product characteristics. (a) Directly applicable / Partially applicable / Not applicable (b) Minor limitations /Potentially serious limitations / Very serious limitations

14 Economic evidence tables Table 5: Slof ,138 Slof J and Gras A. Sativex(R) in multiple sclerosis spasticity: a cost-effectiveness model. Expert review of pharmacoeconomics and outcomes research 12 (4): , Study details Population & interventions Costs Health outcomes Cost effectiveness Economic analysis: CUA (health outcome = QALYs) Study design: Deterministic decision analytic model Approach to analysis: Markov model. Health states x7: responders on treatment with mild, moderate and severe MS spasticity, responders discontinuing treatment with mild, moderate and severe MS spasticity and dead. Cycle length = 28 days. Perspective: Spanish and German healthcare system Time horizon: Five years Treatment effect duration: until discontinuation Discounting: Costs = 3.5%; Outcomes = 3.5% Population: The population modelled was individuals with moderate to severe spasticity due to MS who did not respond adequately to other antispasticity medication. Cohort settings: Start age = NR M = NR Intervention 1: SoC treatment described by the Delphi study panel including specialist and physiotherapy visits and the following drug therapy: oral baclofen, intrathecal baclofen, tizanidine, diazepam, gabapentin, dantrolene sodium, botulinum toxin. Intervention 2: Sativex plus SoC (Sativex dosage: 6.9 spays/day for days 1-28; 8.3 sprays/day for days A costs (mean cost per patient): Spain Intvn 1: 32,397 Intvn 2: 29,161 Incremental (2-1): - 3,236 (CI NR; p = NR) Germany Intvn 1: 32,012 Intvn 2: 34,972 Incremental (2-1): 2,960 (CI NR; p = NR) Currency & cost year: 2010 Euros (presented here as 2010 UK pounds ) Cost components incorporated: Drugs, drug administration, surgery, healthcare visits (homecare worker, GP, nurse, physical therapist, occupational therapist, social worker, hospital emergency and routine) and tests (MRI and lab tests). QALYs (mean per patient): Spain Intvn 1: Intvn 2: Incremental (2-1): (CI NR; p = NR) Germany Intvn 1: NR Intvn 2: NR Incremental (2-1): (CI NR; p = NR) ICER (Intvn 2 vs Intvn 1): Spain Intvn 2 dominant (da) CI: NR Probability Intvn 2 cost-effective ( 20K/30K threshold): NR Germany 9,230 per QALY gained (da) CI: NR Probability Intvn 2 cost-effective ( 20K/30K threshold): NR Analysis of uncertainty: One-way sensitivity analysis of all cost and utility parameters (+/- 20%) for both the Spanish and German analyses was undertaken. For both the Spanish and German analyses, ICER was most sensitive to +/-20% change in cost of Sativex. Deviation in ICER remained below 20,000 threshold. Dosing assumptions challenged by assuming a dose 8.3 sprays/day for the duration of the modelled period. This analysis produced an ICER of 2,185 per QALY gained in Spain and 24,082 per QALY gained in Germany. SoC resource utilisation rates from a German retrospective study were used instead of the Delphi study panel generated rates. This analysis resulted in a small deviation of the

15 Economic evidence tables Data sources linear decrease in dose, to 4.2 sprays/day, was assumed after day 112.) ICER, with the ICER increasing to 11,886 per QALY in Germany. Health outcomes: SoC risks (baseline health outcomes) were taken from a Spanish retrospective observational study. Sativex efficacy data (cycle 1-4) was based on results of the European RCT by Novotna 2011 which is included in the clinical review 113,113. Sativex discontinuation rates from cycle 5-56 were from a long-term open label UK study 164,165. Quality-of-life weights: EQ-5D (from patients in Novotna 2011 study), tariff not stated. Cost sources: Resource use for Sativex from Novotna 2011 and a UK MS patient registry study and for SoC from Delphi study panel and German retrospective study (sensitivity analysis). Unit costs from national Spanish and German published sources (2010). Comments Source of funding: SA Almirall (who manufacture Sativex). Limitations: The study extrapolated effectiveness data from a 16 week trial over 5 years. No description of population baseline characteristics used in model provided such as proportion with moderate-to-severe spasticity, age or gender. Baseline health outcomes based on observational data. EQ-5D tariff not stated. QALY per patient for Germany not reported. Resource use for SoC based on Delphi survey. Costs of side-effects of drugs not included in analysis. No probabilistic sensitivity analysis undertaken. Other: None Overall applicability (a) : Partially applicable. Overall quality (b) : Potential serious limitations. See comments. Abbreviations: CI = 95% confidence interval; CUA = cost-utility analysis; da = deterministic analysis; EQ-5D = Euroqol five dimensions (scale: 0.0 [death] to 1.0 [full health]; <0.0 = worse than death); ICER = incremental cost-effectiveness ratio; MS = multiple sclerosis; NR = not reported; QALYs = quality-adjusted life years; RCT = randomised control trial; SoC = standard of care. Converted using 2010 purchasing power parities 114 (a) Directly applicable / Partially applicable / Not applicable (b) Minor limitations / Potentially serious limitations / Very serious limitations H.4 Non pharmacological treatment H.4.1 Fatigue Table 6: Thomas ,154 Sarah Thomas, Peter W. Thomas, Paula Kersten, Rosemary Jones, Colin Green, Alison Nock, Vicky Slingsby, Angela Davies Smith, Roger Baker, Kathleen T. Galvin, and Charles Hillier. A pragmatic parallel arm multi-centre randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based fatigue management programme (FACETS) for people with multiple sclerosis. J Neurol Neurosurg Psychiatry 84 (10): , Study details Population & interventions Costs Health outcomes Cost effectiveness

16 Economic evidence tables Economic analysis: CUA (health outcome = QALY). Study design: Within trial analysis (RCT) Thomas ,154 See clinical review Appendix G. Approach to analysis: Analysis of individual level data for health outcomes, EQ-5D and resource use. Unit costs applied. Perspective: UK NHS Follow-up: 5.5 months (4 months after final session) Treatment effect duration: 5.5 months (4 months after final session) Discounting: Costs = n/a; Outcomes = n/a Population: Clinically definite MS diagnosis; FSS total score >4; ambulant. Patient characteristics: See clinical review Appendix G. Intervention 1: Current local practice Intervention 2: Group based fatigue management programme (FACETS) for 6 weeks and current local practice See clinical review Appendix G for more information. costs (mean per patient): Intvn 1: Intvn 2: Incremental (2-1): (95% CI NR; p = NR) Currency & cost year: 2010 UK pounds Cost components incorporated: FACETS programme ( 453) which includes training, equipment, session facilitators (two band 7 therapists), venue hire, refreshments, printing, administrative support and psychology support. Estimated costs for NHS and social care services (over a 3 month period) assessed at 4 month follow up for both interventions. These costs are estimated using self-reported resource utilisation and published unit costs. Services included GP, nurse and specialist appointments. QALYs (mean per patient): Intvn 1: NR Intvn 2: NR Incremental (2-1): (95% CI to 0.02; p = 0.31) Global Fatigue Severity (GFS) (mean per patient): Intvn 1: NR Intvn 2: NR Incremental (2-1): (CI = to -0.08; p = 0.01) See clinical review Appendix G. for other health outcome results. ICER (Intervention 2 versus Intervention 1), QALY: Intervention 1 dominates intervention 2 (da) ICER (Intervention 2 versus Intervention 1), GFS: 1259 per 1-point improvement in fatigue (da) Analysis of uncertainty: No PSA for ICER. A PSA was undertaken to analyse the impact of uncertainty in the level of staff input for FACETS programme delivery on costs. The mean cost of the intervention was 453 with 95% of estimates in the range of 331 to 585 per participant. Data sources Health outcomes: QALYs derived from EQ-5D (from patients) with maximum QALY equalling 0.46, assuming full health over 24 weeks. See clinical review for details of other health outcomes. 153,154 Quality-of-life weights: Within RCT analysis: EQ-5D (from patients), tariff used not stated. Cost sources: Resource use from within RCT. Source of costs PSSRU, NHS reference costs and local NHS Trust cost data. No intervention costs were included for the current local practice.

17 Economic evidence tables Comments Source of funding: Multiple Sclerosis Society of Great Britain and Northern Ireland. Limitations: Probabilistic sensitivity analysis for ICER not undertaken and follow-up short. Other: Authors suggest that a longer term follow-up may be required for improvements as a result of changes in attitudes and lifestyle (central to the FACETS programme) to impact on quality of life. Overall applicability (a) : Directly applicable Overall quality (b) : Minor limitations Abbreviations: CUA = cost-utility analysis; CI = 95% confidence interval; da = deterministic analysis; EQ-5D = Euroqol 5 dimensions (scale: 0.0 [death] to 1.0 [full health]; FACETS: Fatigue Applying Cognitive behavioural and Energy effectiveness Techniques to lifestyle; FSS = Fatigue Severity Scale; ICER = incremental cost-effectiveness ratio; GFS = global fatigue scale; NR = not reported; PSA = probabilistic sensitivity analysis; PSSRU = Personal and Social Services Research Unit; QALYs = quality-adjusted life years; RCT = randomised control trial. (a) Directly applicable / Partially applicable / Not applicable (b) Minor limitations / Potentially serious limitations / Very serious limitations

18 Economic evidence tables Table 7: Tosh ,158 J. Tosh, S. Dixon, A. Carter, A. Daley, J. Petty, A. Roalfe, B. Sharrack, and J. M. Saxton. Cost effectiveness of a pragmatic exercise intervention (EXIMS) for people with multiple sclerosis: economic evaluation of a randomised controlled trial. Multiple sclerosis (Houndmills, Basingstoke, England), Study details Population & interventions Costs Health outcomes Cost effectiveness Economic analysis: CUA (health outcome = QALY). Study design: Withintrial analysis (RCT) Carter ,21 See clinical review Error! eference source not found.. Approach to analysis: Analysis of individual level data for health outcomes, EQ-5D and resource use. Unit costs applied. Perspective: UK NHS and Personal Social Services Follow-up: 9 months (6 months after final session) Treatment effect duration: 9 months (6 months after final session) Discounting: Costs = n/a; Outcomes = n/a Data sources Population: Clinically definite MS diagnosis; EDSS score ; able to walk a 10-metre distance and physically able to participate in exercise three times per week. Patient characteristics: See clinical review Appendix G. Intervention 1: Current local practice Intervention 2: Programme incorporating aerobic and resistance exercise and CBT (EXIMS) for 12 weeks and current local practice See clinical review Appendix G for more information. costs (mean per patient): Intvn 1: 932 Intvn 2: 1,398 Incremental (2-1): 466 (95% CI -237 to 1,310; p = NR) Currency & cost year: 2011 UK pounds for all costs except for intervention costs which were reported in 2012 UK pounds. Cost components incorporated: EXIMS programme ( 408 per person) which includes staff (physiotherapists and exercise specialists), equipment, and overheads. Estimated costs for NHS and social care services over 9 month period (intervention start to end of follow-up) assessed for both interventions. These costs are estimated using self-reported and health care professional resource utilisation and published unit costs. Services included GP, community health, specialist and social care visits. QALYs (mean per patient): Intvn 1: Intvn 2: Incremental (2-1): (95% CI to 0.115; p = NR) See clinical review Appendix G for other health outcome results. ICER (Intervention 2 versus Intervention 1): 10,137 per QALY gained (pa) Probability intervention 2 cost-effective ( 20K/30K threshold): 75%/78% Analysis of uncertainty: Scenario analyses conducted: Scenario 1 (EDSS score): <4.0 = dominated; 4.0 = 5,092 per QALY gained Scenario 2 (GLTEQ score): >14 = 9,558 per QALY; <14 = 11,470 per QALY gained Scenario 3 (private provision of intervention): 11,938 per QALY gained Scenario 4 (SF-6D utility score): 19,783 per QALY gained In addition a scenario analysis was conducted taking a societal perspective.

19 Economic evidence tables Health outcomes: QALYs calculated using the trapezium rule to estimate the area under the curve. In the base case using EQ-5D (from patients) and in the scenario analysis using SF-6D (extracting SF-36 items from MSQOL-54 instrument and mapping SF-36 to SF-6D). See clinical review for details of other health outcomes (Appendix G). Quality-of-life weights: Within-RCT analysis: EQ-5D (from patients), tariff used not stated. Cost sources: Resource use from within RCT. Source of costs PSSRU, NHS reference costs and retail prices for equipment. No intervention costs were included for the current local practice as this was included in both arms. Comments Source of funding: Supported by Multiple Sclerosis Society in UK. Limitations: Short follow-up. Overall applicability (a) : Directly applicable Overall quality (b) (b): Minor limitations Abbreviations: CBT = cognitive behavioural therapy; CI = 95% confidence interval; CUA = cost-utility analysis; EDSS = Expanded Disability Status Scale; EQ-5D = Euroqol 5 dimensions (scale: 0.0 [death] to 1.0 [full health]; EXIMS = EXercise Intervention for people with MS; GLTEQ = Godin Leisure Time Exercise Questionnaire; ICER = incremental cost-effectiveness ratio; NR = not reported; pa = probabilistic analysis; PSA = probabilistic sensitivity analysis; PSSRU = Personal and Social Services Research Unit; QALYs = quality-adjusted life years; RCT = randomised control trial; SF-6D = Short form 6 dimension. (a) Directly applicable / Partially applicable / Not applicable (b) Minor limitations / Potentially serious limitations / Very serious limitations H.4.2 Mobility Table 8: Wiles ,168 C. M. Wiles, R. G. Newcombe, K. J. Fuller, S. Shaw, J. Furnival-Doran, Pickersgill T P, and A. Morgan. Controlled randomised crossover trial of the effects of physiotherapy on mobility in chronic multiple sclerosis. J.Neurol.Neurosurg.Psychiatry 70(2): , Study details Population & interventions Costs Health outcomes Cost effectiveness Economic analysis: CCA (health outcome = various health outcomes). Study design: Withintrial analysis (RCT) Wiles ,168 Approach to analysis: Analysis of individual level data for health outcomes and resource use. Hospital Population: Definite or probable MS, complaining of difficulties with walking. Patient characteristics: N = 42 age = 47.2 (: NR) M = 64.3% Intervention 1: No therapy Intervention 2: costs (mean per patient): Intvn 1: 0 Intvn 2: 11 Intvn 3: 25 Incremental (2-1): 11 Incremental (3-1): 25 Incremental (3-2): 14 (CI NR; p = NR) Currency & cost year: UK pounds, year NR From clinical review Wiles ,168 Rivermead mobility index (score of 0-15) [higher better]: Incremental (2-1): MD 1.4 (CI:0.62 to 2.14) Incremental (3-1): MD 1.5 (CI:0.73 to 2.26) Incremental (3-2): MD 0.1 (CI:-0.65 to 0.87) Balance time (s) [higher better]: Incremental (2-1): MD 4.82 (CI: 1.57 to 8.07) Incremental (3-1): MD 5.49 (CI: 2.19 to 8.8) Incremental (3-2): MD 0.68 (CI: to 3.99) Walk A (s) [lower better]: ICER for each comparison: n/a Analysis of uncertainty: NR

20 Economic evidence tables costs applied. Perspective: UK NHS Follow-up: 8 weeks Treatment effect duration: 8 weeks Discounting: Costs = n/a; Outcomes = n/a Data sources Outpatient rehabilitation Intervention 3: Home rehabilitation See clinical review Table 11 for more information. Cost components incorporated: Employment cost of physiotherapist and mileage Incremental (2-1): MD -14 (CI: -23 to -5) Incremental (3-1): MD -14 (CI: -23 to -6) Incremental (3-2): MD 0 (CI: -9 to 8) Nine hole peg test(s) [lower better]: Incremental (2-1): MD -18 (CI: -32 to -4) Incremental (3-1): MD -13 (CI: -27 to 1) Incremental (3-2): MD 5 (CI: -9 to 19) Assessor global mobility change score (0-100, 50 no change) [higher better]: Incremental (2-1): MD 19.8 (CI: 14 to 25.7) Incremental (3-1): MD 22.4 (CI: 16.6 to 28.3) Incremental (3-2): MD 2.6 (CI: -3.2 to 8.4) VAS patient mobility (0-100) [higher better]: Incremental (2-1): MD 25.2 (CI:18.3 to 32) Incremental (3-1): MD 24.2 (CI: 17.3 to 31) Incremental (3-2): MD -1.0 (CI: -7.8 to 5.8) Health outcomes: Within trial analysis (RCT) Wiles ,168. Health outcomes are adjusted for patient, period and baseline. Quality-of-life weights: n/a. Cost sources: Resource use from trial (RCT). Source of costs unclear, assumed from hospital financial records. Comments Source of funding: Welsh office for research and development. Limitations: Source of unit costs unclear. Costs and consequences presented separately. No sensitivity analysis conducted. Other: n/a Overall applicability (a) : Partially applicable Overall quality (b) : Very serious limitations Abbreviations: CCA = cost-consequence analysis; CI = 95% confidence interval; ICER = incremental cost-effectiveness ratio; MD = mean difference; NR = not reported; RCT = randomised control trial; s = seconds; VAS = visual analogue scale. (a) Directly applicable / Partially applicable / Not applicable (b) Minor limitations / Potentially serious limitations / Very serious limitations

21 Economic evidence tables H.4.3 Rehab settings Table 9: WILES ,168 C. M. Wiles, R. G. Newcombe, K. J. Fuller, S. Shaw, J. Furnival-Doran, Pickersgill T P, and A. Morgan. Controlled randomised crossover trial of the effects of physiotherapy on mobility in chronic multiple sclerosis. J.Neurol.Neurosurg.Psychiatry 70(2): , Study details Population & interventions Costs Health outcomes Cost effectiveness Economic analysis: CCA (health outcome = various health outcomes). Study design: Withintrial analysis (RCT) Wiles ,168 Approach to analysis: Analysis of individual level data for health outcomes and resource use. Hospital costs applied. Perspective: UK NHS Follow-up: 8 weeks Treatment effect duration: 8 weeks Discounting: Costs = n/a; Outcomes = n/a Population: Definite or probable MS, complaining of difficulties with walking. Patient characteristics: N = 42 age = 47.2 (: NR) M = 64.3% Intervention 1: No therapy Intervention 2: Outpatient rehabilitation Intervention 3: Home rehabilitation See clinical review Appendix G for more information. costs (mean per patient): Intvn 1: 0 Intvn 2: 11 Intvn 3: 25 Incremental (2-1): 11 Incremental (3-1): 25 Incremental (3-2): 14 (CI NR; p = NR) Currency & cost year: UK pounds, year NR Cost components incorporated: Employment cost of physiotherapist and mileage From clinical review Wiles ,168 Rivermead mobility index (score of 0-15) [higher better]: Incremental (2-1): MD 1.4 (CI:0.62 to 2.14) Incremental (3-1): MD 1.5 (CI:0.73 to 2.26) Incremental (3-2): MD 0.1 (CI:-0.65 to 0.87) Balance time (s) [higher better]: Incremental (2-1): MD 4.82 (CI: 1.57 to 8.07) Incremental (3-1): MD 5.49 (CI: 2.19 to 8.8) Incremental (3-2): MD 0.68 (CI: to 3.99) Walk A (s) [lower better]: Incremental (2-1): MD -14 (CI: -23 to -5) Incremental (3-1): MD -14 (CI: -23 to -6) Incremental (3-2): MD 0 (CI: -9 to 8) Nine hole peg test(s) [lower better]: Incremental (2-1): MD -18 (CI: -32 to -4) Incremental (3-1): MD -13 (CI: -27 to 1) Incremental (3-2): MD 5 (CI: -9 to 19) Assessor global mobility change score (0-100, 50 no change) [higher better]: Incremental (2-1): MD 19.8 (CI: 14 to 25.7) Incremental (3-1): MD 22.4 (CI: 16.6 to 28.3) ICER for each comparison: n/a Analysis of uncertainty: NR

22 Economic evidence tables Data sources Incremental (3-2): MD 2.6 (CI: -3.2 to 8.4) VAS patient mobility (0-100) [higher better]: Incremental (2-1): MD 25.2 (CI:18.3 to 32) Incremental (3-1): MD 24.2 (CI: 17.3 to 31) Incremental (3-2): MD -1.0 (CI: -7.8 to 5.8) Health outcomes: Within trial analysis (RCT) Wiles ,168. Health outcomes are adjusted for patient, period and baseline. Quality-of-life weights: n/a. Cost sources: Resource use from trial (RCT). Source of costs unclear, assumed from hospital financial records. Comments Source of funding: Welsh office for research and development. Limitations: Source of unit costs unclear. Costs and consequences presented separately. No sensitivity analysis conducted. Other: n/a Overall applicability (a) : Partially applicable Overall quality (b) : Very serious limitations Abbreviations: CCA = cost-consequence analysis; CI = 95% confidence interval; ICER = incremental cost-effectiveness ratio; MD = mean difference; NR = not reported; RCT = randomised control trial; s = seconds; VAS = visual analogue scale. (a) Directly applicable / Partially applicable / Not applicable (b) Minor limitations / Potentially serious limitations / Very serious limitations

23 Appendix I: Forest plots I.1 Modifiable risk factors Figure 1: Exacerbations at days Figure 2: Exacerbations at 3-6 months Figure 3: Numbers worsening over follow up

24 Forest plots I.2 Acute relapse with steroids I.2.1 Steroid versus placebo Figure 4: Forest plot of comparison: 1 Steroids versus placebo, outcome: 1.2 Positive response to treatment. Miller 1961 Steroids Placebo Risk Ratio Risk Ratio Events Events 4 18 M-H, Fixed, 95% CI 2.25 [0.86, 5.88] M-H, Fixed, 95% CI (95% CI) 22 events 11 Test for overall effect: Z = 1.66 (P = 0.10) [0.86, 5.88] Favours placebo Favours steroids Figure 5: Durelli 1986 Sellebjerg 1998 Forest plot of comparison: 1 Steroids versus placebo, outcome: 1.3 Subjective improvements. Steroids Placebo Risk Ratio Risk Ratio Events Events % 67.8% M-H, Fixed, 95% CI 1.63 [0.99, 2.70] 1.41 [0.98, 2.02] M-H, Fixed, 95% CI (95% CI) events Heterogeneity: Chi² = 0.21, df = 1 (P = 0.64); I² = 0% Test for overall effect: Z = 2.64 (P = 0.008) 1.48 [1.11, 1.98] Favours placebo Favours steroids Figure 6: Rose 1968 Steroids versus placebo, outcome: 1.4 Minimal/no disability. Steroids Placebo Risk Ratio Risk Ratio Events Events 5 65 M-H, Fixed, 95% CI 1.86 [0.67, 5.15] M-H, Fixed, 95% CI (95% CI) 70 events 10 Test for overall effect: Z = 1.19 (P = 0.23) [0.67, 5.15] Favours placebo Favours steroids Figure 7: Rose 1968 Steroids versus placebo, outcome: 1.5 Restricted to bed/wheelchair. Steroids Placebo Risk Ratio Risk Ratio Events 9 70 Events M-H, Fixed, 95% CI 0.49 [0.24, 1.02] M-H, Fixed, 95% CI (95% CI) 70 events 9 Test for overall effect: Z = 1.90 (P = 0.06) [0.24, 1.02] Favours steroids Favours placebo

25 Forest plots Figure 8: Steroids versus placebo, outcome: 1.6 Clinical improvement (EDSS score change of 1.0) (one week to 15 days). Durelli 1986 Milligan 1987 Steroids Placebo Risk Ratio Risk Ratio Events Events % 20.7% M-H, Fixed, 95% CI 2.31 [1.06, 5.01] 5.54 [0.83, 36.93] M-H, Fixed, 95% CI (95% CI) events 20 5 Heterogeneity: Chi² = 0.83, df = 1 (P = 0.36); I² = 0% Test for overall effect: Z = 2.81 (P = 0.005) 2.98 [1.39, 6.38] Favours placebo Favours steroids Figure 9: Steroids versus placebo, outcome: 1.7 Clinical improvement (EDSS score change of 1.0) (four weeks). Milligan 1987 Steroids Placebo Risk Ratio Risk Ratio Events Events 2 8 M-H, Fixed, 95% CI 3.08 [0.89, 10.60] M-H, Fixed, 95% CI (95% CI) 13 events 10 Test for overall effect: Z = 1.78 (P = 0.07) [0.89, 10.60] Favours placebo Favours steroids Figure 10: Steroids versus placebo, outcome: 1.9 Relapse durations (days). Durelli 1986 Steroids Placebo Difference Difference [-19.98, -5.42] (95% CI) 13 Test for overall effect: Z = 3.42 (P = ) [-19.98, -5.42] Favours steroids Favours placebo Figure 11: Steroids versus placebo, outcome: 1.12 Gastrointestinal symptoms. Sellebjerg 1998 Steroids Placebo Risk Ratio Risk Ratio Events Events 2 25 M-H, Fixed, 95% CI 4.81 [1.17, 19.80] M-H, Fixed, 95% CI (95% CI) 26 events 10 Test for overall effect: Z = 2.17 (P = 0.03) [1.17, 19.80] Favours steroids Favours placebo Figure 12: Steroids versus placebo, outcome: 1.13 Dysphoria. Sellebjerg 1998 Steroids Placebo Risk Ratio Risk Ratio Events 6 26 Events 2 25 M-H, Fixed, 95% CI 2.88 [0.64, 12.97] M-H, Fixed, 95% CI (95% CI) 26 events 6 Test for overall effect: Z = 1.38 (P = 0.17) [0.64, 12.97] Favours steroids Favours placebo I.2.2 Oral versus IV steroids

26 Forest plots Figure 13: Proportion of patients with improvement on EDSS after steroid treatment at 4 weeks. Alam 1993 Barnes 1997 Martinelli 2008 Ramo-Tello 2011 Oral Intravenous Odds Ratio Odds Ratio Events Events % 50.7% 6.2% 19.1% M-H, Random, 95% CI 0.50 [0.11, 2.32] 0.66 [0.23, 1.89] 0.12 [0.01, 2.53] 0.95 [0.17, 5.30] M-H, Random, 95% CI (95% CI) events Heterogeneity: Tau² = 0.00; Chi² = 1.44, df = 3 (P = 0.70); I² = 0% Test for overall effect: Z = 1.35 (P = 0.18) 0.60 [0.28, 1.26] Favours intravenous Favours oral Figure 14: Oral versus iv steroids, outcome: 1.4 Change in Ambulation Index at week 1 after treatment with oral vs. intravenous steroids. Oral Intravenous Difference Difference Barnes IV, Random, 95% CI 0.00 [-0.39, 0.39] IV, Random, 95% CI (95% CI) [-0.39, 0.39] Test for overall effect: Z = 0.00 (P = 1.00) Favours intravenous Favours oral Figure 15: Oral versus iv steroids, outcome: 1.5 Change in Ambulation Index at week 4 after treatment with oral vs. intravenous steroids. Oral Intravenous Difference Difference Barnes IV, Random, 95% CI 0.40 [-0.11, 0.91] IV, Random, 95% CI (95% CI) [-0.11, 0.91] Test for overall effect: Z = 1.55 (P = 0.12) Favours intravenous Favours oral Figure 16: Oral versus iv steroids, outcome: 1.6 Relapse rate 6 months after treatment with oral vs. intravenous steroids. Oral Intravenous Difference Difference Barnes IV, Random, 95% CI 0.21 [-0.06, 0.48] IV, Random, 95% CI (95% CI) [-0.06, 0.48] Test for overall effect: Z = 1.52 (P = 0.13) Favours oral Favours intravenous Figure 17: Oral versus iv steroids, outcome: 1.7 Relapse rate at one year after treatment with oral vs. intravenous steroids.

27 Forest plots Barnes 1997 Oral Intravenous Difference Difference IV, Random, 95% CI 0.34 [-0.13, 0.81] IV, Random, 95% CI (95% CI) [-0.13, 0.81] Test for overall effect: Z = 1.43 (P = 0.15) Favours oral Favours intravenous Figure 18: Oral versus iv steroids, outcome: 1.8 Relapse rate at years 1-2 after treatment with oral vs. intravenous steroids. Oral Intravenous Difference Difference Barnes IV, Random, 95% CI 0.21 [-0.16, 0.58] IV, Random, 95% CI (95% CI) [-0.16, 0.58] Test for overall effect: Z = 1.11 (P = 0.27) Favours oral Favours intravenous Figure 19: Oral versus iv steroids, outcome: 1.9 Relapse rate at two years after treatment with oral vs. intravenous steroids. Oral Intravenous Difference Difference Barnes IV, Random, 95% CI 0.28 [-0.08, 0.64] IV, Random, 95% CI (95% CI) [-0.08, 0.64] Test for overall effect: Z = 1.52 (P = 0.13) Favours oral Favours intravenous Figure 20: Oral versus iv steroids, outcome: 1.10 Proportion relapse free at 2 years after treatment with oral vs. intravenous steroids. Oral Intravenous Odds Ratio Odds Ratio Barnes 1997 Events Events M-H, Random, 95% CI 0.77 [0.28, 2.08] M-H, Random, 95% CI (95% CI) [0.28, 2.08] events Test for overall effect: Z = 0.52 (P = 0.60) Favours intravenous Favours oral Figure 21: Oral versus iv steroids, outcome: 1.11 number of days to next relapse after treatment with oral vs. intravenous steroids. Oral Intravenous Difference Difference Barnes IV, Random, 95% CI IV, Random, 95% CI [ , 56.53] (95% CI) [ , 56.53] Test for overall effect: Z = 0.89 (P = 0.37) Favours oral Favours intravenous Figure 22: Oral versus iv steroids, outcome: 1.12 change in EDSS at first relapse within 2 year period after treatment with oral vs. intravenous steroids Oral Intravenous Difference Difference Barnes IV, Random, 95% CI 0.03 [-0.47, 0.53] IV, Random, 95% CI (95% CI) [-0.47, 0.53] Test for overall effect: Z = 0.12 (P = 0.91) Favours oral Favours intravenous Figure 23: Oral versus iv steroids, outcome: 1.13 Proportion hospitalized at week 1 after

28 Forest plots treatment with oral vs. intravenous steroids. Oral Intravenous Odds Ratio Odds Ratio Barnes 1997 Events Events M-H, Random, 95% CI 0.99 [0.37, 2.69] M-H, Random, 95% CI (95% CI) [0.37, 2.69] events Test for overall effect: Z = 0.01 (P = 0.99) Favours oral Favours intravenous Figure 24: Oral versus iv steroids, outcome: 1.14 Proportion hospitalized at week 4 after treatment with oral vs. intravenous steroids. Oral Intravenous Odds Ratio Odds Ratio Barnes 1997 Events 2 42 Events 1 38 M-H, Random, 95% CI 1.85 [0.16, 21.26] M-H, Random, 95% CI (95% CI) [0.16, 21.26] events 2 1 Test for overall effect: Z = 0.49 (P = 0.62) Favours oral Favours intravenous Figure 25: Oral versus iv steroids, outcome: 1.15 Proportion with rash. Oral Intravenous Odds Ratio Odds Ratio Martinelli 2008 Ramo-Tello 2011 Events Events % 76.6% M-H, Random, 95% CI 0.30 [0.03, 3.15] 0.95 [0.26, 3.48] M-H, Random, 95% CI (95% CI) events 7 9 Heterogeneity: Tau² = 0.00; Chi² = 0.71, df = 1 (P = 0.40); I² = 0% Test for overall effect: Z = 0.56 (P = 0.58) 0.72 [0.23, 2.26] Favours oral Favours iv Figure 26: Oral versus iv steroids, outcome: 1.16 Proportion with mood disturbance. Oral Intravenous Odds Ratio Odds Ratio Ramo-Tello 2011 Events Events 7 24 M-H, Random, 95% CI 2.87 [0.87, 9.45] M-H, Random, 95% CI (95% CI) [0.87, 9.45] events 13 7 Test for overall effect: Z = 1.73 (P = 0.08) Favours oral Favours intravenous I.2.3 Outpatients versus home Figure 27: Outpatients versus home, outcome: 3.1 MSIS-29 physical impact. Figure 28: Outpatients versus home, outcome: 3.2 MSIS-29 psychological impact.

29 Forest plots Figure 29: Outpatients versus home, outcome: 3.3 MSWS-12 walking score. Figure 30: Outpatients versus home, outcome: 3.4 SF-36 role emotional. Outpatients Home Difference Difference Chattaway [-7.69, 26.29] (95% CI) [-7.69, 26.29] Test for overall effect: Z = 1.07 (P = 0.28) Favours outpatients Favours home Figure 31: Outpatients versus home, outcome: 3.5 SF-36 role physical. Outpatients Home Difference Difference Chattaway [-2.67, 22.07] (95% CI) [-2.67, 22.07] Test for overall effect: Z = 1.54 (P = 0.12) Favours outpatients Favours home Figure 32: Outpatients versus home, outcome: 3.6 SF-36 pain. Outpatients Home Difference Difference Chattaway [-5.19, 11.99] (95% CI) [-5.19, 11.99] Test for overall effect: Z = 0.78 (P = 0.44) Favours outpatients Favours home Figure 33: Outpatients versus home, outcome: 3.7 SF-36 energy and vitality. Outpatients Home Difference Difference Chattaway [-5.31, 7.31] (95% CI) [-5.31, 7.31] Test for overall effect: Z = 0.31 (P = 0.76) Favours outpatients Favours home Figure 34: Outpatients versus home, outcome: 3.9 SF-36 general health perceptions.