TITRATE (Treatment Intensities and Targets in Rheumatoid Arthritis Therapy)

Transcription

1 A PRAGMATIC RANDOMISED CONTROLLED OPEN TRIAL OF THE EFFECT OF INTENSIVE MANAGEMENT (IM) COMPARED WITH STANDARD CARE (SC) ON REMISSION RATES AT 12 MONTHS IN RHEUMATOID ARTHRITIS PATIENTS WITH INTERMEDIATE DISEASE ACTIVITY TITRATE (Treatment Intensities and Targets in Rheumatoid Arthritis Therapy) Trial Registration ISRCTN: ISRCTN REC Number: 13/LO/1308 Trial Sponsors Co-sponsor Name: King s College London Address: Strand, London, WC2R 2LS. Contact: Keith Brennan Telephone: [email protected] Co-sponsor Name: Address: King s College Hospital NHS Foundation Trust R&D Department, First Floor, Jennie Lee House, King's College Hospital NHS Foundation Trust, 34 Love Walk, Denmark Hill, London SE5 5AD. Zoe Harris Contact: Telephone: [email protected] Chief Investigator Name: Professor David L. Scott Role: Professor of Clinical Rheumatology Address: Academic Department of Rheumatology, King s College London, Weston Education Centre, Cutcombe Road, Denmark Hill, London SE5 9RJ. Telephone: Fax: [email protected] Co-Investigators and Co-Applicants Name: Dr James Galloway Role: Consultant Rheumatologist Address: Academic Department of Rheumatology, King s College London, Weston Education Centre, Cutcombe Road, Denmark Hill, London SE5 9RJ. Telephone: Fax: [email protected] Page 1 of 36

2 Name: Dr Nicola Gullick Role: Consultant Rheumatologist Address: Rheumatology Department, King s College Hospital, Denmark Hill, London SE5 9RS. Telephone: Fax: [email protected] Name: Role: Address: Dr Gabrielle Kingsley Co-applicant and Consultant Rheumatologist Academic Department of Rheumatology, King s College London, Weston Education Centre, Cutcombe Road, Denmark Hill, London SE5 9RJ. Telephone: [email protected] Name: Professor Allan Wailoo Role: Co-applicant and Senior Health Economist Address: University of Sheffield Telephone: Fax: (Public) [email protected] Name: Mr Jonathan Tosh Role: Co-applicant and Health Economist Address: University of Sheffield Telephone: Fax: (Public) [email protected] Name: Ms Carol Simpson Role: Co-applicant and Patient representative Address: Not relevant Telephone: [email protected] Name: Role: Address: Professor Trudie Chalder Co-applicant and Professor of Cognitive Behavioural Psychotherapy Psychological Medicine, Institute of Psychiatry, King s College London, Weston Education Centre, Cutcombe Road, Denmark Hill, London SE5 9RJ. Telephone: [email protected] Name: Role: Address: Dr Claire Henderson Co-applicant and Consultant Psychiatrist Health Service and Population Research Department, Institute of Psychiatry, King s College London, De Crespigny Park, London SE5 8AF. Telephone: [email protected] Name: Role: Address: Ms Deborah Johnson Co-applicant and Specialist Nurse Lewisham Healthcare NHS Trust, University Hospital Lewisham, Lewisham High Street, London SE13 6LH. Telephone: (ext 8148) [email protected] Page 2 of 36

3 Name: Role: Address: Dr Heidi Lempp Co-applicant and Medical Sociologist Academic Department of Rheumatology, King s College London, Weston Education Centre, Cutcombe Road, Denmark Hill, London SE5 9RJ. Telephone: [email protected] Name: Role: Dr Ruth Williams Co-applicant, General Practitioner and Lewisham Primary Care Trust MSK Lead. Wells Park Practice, 1 Wells Park Road, London SE26 6JQ. Address: Telephone: [email protected] Name: Role: Address: Mrs Ailsa Bosworth Co-applicant and Chief Executive of National Rheumatoid Arthritis Society National Rheumatoid Arthritis Society, Unit B, Westacott Business Centre, Westacott Way, Littlewick Green, Maidenhead, Berkshire SL6 6RT Telephone: [email protected] Name: Dr Brian Tom Role: Senior Statistician Address: MRC Biostatistics Unit, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge CB2 0SR Telephone: Fax: [email protected] Trial statistician Name: Fowzia Ibrahim Role: Trial Statistician Address: Academic Department of Rheumatology, King s College London, Weston Education Centre, Cutcombe Road, Denmark Hill, London SE5 9RJ. Telephone: Fax: [email protected] Trial Coordinating Team Address: Clinical Trials Group, Academic Department of Rheumatology, King s College London, Weston Education Centre, Cutcombe Road, Denmark Hill, London SE5 9RJ. Telephone: Fax: [email protected] For details of recruiting study sites, see TITRATE website: research/trials/titrate/index.aspx Page 3 of 36

4 1. Study Synopsis Title of clinical trial Protocol Short Title/Acronym Study Phase if not mentioned in title Sponsor name Chief Investigator REC number Medical condition or disease under investigation Purpose of clinical trial Primary objective Secondary objectives A pragmatic randomised controlled open trial of the effect of intensive management (IM) compared with standard care (SC) on remission rates at 12 months in rheumatoid arthritis patients with intermediate disease activity. TITRATE: Treatment Intensities and Targets in Rheumatoid Arthritis Therapy Phase IV King s College London (lead) and King s College Hospital NHS Foundation Trust Professor David L Scott 13/LO/1308 Rheumatoid Arthritis (intermediate disease activity) To compare intensive management with standard care in RA patients with intermediate disease activity. To improve outcomes (defined primarily through achieving remission at 12 months) for RA patients with intermediate disease activity using intensive management versus standard care. To reduce disability, enhance quality of life, and show that intensive management is acceptable to RA patients with intermediate disease activity. To estimate the cost-effectiveness of intensive management compared to standard care. Trial Design A pragmatic, randomised, open-label, two-arm, parallel group, multicentre trial. Endpoints Number of patients fulfilling the definition of remission as measured by DAS28-ESR (remission defined as DAS28-ESR<2.6) at 12 months. Sample Size 398 Summary of eligibility criteria Inclusion criteria: Participants must be aged over 18 years; have had a diagnosis of rheumatoid arthritis for 6 months-10 years; have intermediate disease activity (DAS28-ESR with at least 3 active joints); and have received at least one DMARD for a period of six months or more. Exclusion criteria: Participants who have failed 5 DMARDS or have received biologics; have irreversible disability from extensive joint damage; have major comorbidities (e.g., heart failure); are pregnant, breast-feeding or at risk of conceiving; are unable or unwilling to give informed consent; are currently or have recently participated in another interventional trial; or are currently in an early RA pathway. Page 4 of 36

5 Intervention Intensive Management will involve monthly clinical reviews which will allow immediate adjustments of patients management in response to their clinical status. Part of the management will be the optimal intensive use of standard drug treatments. These will all be given within their licensed indication, at licensed doses and routes of administration. Comparator Maximum duration of treatment of a subject Version and date of protocol amendments Intensive management will also involve supportive non-drug interventions which will be individualised to meet patients specific needs. These non-drug approaches will be combined in a treatment support programme. They will span psychoeducation, goalsetting and skills teaching to address identified problem areas, such as pain, fatigue and low physical activity, and will be outlined in a treatment support manual. Standard care, which consists of at least one routine clinical review. 12 months Version 1.0, 26/07/2013 Version 2.0, 18/10/2013 Page 5 of 36

6 2. Glossary of Terms ACR BIPQ BMQ BSR CRP CSRI DAS DAS28 DAS28-CRP DAS28-ESR DMARD DMEC ecrf EDC EQ-5D-5L ESR GAD-7 HAQ HES IM IQR Kg MARS Mg MHRA NHS NICE PHQ-9 RA RCT REC SD TNFi VAS American College of Rheumatology Brief Illness Perceptions Questionnaire Beliefs about Medicines Questionnaire British Society For Rheumatology C-Reactive Protein Client Service Receipt Inventory Disease Activity Score Disease Activity Score for 28 Joints Disease Activity Score for 28 Joints based on C-Reactive Protein Disease Activity Score for 28 Joints based on Erythrocyte Sedimentation Rate Disease Modifying Anti-Rheumatic Drug Data Monitoring And Ethics Committee Electronic Case Report Form Electronic Data Capture EuroQol 5 Dimension (5 levels) Erythrocyte Sedimentation Rate Generalized Anxiety Disorder-7 Health Assessment Questionnaire Hospital Episode Statistics Intra-Muscular Inter-Quartile Range Kilogram Medication Adherence Rating Scale Milligram Medicines and Healthcare Products Regulatory Agency National Health Service National Institute for Health and Clinical Excellence Patient Health Questionnaire-9 Rheumatoid Arthritis Randomised Controlled Trial Research Ethics Committee Standard Deviation Tumour Necrosis Factor Inhibitor Visual Analogue Scale Page 6 of 36

7 3. Contents 1. Study Synopsis Glossary of Terms Contents Background and Rationale Rheumatoid Arthritis Importance for the NHS Current Management of RA Treating-To-Target and Remission Guidelines Disease Activity Levels and Treatment Intensity Current Management of Intermediate Activity RA Patients Rationale for TITRATE Trial Trial Objectives and Design Trial Objectives Primary Endpoint Secondary Endpoints Trial Design Standard care Intensive management Trial Flowchart and Summary Flowchart Summary of Milestone Assessments (all patients in trial) Summary of Visits for Intensive Management Intervention (patients allocated to Intensive Management arm only) Interventions Drug Treatment Disease Modifying Anti-Rheumatic Drugs (DMARDs) Steroids Biologics Analgesics Dosing Regimens Drug Risks Other Treatment Treatment Support Programme Delivering Interventions Selection and Withdrawal of Subjects Inclusion Criteria Exclusion Criteria Selection of Participants Randomisation Procedure Withdrawal of Subjects Expected Duration of Trial Trial Procedures By visit Screening Baseline visit (day 0) First intermediate monthly visit (Intensive management arm only) Subsequent intermediate monthly visits (Intensive management arm only) Midpoint (six month) assessment visit (week 26, day 182) Page 7 of 36

8 Final (12 month) assessment visit (week 52, day 364) / Withdrawal Laboratory Tests Assessment of Efficacy Primary Efficacy Parameter Secondary Efficacy Parameters Assessment of Safety Specification, Timing and Recording of Safety Parameters Recording and Reporting Adverse Events Definitions Reporting responsibilities Procedures for Recording and Reporting Adverse Events Treatment Stopping Rules Statistics Sample Size Randomisation Analysis Cost Utility Analysis Trial Steering Committee Data Monitoring Committee Direct Access to Source Data and Documents Ethics and Regulatory Approvals Quality Assurance Data Handling Data Management Publication Policy Insurance / Indemnity Financial Aspects References Signatures Page 8 of 36

9 4. Background and Rationale 4.1. Rheumatoid Arthritis Rheumatoid arthritis (RA) is an immunologically-driven progressive long-term condition characterised by persistent synovitis, systemic inflammation and autoantibodies, including rheumatoid factor and anti-cyclic citrullinated peptide antibody [1]. Ongoing joint inflammation damages cartilage, bone and tendons; systemic inflammation causes extraarticular complications like vasculitis and lung disease. Uncontrolled active RA therefore leads to disability, decreased quality of life and increased co-morbidity, notably cardiovascular disease. The end result is loss of work, major medical and social costs and high morbidity and mortality [2,3]. In industrialised countries, RA affects 0.5-1% of adults [4]. It mainly affects women and older adults. There are 5-50 per 100,000 new cases annually [5]; the variation in incidence reflects differences between populations including environmental risks. 50% of RA risk is genetic [6] and smoking is the key environmental risk [7] Importance for the NHS In 2009, the National Audit Office estimated 580,000 English adults had RA with 26,000 new diagnoses each year [8]. RA management dominates specialist rheumatology services. Inflammatory arthritis, mainly RA, constitutes 10-20% of new referrals and 40-60% of followup visits. English Hospital Episode Statistics (HES) data (2009/10) showed 1,200,000 rheumatology outpatient follow-ups, about 600,000 for RA (1.3% NHS outpatient follow-ups) [9]. RA also has a major and increasing impact on primary care in providing support for the person with RA and their family, lifestyle advice (e.g., smoking cessation), disease and drug monitoring, management of co-morbidities, vaccination and first-line management of disease flares. The financial impact of RA is substantial for the NHS and the UK as a whole. The National Audit Office estimated direct NHS costs at 560M/year whilst work-related disability cost an additional 1,800M/year [8]. Most costs are due to patients with high disability levels [10]. Early intensive treatment targeted at remission has the potential to reduce future disability and hence decrease costs. Conversely, despite the UK s conservative approach, biologic costs, already in excess of 300M per year, are still rising rapidly [11], mainly due to longterm prescribing for those with intermediate disease activity. The long-term aim of early treatment is to maintain the beneficial effect of intensive therapy (with biologics where needed) on disability and quality of life but to enhance their cost effectiveness. In the fullness of time the UK RA treatment paradigm needs to change so that patients receive early shortterm high intensity treatment resulting in remission followed by treatment tapering to a maintenance regime Current Management of RA RA requires a multi-disciplinary team of rheumatologists, specialist nurses, therapists and others to provide education, particularly on self-management skills, medication, psychological support, exercise and joint protection [12]. Surgical intervention may be needed for joint failure. In terms of medication, symptom reduction was historically crucial [13] but emphasis has moved to early prevention of disease progression using disease-modifying anti-rheumatic drugs (DMARDs) which reduce synovitis, systemic inflammation and disability. Methotrexate is the dominant DMARD; others include sulfasalazine and leflunomide [14]. The current recommended therapy for active RA, which was developed by the National Institute for Health and Clinical Excellence (NICE) in 2009, is to maximise DMARD effects by using them in combination. However, DMARD use is often limited by serious adverse events [12]. Page 9 of 36

10 Steroids (glucocorticoids) can be used short-term to reduce joint inflammation [15]. They can also be used as part of DMARD combination regimes to reduce erosions and to treat systemic disease. Long-term use causes unacceptable toxicity [16]. Biological agents, given when RA is not controlled by DMARDs, have revolutionised RA care. These agents tumour necrosis factor inhibitors (TNFi), rituximab, abatacept and tocilizumab though highly effective [17] are usually given with methotrexate or other DMARDs to increase efficacy and reduce blocking antibodies [18].Their main risk is infection [19]. Their use is limited by cost - about 10,000/patient/year [20]. Although they have substantially improved RA outcome, they do not cure it Treating-To-Target and Remission Recent work has shown outcomes can also be improved by a strategy of treating patients to pre-defined targets [21-23]; there is growing recognition that the appropriate target is remission. A 2010 British Medical Journal editorial recommended remission should be a UK quality standard when treating RA [24]. The importance of achieving remission is further highlighted by the personal stories of two patient applicants, published in the BMJ [25,26], which graphically highlight the disadvantages of treatment which is too little and too late Guidelines The 2009 guidance from the National Institute for Health and Clinical Excellence (NICE) outlines optimal management of active RA for the UK [27]; biologics also have specific NICE Health Technology Appraisals [28]. Though guidance from the USA and continental Europe also emphasises intensive early management for active RA, the relative emphasis on DMARD combinations and biologics differs [29,30]. All guidelines recognise that one key unresolved question is the best management of patients with "intermediate disease activity" who now constitute the majority of patients in practice Disease Activity Levels and Treatment Intensity RA patients are sub-divided by their disease activity levels. This is currently undertaken on the basis of the Disease Activity Score for 28 joints (DAS28), which is a composite measure including tender and swollen joint counts (based on 28 joints), the erythrocyte sedimentation rate (ESR) and patient global assessments on a 100mm visual analogue scale (VAS) [31]. DAS28 scores divide patients with established RA into four categories. These are as follows: 5.10 or more active RA patients: they are known to need intensive treatment with DMARDs or biologics intermediate RA patients: there is no agreed treatment plan for these patients other than continuing on their current therapy 2.61 to 3.20 low disease activity RA patients: they need no changes in treatment, except for toxicity, but there is no optimal control of their disease 2.60 or less RA patients in remission: they have achieved the therapeutic goal in RA. The main group of RA patients currently attending UK rheumatology clinics are patients with intermediate disease activity in whom there is no evidence based treatment approach to follow Current Management of Intermediate Activity RA Patients The NICE 2009 guidelines provide some general recommendations on the current management of the majority of patients with intermediate disease. These recommendations can be summarised as follows: Maintain suppressive treatment with DMARDs and steroids Maintain symptomatic therapy (analgesics/non-steroidal anti-inflammatory drugs) Annual specialist reviews Page 10 of 36

11 Urgent specialist review and treatment modification for flares (DAS28 over 5.1) or clinically significant adverse events. There has been discussion about the relative merits of giving treatments such as biologics to patients with intermediate disease activity, but no nationally agreed protocols exist. The absence of any agreed treatment protocols for patients with intermediate disease activity is a major challenge in defining the most appropriate way to treat the majority of RA patients attending specialist clinics in the UK Rationale for TITRATE Trial We have been commissioned to undertake a programme of research, supported by the National Institute for Health Research, that will extend the evidence base to resolve these critical questions, considering both patients and specialists perspectives. The TITRATE trial is the centrepiece of this research. The NICE guidance identified many unresolved questions around self-management, drug treatment and non-drug treatment. Three of the most crucial issues were: How should patients with intermediate disease activity be managed and will they benefit from receiving more intensive treatment? What role can self-management play and how can patients be supported in this? Will enhancing remission rates reduce ultimate disability? Original research on pathogenesis has led to major innovations, notably biologics. Of particular relevance to our programme is the emerging evidence that RA is not a single disease, but represents a final common pathway for a range of pathological processes [32]. This suggests that, rather than a single cure, individualised bespoke management strategies may be needed. Key underpinning research for our programme and the TITRATE trial is evidence about effective treatments, knowledge about disease outcomes, and the recognition that national guidance can improve the quality of care. DMARD mono- or combination therapy and biologics are all effective in active RA by reducing pain and joint inflammation, improving function and quality of life and limiting erosive damage [33,34]. There is uncertainty about the relative benefits and costs of treatments notably combination DMARDs compared to biologics [35]. We have recently completed the HTA-funded TACIT trial (Tumour-Necrosis- Factor Inhibitors Against Combination Intensive Therapy with conventional DMARDs in established RA) and this trial, the results of which will be presented to the British Society for Rheumatology 2013 Annual General Meeting [36], have contributed to treatment choice in the TITRATE trial. TACIT enrolled patients with active RA (with high disease activity scores) who had failed to respond to methotrexate and another DMARD. These patients would currently receive TNFis. TACIT showed that intensive treatment using a combination DMARD strategy achieved equivalent results to a treatment strategy based on TNFis and that the DMARD strategy was substantially more cost-effective than using TNFis, provided patients who failed to respond to combination DMARDs could subsequently start TNFis. This finding implies that it is treatment intensity rather than the nature of treatment which is crucial. A number of strategy trials have shown the benefits of combining treatments DMARDs, steroids and, in some trials, biologics - to optimise outcomes and have confirmed the benefit of treating to target. Intensive management approaches used in these strategy trials give the best outcomes for RA so far reported [37]. A characteristic feature of RA trials is their focus on increasing treatment in patients with active disease. One reason is that active patients have pressing needs to justify treatment change. A second is the relative ease of showing treatment benefit in patients with high Page 11 of 36

12 disease activity. As a consequence trials rarely enrol patients with intermediate disease activity [38]. Against this background, the key reasons for undertaking the TITRATE trial are: Remission is the most appropriate target in RA [39] Intensive management regimens using DMARD combinations, steroids and sometimes biologics, together with a treatment support programme of effective non-drug interventions are most likely to achieve remission [40, 41] The most important group of patients in which to investigate whether intensive management achieves remission are those with intermediate disease activity ; these patients currently continue to have persisting disease activity and as a consequence they develop progressive disability [42]. The TITRATE trial is designed to show whether patients with intermediate disease activity benefit from such intensive management. As well as evaluating remission, we will also look at a range of secondary outcomes that will incorporate disability, quality of life and acceptability of intensive management to patients. These will include a combination of patient-reported outcomes and objective measures. The TITRATE trial forms part of a larger programme of work, commissioned by the National Institute for Health Research via their Programme Grant for Applied Research funding stream (Reference: RP-PG ). Other aspects of research within the programme which will impact the implementation of the findings in the trial include assessing patients views of intensive treatment and examining the relationship between remission and disability. These other research areas will be the subject of additional studies, each of which will seek separate ethical approval. 5. Trial Objectives and Design 5.1. Trial Objectives The goal of TITRATE is to improve outcomes for RA patients with intermediate disease activity by using intensive management to increase remissions, reduce disability and enhance quality of life. TITRATE will formally test the hypothesis that patients with established RA (of at least 6 months duration), who currently have intermediate disease activity (defined as DAS28-ESR with at least 3 active joints) and are currently receiving at least one DMARD, are more likely to achieve remission at 12 months if they receive intensive management than if they continue to have standard care. The intensive management regimen will be based on reviewing patients monthly and immediately adjusting treatment regime based on changes in their clinical care, by giving DMARD combinations, steroids and, in some patients, biologics, with the aim of achieving remission. Patients will be seen monthly for intensive treatment. Standard care will involve maintaining suppressive treatment with DMARDs and steroids. Patients will also receive biological treatments if they flare and meet current NICE guidance for using these interventions. In standard care, patients are reviewed at least once each year. Urgent specialist reviews will be arranged for patients in either treatment arm using routine approaches if there is a clinical need. The primary objective is to improve outcomes (defined primarily through achieving remission at 12 months) for RA patients with intermediate disease activity using intensive management. Page 12 of 36

13 The secondary objectives are to reduce disability, enhance quality of life, to show that intensive management is acceptable to RA patients with intermediate disease activity and to determine the cost-effectiveness of intensive management Primary Endpoint The primary endpoint will be the number of patients in each treatment arm fulfilling the definition of remission as measured by DAS28-ESR (remission defined as DAS28-ESR <2.6) [43, 44] at 12 months Secondary Endpoints These will assess the following outcomes at six and/or 12 months: Alternative Assessments of Remission: Remission measured by the DAS28-CRP [43,44] the Simplified Disease Activity Index (SDAI) (remission defined as SDAI 3.3) [45] at 12 months; remission assessed by all measures at six months. Assessment of Individual Components of Remission: Tender joint counts (68 joints), swollen joint counts (66 joints), patient global assessments on 100mm visual analogue scales (VAS), assessor global assessments on 100mm VAS, C-Reactive protein (CRP) and Erythrocyte Sedimentation Rate (ESR). Disability: Health Assessment Questionnaire (HAQ) [46]. Joint Imaging (Predictor of future disability): Plain X-rays of the hands and feet read by a modified Larsen s score [47]. Quality of Life: EuroQOL 5 Dimensional score (EQ5D-5L) [48], Fatigue rating (VAS). Patient Acceptability: Modified Measuring Actual Patient-led Expectations in Rheumatoid Arthritis (MAPLe-RA) [49], Medication Adherence Rating Scale (MARS) [50] and adverse events. (We plan to make minor adjustments to the MAPLe-RA questionnaire so that it specifically captures issues crucial to this patient group.) Economic Assessments: Modified Client Service Receipt Inventory (CSRI) [51] Trial Design The TITRATE trial is a 12-month, pragmatic, randomised, open-label, two-arm, parallel group, multicentre trial undertaken at specialist rheumatology clinics in England. The target population will be patients attending specialist rheumatology clinics who meet the most recent classification criteria for RA (American College of Rheumatology 2010 criteria), who have established RA of at least six months duration, who currently have intermediate disease activity (DAS28-ESR and at least three active joints) and who are receiving at least one conventional DMARD. Baseline assessments will include evaluation of a number of potential outcome predictors, which will be used in exploratory analyses. These will include: Lifestyle factors: alcohol consumption and tobacco smoking Mood and anxiety: Patient Health Questionnaire-9 (PHQ-9) [52] and Generalized Anxiety Disorder-7 (GAD-7) [53] Health beliefs/illness perceptions: Beliefs about Medicines Questionnaire (BMQ) [54] and Brief Illness Perceptions Questionnaire (BIPQ) [55] Quality of life: EuroQOL 5 Dimensional score (EQ5D-5L) [48]. Patients will be randomised to standard care or intensive management Standard care In the standard care arm, clinicians will follow their local pathways for managing RA patients with intermediate disease activity. These will be based on national guidance from NICE. The key components of the standard care algorithm comprise: Page 13 of 36

14 Maintaining suppressive treatment with DMARDs and steroids Seeing patients at least once each year in line with local pathways of care Arranging urgent specialist reviews using routine approaches if there be a clinical need Intensive management In the intensive management arm, patients will be seen monthly by trained rheumatology specialist practitioners (e.g., nurses, physiotherapists) identified by the Principal Investigator as being competent to provide the intervention, who will: Assess their RA and current general functioning Evaluate their drug treatment Modify the drug treatment according to a decision tool in line with a shared treatment plan formulated during the first visit. Shared treatment plans will involve agreements with patients about drugs, dosages and therapeutic sequences. Templates for potential shared treatment plans will be developed in advance of the trial as part of a preparatory study within the TITRATE programme. Provide supportive care according to a Treatment Support Manual. The Intensive Management Programme will address the following: a. Provide information: there will be a handbook for patients which will describe in detail the various aspects of intensive treatment. b. Optimise DMARDs/Biologics: drug treatment will be modified following a decision tool/treatment algorithm, which will recommend treatment options based on previous treatment, present treatment, contraindications, the patient s preferences and clinical assessments. The premise of the decision tool is that whatever the current treatment strategy, the recommended strategy will always reflect potential intensification of treatment. All medication given to patients in the intensive management group will be in line with national guidance from NICE or the national specialist society (British Society for Rheumatology) the only differences being that patients will be reviewed more frequently than they would be under standard care and if their disease is not fully controlled may be given biological therapies in line with British Society for Rheumatology recommendations. c. Give steroids: patients will receive intra-muscular steroids (depomedrone or equivalent) if their arthritis is not fully controlled up to a maximum of 600mg depomedrone (or equivalent) over the 12 month period. The dose of steroids given will range from mg depending on specific clinical circumstances. d. Provide Treatment Support : Along with treating patients more intensively with medication, the trained rheumatology practitioner will also provide patients in this group with supportive care, which will be detailed in a Treatment Support Manual. In summary, patients will be educated and supported in a number of domains commonly affected by RA, with a particular focus on: Pain and fatigue management Physical activity Medication adherence Sleep. Local safety screening for tuberculosis and other infections will be performed according to local guidelines for patients in the intensive management arm at either their fourth or fifth monthly visit if it is likely that they may need biologics in line with British Society for Rheumatology guidance to avoid delay in starting biologics if needed. Decision tool The principle of the decision tool is that the trained rheumatology practitioner will use a predefined algorithm to recommend treatment options based on previous treatment, present treatment, patient s preferences and previous and current clinical assessments. Page 14 of 36

15 The decision tool will use the current tender and swollen joint counts supported by the most recent DAS28-ESR. This is because DAS28-ESR requires the laboratory assessment of ESR and cannot be calculated during an appointment. If there is more than one tender joint or any swollen joint out of 28 the patient is unlikely to be in remission and therefore treatment intensification is appropriate. The premise of the treatment approach is that whatever current treatment is being given, the recommended strategy will always reflect potential intensification of treatment. The algorithm will also take into account any contraindications. All medication given to patients in the intensive management arm will be in line with existing UK guidance supported by the National Specialist Body (the British Society for Rheumatology) [56] the only difference being that patients will be reviewed more frequently and managed using the agreed algorithm. The decision tool may be updated during the trial on the basis of feedback from clinicians and patients involved in the trial and any new evidence available. A decision tool will be developed to support the application of the treatment algorithm. All specialist rheumatology practitioners involved in delivering the intensive management intervention will be trained according to a manualised training programme to ensure that the intervention provided is standardised across sites and participants. To measure adherence to the intensive management intervention across sites, monthly sessions will be audiotaped and then rated by an independent rater. Page 15 of 36

16 5.3. Trial Flowchart and Summary Flowchart Page 16 of 36

17 Summary of Milestone Assessments (all patients in trial) Screening* Baseline Month 6 Month 12/ Withdrawal Patient registration X Screening DAS28 (ESR) and Extended Joint Count X Inclusion criteria X Exclusion criteria X DAS28 (ESR & CRP) and Extended Joint Count X X X Assessor global rating (VAS) X X X Pain rating (VAS) X X X Fatigue rating (VAS) X X X RA medication in trial X X X RA medication before trial X Medical history X X Alcohol consumption X Smoking History X Smoking status X X X X-rays (plain hands & feet) X X HAQ X X X CSRI X X X EQ-5D-5L X X X PHQ9 X GAD7 X MARS X X X BIPQ X BMQ X MAPLe-RA (modified) X X Randomisation X Adverse events X X Status form X X Withdrawal form X^ NB. DAS28-ESR will be calculated from joint count, patient global rating (VAS) and ESR during every visit; SDAI will be calculated from joint count, patient global rating (VAS), assessor global rating (VAS) and CRP at baseline, mid-point and final assessments. * Screening/baseline assessments may be undertaken at the same visit or up to one calendar month apart according to local practices and/or patient preference and availability of ESR. ^ If patient withdraws from trial. Page 17 of 36

18 Summary of Visits for Intensive Management Intervention (patients allocated to Intensive Management arm only) Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Visit 11 Visit 12 Provision of patient handbook X Shared treatment plan X Trial medication change^ X X X X X X X X X X X X Biologics screening X # X # DAS28 (ESR & CRP) and Assessor Global Rating X X X X X X X X X X X X Medication review X X X X X X X X X X X X Adverse events review X X X X X X X X X X X X Delivery of treatment support programme X X X X X X X X X X X X # Biologics screening will usually take place at either visit 5 or visit 6 if it is likely that patients may need biologics in line with British Society for Rheumatology guidance. Biologics will not be initiated after visit 9. ^According to decision tool. Page 18 of 36

19 6. Interventions 6.1. Drug Treatment All drugs will be used within licensed indications and at licensed doses as outlined in their various Summaries of Product Characteristics (SPCs). They will all be prescribed through routine NHS prescribing mechanisms as part of standard care. They will include disease modifying anti-rheumatic drugs, steroids, biologics and analgesics. Disease Modifying Anti-Rheumatic Drugs (DMARDs) All available, licensed DMARDs can be used within their licensed indications. Steroids Intramuscular (IM) corticosteroid (methylprednisolone 80mg or triamcinolone 40mg). IM Depomedrone (or equivalent licensed steroid) can be given at appropriate doses with an upper recommended limit of 600mg over the 12 month trial (which represents 4 injections of 120mg). Biologics Participants who meet NICE criteria for use of biologics during the course of the trial can receive any biologic available according to local pathways. For participants in the intensive management arm who require biologics in line with the national specialist guidelines (from the British Society of Rheumatology) and European guidance from EULAR (European specialist body) but who do not meet NICE criteria for biologics, local arrangements will be made to provide licensed biologics in this situation. We anticipate this will include at least one biologic, a TNF inhibitor. Analgesics Paracetamol, co-codamol, co-dydramol and tramadol will be used for pain control Dosing Regimens There are no specified dosing regimens because the purpose of the trial is to individualise treatment by continual adjustment of the dose of DMARDs and other drugs depending on the degree of disease activity recorded using joint counts and DAS28-ESR. This is a standard approach indicated in current NICE Guidance for early rheumatoid arthritis extended to patients with established RA who have intermediate disease activity Drug Risks The risks of each individual drug are listed in the SPCs ( The level of risks in the trial are those of standard care; there is no evidence that intensive treatment with DMARDs significantly increases the risks above more conservative treatment because giving combination therapy with several DMARDs often allows them to be used at lower doses, and thus reduces toxicity Other Treatment a. Other treatments will continue unchanged, this will include oral steroids, the dose of which will be maintained throughout the trial if clinically practical. b. Non-steroidal anti-inflammatory drugs for appropriate pain control. c. Folic acid (at least 5mg weekly) if methotrexate used. d. Gastroprotection (usually omeprazole) with NSAIDs. e. Bone protection (usually calcium/vitamin D and bisphosphonate) with steroids. f. Treatment will be modified for inter-current illness or surgical procedures. We will not record other treatment in the trial with the exception of the dose of oral steroids and any intra-articular steroids given during the trial. Page 19 of 36

20 6.2. Treatment Support Programme A range of supportive treatments (detailed in a Treatment Support Manual) will be provided. Patients will be educated and supported in a number of domains commonly affected by RA, with a particular focus on: Pain and fatigue Physical activity Medication adherence Sleep Each patient will first be assessed to identify the main problem areas to focus on and any potential barriers. The patient will then be supported in setting goals to achieve the desired outcomes. Interventions may include techniques such as psychoeducation, problem-solving and diaries/worksheets for monitoring activities/sleep/ pain. These will aim to encourage the patient to gain control of their RA and cope more effectively with aspects of the disease they identify as having the biggest impact on their quality of life, as well as contributing to improving medication adherence. 6.3 Delivering Interventions To minimise contamination the rheumatology practitioner who is trained in and delivering the intensive management intervention will not be involved in treating patients in the standard care arm. The care of these latter patients will be delivered by other members of the rheumatology team for the duration of the trial. 7. Selection and Withdrawal of Subjects 7.1. Inclusion Criteria a. Males and females aged over 18 years b. Diagnosis of Rheumatoid Arthritis (by ACR, 2010 criteria) [57]; duration six months to 10 years c. Have received at least one DMARD for at least six months, and currently receiving at least one DMARD d. Have intermediate disease activity, defined by: I. DAS28-ESR II. At least three swollen joints and three tender joints on 66/68 joint count e. Willing and able to follow an intensive management programme f. Able and willing to give informed consent Exclusion Criteria a. Major co-morbidities making intensive treatment inadvisable (e.g. heart failure) b. Previously failed multiple DMARDs ( 5 treatments) or having received biologics c. Irreversible disability from extensive joint damage (for example, replacement of three or more major joints) d. Women who are pregnant, breast-feeding or at risk of conceiving e. Current or recent (within the 12 weeks prior to randomisation) participation in another interventional trial f. Currently in early RA pathway Selection of Participants 398 patients will be recruited from between 20 and 40 centres in England. Patients will be recruited from rheumatology outpatient clinics in England. Patients identified by rheumatologists, clinic nurses or suitably trained members of the research team at participating centres will be approached by their rheumatologist (or suitably trained member of the research team) and given details of the trial. If the patient is interested in participating, the patient will be given a patient information sheet / brochure to read. The Page 20 of 36

21 patient will then be contacted by telephone at least 24 hours after receiving the patient information sheet / brochure to see if they are interested in participating in the trial. If they are, a screening visit (and, if eligible, baseline assessment) will be arranged. If a patient does not wish to participate they will be reassured that their routine care will not be affected and a routine appointment will be made. Non-identifiable details of all patients approached to participate in the trial will be documented on the trial screening logs or electronically on the Electronic Data Capture (EDC) system Randomisation Procedure If the patient is happy to participate in the trial, informed consent will be obtained at or prior to the screening visit. The screening source data worksheets will be completed and transcribed to the Electronic Data Capture (EDC) system (InferMed MACRO), using only the patient s initials and date of birth as identifiers. Once registered, a unique Patient Identification Number is generated by the system and will be used to identify the patient throughout the trial. If eligible, the patient will be asked to complete all baseline measures. The EDC system is hosted at the King s Clinical Trials Unit, on a King s College London server. Only when all baseline measures are complete and data is entered will patients be randomised. Randomisation will be at the level of the individual using block randomisation with randomly varying block sizes, to ensure pre-randomisation allocation concealment, stratified by region. Patients will be randomised to Intensive Management (IM) or standard care (SC) in a ratio of 1:1. All staff involved in the conduct of the trial will be unaware of the allocation sequence. To randomise, authorised site staff will access the randomisation system at by clicking the randomisation-advanced option and selecting TITRATE. The patient s PIN, initials, date of birth and stratifiers will be entered and the randomisation program will automatically the site staff, and trial coordinating centre. The patient can then be informed of their allocation and appropriate follow-up visits can be arranged. For CONSORT reporting, data will be collected on: a. Patients consented and screened for trial entry. b. Patients randomised. c. Patients consented and not randomised with reasons (disease activity, other exclusions, non-consent, other reasons) Withdrawal of Subjects Participants have the right to withdraw from the study at any time for any reason. Patients wishing to withdraw from the study will be asked to complete a withdrawal questionnaire including reasons for withdrawal. Patients in the intensive management arm who wish to withdraw will be given the following options: a) Revert to treatment as usual and complete six and/or 12 month follow-up assessments withdrawal from intervention. b) Revert to treatment as usual but consent to collection of data from routine medical notes (no follow-up assessments completed) medical note review only. c) Refuse any further collection of outcome data, either through follow-up assessments or medical note review withdrawal from research. Page 21 of 36

22 Patients in the standard care arm who wish to withdraw will be given the following options: a) Consent to collection of data from routine medical notes (no follow-up assessments completed) medical note review only. b) Refuse any further collection of outcome data, either through follow-up assessments or medical note review withdrawal from research. It will be made clear to all participants wishing to withdraw that collection of any further outcome data will be entirely at their own discretion. The Investigator also has the facility to withdraw patients from the study. It is understood that an excessive rate of withdrawals can render the study uninterpretable; therefore, unnecessary withdrawal of patients should be avoided Expected Duration of Trial Following screening and randomisation, patients will participate in the trial for 12 months. The end of the trial will be defined as the last recruited patient s final assessment. The total length of the trial, from first randomised patient to final assessment, is estimated to be three years. 8. Trial Procedures 8.1. By visit Patients will follow the visit schedule summarised in sections and The baseline assessment should be performed within four weeks of the screening assessment. Screening and assessment visits may take place on the same day provided that ESR (and CRP) results are available, and according to staff and patient preference. Midpoint and final milestone assessments will be at 26 and 52 weeks from baseline. If patients cannot attend their assessment on the due date, these assessments should ideally take place within a seven-day window either side of the due date. In exceptional circumstances a longer 14-day window will be allowed. For patients randomised to the intensive management arm, the first treatment visit should take place as soon as possible after randomisation. Ideally this would be within one week. Exceptionally a longer delay may be necessary but this should not exceed four weeks. Subsequent visits should take place approximately every four weeks. This means they should be planned so that there are six visits before the midpoint milestone and six visits after the midpoint milestone. Although the timing of visits needs some flexibility they should be a minimum of two weeks apart and a maximum of six weeks apart. There also needs to be a minimum of two weeks between visit 12 and the final milestone assessment. To minimise visits the seventh intensive management visit can occur immediately after the midpoint milestone assessment if this is convenient for the patient. In the event that a patient cannot attend a monthly intensive management visit or a milestone assessment visit within the ideal time window, the trial coordinator should be contacted and will determine on a case-by-case basis the best way to proceed. For purposes of screening and subsequent assessments, ESR (and CRP) measured within two weeks prior to assessments will be accepted. Patients in either treatment arm who consider that they are experiencing a flare will be seen urgently by a specialist using routine approaches. Patients should then attend their next Page 22 of 36

23 scheduled trial assessment or monthly visit as usual and any additional interventions will be recorded in the ecrf Screening For screening, the following will be performed and recorded in the patient s ecrf: 1. Written informed consent (taken by a suitably trained member of research/clinic team, according to local guidelines) 2. Patient Registration (date of birth, ethnicity, gender, height, weight, and first half of postcode to calculate the Townsend Deprivation Score [58]) 3. Inclusion/exclusion criteria review (including medical and drug history) 4. Confirmation of rheumatoid arthritis diagnosis (by ACR, 2010 criteria) [57] 5. DAS-28 (tender and swollen joint counts, patient global, ESR) 6. Extended joint count 66/68 7. PI approval of patient eligibility 8. Assignment of patient PIN Baseline visit (day 0) If patient eligibility is confirmed, the following baseline measures will be performed and recorded in the ecrf: 1. Current treatment for RA 2. Previous RA medication 3. Medical history 4. ESR 5. CRP 6. Extended joint count 66/68 7. Patient global rating (VAS) 8. Assessor global rating (VAS) 9. Pain (VAS) 10. Smoking history and current smoking status, and alcohol consumption 11. Plain x-rays of hands and feet 12. HAQ 13. Client service receipt inventory 14. EuroQol (EQ-5D-5L) 15. Fatigue rating (VAS) 16. PHQ GAD MARS 19. BIPQ 20. BMQ 21. MAPLe-RA (modified version) Following completion of all baseline measures, patients will be randomised to either standard care or intensive management. For patients in the standard care arm, a date will be arranged for assessment at six months. For those in the intensive management arm, the first intermediate monthly visit will be scheduled one calendar month from baseline First intermediate monthly visit (Intensive management arm only) Disease activity will be assessed using the following clinical measures (to be recorded in the ecrf): ESR CRP 28 joint count Patient global assessment of disease activity Assessor global assessment of disease activity Page 23 of 36

24 The following will be reviewed: Medication Adverse events Local safety screening for tuberculosis and other infections will usually be performed at visit 5 or 6 according to local guidelines to avoid delay in starting biologics if necessary in patients whom may need these treatments. Delivery of the Treatment Support Programme (supported by the Treatment Support Manual for practitioners) will commence. This will include providing the patient with a handbook on intensive management, and agreement between patient and trained rheumatology specialist practitioner of a shared treatment plan. Based on the treatment algorithm outlined in section 5.2.2, and in line with the shared treatment plan, the first treatment change will be initiated Subsequent intermediate monthly visits (Intensive management arm only) Disease activity will be assessed using the following clinical measures (recorded in the ecrf): ESR CRP 28 joint count Patient global assessment of disease activity Assessor global assessment of disease activity The following will be reviewed: Medication Adverse events Based on the treatment algorithm outlined in section 5.2.2, and in line with the shared treatment plan, another treatment change will be initiated. Delivery of the Treatment Support Programme will continue. For patients in the intensive management arm only, at the end of the final (12-month) visit, patient outcomes will be reviewed and ongoing management discussed with the patient Midpoint (six month) assessment visit (week 26, day 182) The following measures will be performed and recorded in the ecrf: 1. CRP 2. ESR 3. Extended joint count 66/68 4. Patient global rating (VAS) 5. Assessor global rating (VAS) 6. Pain (VAS) 7. Smoking status 8. Medication review 9. Adverse event review 10. HAQ 11. CSRI 12. EuroQol (EQ-5D-5L) 13. Fatigue rating (VAS) 14. MARS 15. Status form Page 24 of 36

25 For patients in the intensive management arm only, a treatment change will be initiated as in intermediate monthly visits (outlined in section 8.1.3) Final (12 month) assessment visit (week 52, day 364) / Withdrawal The following measures will be performed and recorded in the ecrf: 1. CRP 2. ESR 3. Extended joint count 66/68 4. Patient global rating (VAS) 5. Assessor global rating (VAS) 6. Pain (VAS) 7. Smoking status 8. Medical history review 9. Medication review 10. Adverse event review 11. Plain x-rays of hands and feet 12. HAQ 13. CSRI 14. EQ-5D-5L 15. Fatigue rating (VAS) 16. MARS 17. MAPLe-RA (modified version) 18. Status form 19. Withdrawal form (if patient withdraws) 8.2. Laboratory Tests ESR and CRP will be measured at every visit for both treatment arms. Other tests will be required for drug monitoring. These will be variable depending on the drug, but could include FBC and biochemistry. Additional tests may be required for drug monitoring purposes, as per routine care. 9. Assessment of Efficacy 9.1. Primary Efficacy Parameter DAS28-ESR, to measure the proportion of patients achieving remission Secondary Efficacy Parameters a. Simplified Disease Activity Index (SDAI) to measure the number of patients achieving remission. b. DAS28-CRP c. Short Health Assessment Questionnaire d. 66/68 joint count e. X-rays (plain hands and feet) f. Assessor global rating g. EuroQOL (EQ-5D-5L) h. Medication Adherence Rating Scale (MARS) i. Fatigue rating (VAS) j. Client Service Receipt Inventory k. MAPLe-RA (modified version) 10. Assessment of Safety Specification, Timing and Recording of Safety Parameters As the study involves potential biologic treatment, all patients randomised to the intensive management arm will be screened routinely for tuberculosis, HIV and hepatitis B/C during Page 25 of 36

26 their first monthly visit [59]. Patients will have a chest x-ray if this is needed within local screening policies. Patients will have standard safety monitoring as recommended in national guidelines [60]. These will be organised by the hospital in the intensive management arm and following local shared care guidance in the standard care arm Recording and Reporting Adverse Events Definitions The National Research Ethics Service (NRES), for the purposes of non-ctimps, defines a serious adverse event (SAE) as an untoward occurrence that: a) Results in death b) Is life-threatening c) Requires hospitalisation or prolongation of existing hospitalisation d) Results in persistent or significant disability or incapacity e) Consists of a congenital anomaly or birth defect f) Is otherwise considered medically significant by the investigator Reporting responsibilities The co-sponsors (KCL and KCH) have delegated responsibility for pharmacovigilance to the Chief Investigator. The Principal Investigator at each site is responsible for reviewing all AEs and recording them appropriately in the ecrf/ reporting AEs to the Chief Investigator according to the Procedures for Recording and Reporting Adverse Events detailed in section Procedures for Recording and Reporting Adverse Events All non-serious adverse events reported by patients at six and 12-month milestone assessments or during Intensive Management sessions (for patients in the treatment arm) will be recorded on the EDC system. All Serious Adverse Events (SAEs), irrespective of causality, will be reported to the trial team within 24 hours of the site becoming aware of them. Any SAEs reported by patients on etanercept will be onward reported to Pfizer at the request of the company. Any SAE found to be both unexpected and related to administration of any of the research procedures will be reported to the main Research Ethics Committee by the Chief Investigator within 15 days of receiving the initial report Treatment Stopping Rules The trial may be prematurely discontinued by the Sponsor or Chief Investigator on the basis of new safety information or recommendations given by the Data Monitoring & Ethics Committee to the Trial Steering Committee. If the trial is prematurely discontinued, active participants will be informed, final data will be collected and no further participant data will be collected thereafter. The Research Ethics Committee will be informed within 15 days of the early termination of the trial. 11. Statistics Sample Size The most relevant UK trial (TICORA) which compared tight control versus standard treatment in patients with RA for less than 5 years reported that 16% of patients receiving standard care achieved DAS remission at the end of the trial [61]. Patients receiving standard treatment showed decreases in DAS until 12 months but no further falls from Page 26 of 36

27 months. Analysis of routine care patients from the King s Health Partners database showed 16% of those patients with initial intermediate disease activity treated with DMARDs were in remission at their second visit between 9-15 months. Similar data was found in the analysis of an early RA trial (CARDERA) [62]. We therefore assume that with standard care 16% of patients will have achieved DAS remission at one-year follow-up. We will reject the null hypothesis (RA patients with intermediate disease activity (DAS ) despite DMARDs will have no difference in remission rates intensive management at 12 months than with standard care) if the difference in remission rates at 12 months between the intensive management arm and the standard care arm is 15% or greater. Demonstrating such a difference with 5% significance and 90% power requires randomising 358 patients in total, under 1:1 allocation (i.e. 179 patients per group). After allowance is made for a 10% drop-out overall, the required total sample size increases to 398 patients. Although the CARDERA trial suggests DAS28 and SDAI remissions occur with similar frequencies, there is limited comparative data for SDAI remission and we based sample size calculations on DAS28 remissions Randomisation Equal numbers of patients will be randomised into the two treatment strategy groups. The Electronic Data Capture (EDC) system will be used to generate a unique Patient Identification Number. Once the patient is consented, confirmed eligible and all baseline data is collected and entered in the EDC system, sites will access the web-based randomisation system ( click randomisation-advanced and select TITRATE) and submit the patient s details for randomisation. Patients will be randomised at the level of the individual, using block randomisation with randomly varying block sizes. Staff at individual centres and the sponsor will be unaware of the allocation sequence. Once a randomisation has been completed, the randomisation program will automatically inform the trial coordinating centre, study site staff and site Principal Investigator by automated . The patient can then be informed that they have been recruited to the trial and appropriate follow-up visits arranged, depending on their allocation. s will be generated in a blinded format to outcome assessors, so they can schedule appointments for outcome assessments without knowing treatment allocation. s will be generated in an unblinded format to those staff who need to know the treatment allocation. The trial will not be blinded. Patients are an integral part of the intensive treatment algorithm and there is no possible way to blind such a trial. However, the milestone assessments (at 0, 6 and 12 months) on which the presence or absence of remission are assessed will be undertaken by an assessor who is not involved in the patients treatment Analysis Analysis will be on an intention-to-treat (ITT) basis to reflect the randomisation process. We will also carry out two additional analyses populations: a complete case population: these will be observations that subjects complete the trial without missing data or violation of the protocol and therefore referred to as `complete case analysis`. A per protocol population: these will be observations that will be excluded from these analyses if patients are found to deviate from the protocol and referred to as `per protocol analysis`. Baseline characteristics will be summarised by randomised group. Multiple imputations (MI) method will be used to impute missing primary or secondary outcomes. The robustness of the analyses performed to the missing at random assumption under MI model will be assessed by Linear Increment method of Diggle et al. [63] to handle the missingness. A logistic regression analysis will be used to analyse the primary outcome remission at 12 months. For secondary analyses that involve longitudinal measurements, generalised estimating equations (GEE) and/or mixed models will be used to estimate the effect of Page 27 of 36

28 treatment, including baseline value as a covariate. Working correlation matrices will be unstructured, which is not unduly restrictive given that measurements will be taken at three time points. Valid/robust estimates of the precision of effects will be obtained through use of the information sandwich estimator for GEE analyses. Treatment, and the demographic factors (age, ethnicity, gender, disease duration) as well as the design factor (region) will be included as explanatory variables in the multivariate analysis. The design factor will also be accounted for in the univariate model. The estimates for primary outcome will be presented as odds ratios (OR) with 95% confidence intervals for the effect of intensive management. Statistical significance will be determined at the 5%- level using a 2-sided test throughout. Serious adverse event and adverse rates in the two arms will be compared using comparisons of two independent proportions. A full statistical analysis plan will be developed prior to the start of the trial Cost Utility Analysis A cost utility analysis will be undertaken to estimate the incremental cost per Quality Adjusted Life Year (QALY) of intensive management compared to standard care in RA patients with intermediate disease activity, alongside the clinical trial. The cost utility analysis will be conducted in line with NICE Guide to the Methods of Technology Appraisal (2013) [64]. In particular, an NHS and Personal Social Services (PSS) perspective will be taken for costs, and health benefits will be quantified using QALYs. The primary analysis will be an economic evaluation alongside the clinical trial, and will use the one year follow-up period of the trial to estimate expected one year costs and QALYs for the intervention and control groups. QALYs will be estimated using the EuroQol (5 level) questionnaire reported at baseline, 6 months and 12 months. The EuroQol will be valued using population tariff values to estimate EQ-5D-5L scores. Although these are not yet published, they are expected to be available during QALYs will be estimated using the trapezium rule to calculate the area under the curve. NHS resource use will be measured for each participant between baseline and final followup. This will include all medication costs, visits to health services and any social care and community support. Medical costs will be taken from the trial medication records, and other NHS and resources used will be self-reported using the widely used and validated Client Service Receipt Inventory (CSRI) questionnaire [51]. Unnecessary questions in the CSRI will be removed to reduce the burden for patients; however questions relating to personal costs incurred and time-off-work will be retained for a sensitivity analysis. The estimate of cost-effectiveness will be reported as the incremental cost-effectiveness ratio (ICER). Patient variation in resource use and effectiveness will be captured by confidence intervals of the cost and outcome estimates separately. Due to the ratio property of the ICER, confidence intervals are less reliable and therefore bootstrapped estimates of the ICERs will be sampled, to allow the probability of the intervention being cost-effective to be determined. This estimate of uncertainty will be reported using cost-effectiveness acceptability curves (CEACs), which report the probability that the intervention is costeffective for any given level of willingness to pay. A secondary analysis will be undertaken with a wider societal perspective. Personal costs and time off work will be included, as reported by patients using the CSRI questionnaire. Time off work will be valued as productivity losses using the human capital method. Page 28 of 36

29 A potential tertiary analysis will include an extrapolation of the costs and benefits of the intervention, to allow a life-time estimate of expected costs and QALYs. Time to loss of efficacy of the intervention will be determined by a survival analysis of the within-trial data. This will be included in an established decision analytic model (The Sheffield RA Model) [65]. The model will determine the future treatment pathway for the patient populations once a switch from intensive DMARD therapy is estimated, including biologics if patients progress to severe RA. 12. Trial Steering Committee A Trial Steering Committee (TSC) will be formed to provide oversight of this trial and ensure that it is being conducted in accordance with the principles of GCP and the relevant regulations. The Trial Steering Committee will agree the trial protocol and any protocol amendments and will provide advice to the investigators on all aspects of the study. It will have an independent chair who will be an established clinical trial expert in rheumatoid arthritis. Other members will include independent rheumatologists, at least two patient representatives, and members of the trial management team. The committee will meet every 6-12 months during the trial. 13. Data Monitoring Committee A Data Monitoring and Ethics Committee (DMC) will assess the trial s progress, occurrence of adverse events and all other aspects. It will meet at least annually for the duration of the trial. It will have an alternative independent chair, and at least three other independent members will be invited to join, including a statistician. 14. Direct Access to Source Data and Documents The Investigator(s) will permit trial-related monitoring, audits, REC review, and regulatory inspections (where appropriate) by providing the Sponsors, Regulators and REC with direct access to source data and other documents (for example, hospital case notes, electronic patient records, completed forms and questionnaires, and the investigator site file). All reasonable precautions to maintain the confidentiality of participants identities and protect the integrity of the data will be taken within the constraints of the applicable regulatory requirements. 15. Ethics and Regulatory Approvals This trial will be conducted in compliance with the principles of the Declaration of Helsinki (1996), the principles of GCP and in accordance with all applicable regulatory requirements including but not limited to the Research Governance Framework. This protocol and related documents will be submitted for review to a Research Ethics Committee (REC)). Any amendments to approved documents or newly created documents will likewise be submitted for approval. Annual progress and safety reports and a final report at conclusion of the study will be submitted to the REC within the timelines defined in the Regulations. 16. Quality Assurance This trial will be monitored to ensure compliance with the trial protocol, Good Clinical Practice and all applicable regulations, and to protect scientific integrity. Study co-ordinating staff will undertake routine quality control checks of the data. This will include additional central and site-based data checking to ensure the data quality is robust. Data queries will be raised, responded and closed within the EDC system. Range and validation checks will be programmed into the EDC system to minimise transcription errors. Source data verification checks undertaken at site will be documented within the EDC system, as this will ensure the final dataset has not been amended after checks have been Page 29 of 36

30 completed. Checks of randomisation data will be undertaken periodically to identify any errors. Prior to database lock, all SAEs reported via fax or will be cross-checked with the EDC system to ensure all are present in the analysis dataset. Any data issues identified by the trial statistician during preparation of DMC reports will be reported to the trial coordinator and systematically rectified across the dataset, either through central or site data checks. 17. Data Handling The Chief Investigator will act as custodian for the trial data once the study is compete. The following guidelines will be strictly adhered to: Data will be entered on the EDC system (InferMed MACRO), hosted by the King s Clinical Trial Unit (KCTU) and stored on a KCL server. The ecrf/edc will be accessible via web-based secure application. Usernames and passwords will be used to authenticate each individual user. The trial coordinator will request access for relevant personnel and all access must be authorised by the trial coordinator. Different roles may be assigned. A data entry role allows site staff to enter data and respond to data discrepancies. A monitor role allows co-ordinating centre staff or sponsor monitors to review data, raise and close discrepancies, source data verify data items but not amend any data. A PI role allows the site principle investigator to electronically sign each patient s ecrf at the end of the study. Only designated, suitably trained clinical and designated research staff will be given access to the data. The trial coordinator will only authorise passwords to personnel designated on the study s signature and delegation log as requiring login details to enter data. Central password lists will not be stored external to the system. All study data will be stored and archived for an appropriate period of time in accordance with the Research Governance Framework for Health and Social Care (2005). 18. Data Management The InferMed MACRO Electronic Data Capture will be used in this study. KCTU has extensive experience of this system. Password management and data exports will be controlled by the KCTU. No outcome data will be exported without the explicit consent of the trial statistician. Changes to the EDC system once the study has begun will be minimised and will only be undertaken with the full agreement of the trial statistician, CI and KCTU where it is essential to the successful conduct of the study. 19. Publication Policy It is intended that the results of the study will be reported and disseminated at international conferences and in peer-reviewed scientific journals. The Trial Steering Committee, together with the Chief Investigator and Principal Investigators will ensure that on completion of the study, the results are analysed, written up, reported and disseminated. Trial findings will be submitted to peer-reviewed journals, irrespective of the results of the study. Findings will also be publicised to the National Commissioning Board, other commissioners and appropriate established networks. And the outcomes of the trial will be disseminated to appropriate patient groups through national patient organisations. 20. Insurance / Indemnity Trial participants and staff working on the trial will be fully insured. Negligence will be covered by the participating NHS Trust's insurance. King's College London indemnity will cover non-negligent harm including that arising from the design of the research. 21. Financial Aspects This trial is part of a larger programme of work funded by a National Institute of Health Research (NIHR) via the Programme Grant for Applied Research funding stream. Page 30 of 36

31 As this is a non-commercial research study eligible for adoption onto the National Institute for Health Research (NIHR) Clinical Research Network Portfolio database, NHS Support Costs, including the additional patient-related costs associated with the research (costs which would end once the R&D activity in question has stopped) for example extra patient tests, extra in-patient days, and extra nursing attention, will be met by NHS R&D Support Funding (Clinical Local Research Network (CLRN) funding). [Ref: DoH ReSeT guidance]. Likewise treatment costs (patient care costs incurred by the NHS which would continue to be incurred if the patient care service in question continued to be provided after the R&D activity had stopped) and excess treatment costs (the difference between the total treatment costs incurred by the research activity and the costs of the standard treatment) are the responsibility of the NHS and are funded through normal arrangements for commissioning patient care. This is because funding to cover these costs is allocated to Commissioners as part of their overall revenue allocations. Biologics for use in the trial may be made available without cost by pharmaceutical companies for patients in the intensive management arm only. 22. References 1. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 376: Pugner KM, Scott DL, Holmes JW, Hieke K. The costs of rheumatoid arthritis: an international long-term view. Semin Arthritis Rheum 2000; 29: Scott DL, Steer S. The course of established rheumatoid arthritis. Best Pract Res Clin Rheumatol 2007; 21: Symmons D, Turner G, Webb R, Asten P, Barrett E, Lunt M, Scott D, Silman A. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology 2002; 410: Rodríguez LA, Tolosa LB, Ruigómez A, Johansson S, Wallander MA. Rheumatoid arthritis in UK primary care: incidence and prior morbidity. Scand J Rheumatol 2009; 38: Barton A, Worthington J. Genetic susceptibility to rheumatoid arthritis: an emerging picture. Arthritis Rheum 2009; 61: Lee HS, Irigoyen P, Kern M, Lee A, Batliwalla F, Khalili H, Wolfe F, Lum RF, Massarotti E, Weisman M, Bombardier C, Karlson EW, Criswell LA, Vlietinck R, Gregersen PK. Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide: a mixed picture in three large North American rheumatoid arthritis cohorts. Arthritis Rheum 2007; 56: National Audit Office Services for people with rheumatoid arthritis. 9. Outpatient data Kobelt G, Lindgren P, Lindroth Y, Jacobson L, Eberhardt K. Modelling the effect of function and disease activity on costs and quality of life in rheumatoid arthritis. Rheumatology (Oxford) 2005; 44: Hospital Prescribing England 2011, The NHS Information Centre, Prescribing and Primary Care Services, November Deighton C, O'Mahony R, Tosh J, Turner C, Rudolf M; Guideline Development Group. Management of rheumatoid arthritis: summary of NICE guidance. BMJ 2009; 338: b Finckh A, Bansback N, Marra CA, Anis AH, Michaud K, Lubin S, White M, Sizto S, Liang MH. Treatment of very early rheumatoid arthritis with symptomatic therapy, diseasemodifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis. Ann Intern Med 2009; 151: Donahue KE, Gartlehner G, Jonas DE, Lux LJ, Thieda P, Jonas BL, Hansen RA, Morgan LC, Lohr KN. Systematic review: comparative effectiveness and harms of diseasemodifying medications for rheumatoid arthritis. Ann Intern Med. 2008; 148: Page 31 of 36

32 15. Mouterde G, Dernis E, Ruyssen-Witrand A, Claudepierre P, Schaeverbeke T, Cantagrel A, Gaudin P, Maillefert JF, Pham T, Saraux A, Tebib J, Wendling D, Fautrel B, Le Loët X. Indications of glucocorticoids in early arthritis and rheumatoid arthritis: recommendations for clinical practice based on data from the literature and expert opinion. Joint Bone Spine 2010; 77: Jacobs JW, Bijlsma JW. Glucocorticoids in rheumatoid arthritis: lessons from the Utrecht study. Clin Exp Rheumatol 2011; 29(5 Suppl 68): S Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, Ghogomu ET, Tugwell P. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview CMAJ 2009; 181: Strangfeld A, Hierse F, Kekow J, von Hinueber U, Tony HP, Dockhorn R, Listing J, Zink A. Comparative effectiveness of tumour necrosis factor alpha inhibitors in combination with either methotrexate or leflunomide. Ann Rheum Dis 2009; 68: Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Fu B, Ustianowski AP, Watson KD, Lunt M, Symmons DP; BSRBR Control Centre Consortium; British Society for Rheumatology Biologics Register. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology 2011; 50: Furneri G, Mantovani LG, Belisari A, Mosca M, Cristiani M, Bellelli S, Cortesi PA, Turchetti G. Systematic literature review on economic implications and pharmacoeconomic issues of rheumatoid arthritis. Clin Exp Rheumatol 2012; 30(4 Suppl 73): S Pincus T, Castrejón I, Bergman MJ, Yazici Y. Treat-to-target: not as simple as it appears. Clin Exp Rheumatol 2012; 30 (4 Suppl 73): S Scott IC, Wailoo A, Scott DL. Payers' views on treating-to-target in rheumatoid arthritis: an English perspective. Clin Exp Rheumatol 2012; 30 (4 Suppl 73): S Vermeer M, Kuper HH, Moens HJ, Drossaers-Bakker KW, van der Bijl AE, van Riel PL, van de Laar MA. Sustained beneficial effects of a protocolized treat-to-target strategy in very early rheumatoid arthritis: Three year results of the DREAM remission induction cohort. Arthritis Care Res 2013, in press. 24. Deighton C, Scott DL. Treating inflammatory arthritis early. BMJ 2010; 341: c Simpson C, Franks C, Morrison C, Lempp H. The patient's journey: rheumatoid arthritis. BMJ 2005; 331: Bosworth AM, Steuer A. Rheumatoid arthritis. BMJ 2010; 341: c National Institute for Health and Clinical Excellence The management of rheumatoid arthritis in adults Completed appraisals Smolen JS, Landewé R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C,Gorter S, Knevel R, Nam J, Schoels M, Aletaha D, Buch M, Gossec L, Huizinga T, Bijlsma JW, Burmester G, Combe B, Cutolo M, Gabay C, Gomez-Reino J, Kouloumas M, Kvien TK, Martin-Mola E, McInnes I, Pavelka K, van Riel P, Scholte M, Scott DL, Sokka T, Valesini G, van Vollenhoven R, Winthrop KL, Wong J, Zink A, van der Heijde D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69: Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 2012; 64: Dougados M, Aletaha D, van Riel P. Disease activity measures for rheumatoid arthritis. Clin Exp Rheumatol 2007; 25(5 Suppl 46): S van der Helm-van Mil AH, Huizinga TW. Advances in the genetics of rheumatoid arthritis point to subclassification into distinct disease subsets. Arthritis Res Ther 2008; 10: 205. Page 32 of 36

33 33. Choy EH, Smith C, Dore CJ, Scott DL. A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology 2005; 44: Ma MH, Kingsley GH, Scott DL. A systematic comparison of combination DMARD therapy and tumour necrosis inhibitor therapy with methotrexate in patients with early rheumatoid arthritis. Rheumatology 2010; 49: van der Velde G, Pham B, Machado M, Ieraci L, Witteman W, Bombardier C, Krahn M. Cost-effectiveness of biologic response modifiers compared to disease-modifying antirheumatic drugs for rheumatoid arthritis: a systematic review. Arthritis Care Res 2011; 63: Scott DL, Ibrahim F, Kelly C, Birrell F, Chakravarty K, Walker D, Maddison P, Kingsley G. Randomised controlled trial of tumour-necrosis-factor inhibitors (TNFis) against combination intensive therapy with conventional disease modifying anti-rheumatic drugs (cdmards) in established rheumatoid arthritis (RA): the TACIT trial. Rheumatology, 2013, in press. 37. Knevel R, Schoels M, Huizinga TW, Aletaha D, Burmester GR, Combe B, Landewé RB, Smolen JS, Sokka T, van der Heijde DM. Current evidence for a strategic approach to the management of rheumatoid arthritis with disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2010; 69: Kingsley GH, Khoshaba B, Smith CM, Choy EH, Scott DL. Are clinical trials in rheumatoid arthritis generalizable to routine practice? A re-evaluation of trial entry criteria. Rheumatology 2005; 44: Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, Combe B, Cutolo M, de Wit M, Dougados M, Emery P, Gibofsky A, Gomez-Reino JJ, Haraoui B, Kalden J, Keystone EC, Kvien TK, McInnes I, Martin-Mola E, Montecucco C, Schoels M, van der Heijde D; T2T Expert Committee. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010; 69: Klarenbeek NB, Kerstens PJ, Huizinga TW, Dijkmans BA, Allaart CF. Recent advances in the management of rheumatoid arthritis. BMJ 2010; 341: c Forestier R, André-Vert J, Guillez P, Coudeyre E, Lefevre-Colau MM, Combe B,Mayoux- Benhamou MA. Non-drug treatment (excluding surgery) in rheumatoid arthritis: clinical practice guidelines. Joint Bone Spine 2009; 76: Kiely P, Walsh D, Williams R, Young A; for the Early Rheumatoid Arthritis Network (ERAN). Outcome in rheumatoid arthritis patients with continued conventional therapy for moderate disease activity--the early RA network (ERAN). Rheumatology 2011; 50: Klarenbeek NB, Koevoets R, van der Heijde DM, Gerards AH, Ten Wolde S,Kerstens PJ, Huizinga TW, Dijkmans BA, Allaart CF. Association with joint damage and physical functioning of nine composite indices and the 2011 ACR/EULAR remission criteria in rheumatoid arthritis. Ann Rheum Dis 2011; 70: Inoue E, Yamanaka H, Hara M, Tomatsu T, Kamatani N. Comparison of disease activity score (DAS)28- erythrocyte sedimentation rate and DAS28- C-reactive protein threshold values. Ann Rheum Dis 2007;66: Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, Aletaha D, Allaart CF, Bathon J, Bombardieri S, Brooks P, Brown A, Matucci-Cerinic M, Choi H, Combe B, de Wit M, Dougados M, Emery P, Furst D, Gomez-Reino J, Hawker G, Keystone E, Khanna D, Kirwan J, Kvien TK, Landewé R, Listing J, Michaud K, Martin-Mola E, Montie P, Pincus T, Richards P, Siegel JN, Simon LS, Sokka T, Strand V, Tugwell P, Tyndall A, van der Heijde D, Verstappen S, White B, Wolfe F, Zink A, Boers M; American College of Rheumatology; European League Against Rheumatism. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 2011; 63: Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: a review of its history, issues, progress, and documentation. J Rheumatol 2003; 30: Page 33 of 36

34 47. Scott, DL, Houssein, DA, Laasonen, L. Modification to Larsen's scoring system. Br J Rheumatol 1995; 34: The EuroQol Group (1990). EuroQol a new facility for the measurement of healthrelated quality of life. Health Policy 1990; 16: Hofmann D, Ibrahim F, Rose D, Scott DL, Cope A, Wykes T, Lempp H. Expectations of new treatment in rheumatoid arthritis: developing a patient-generated questionnaire DOI: /hex Horne R, Weinman J. Patients beliefs about prescribed medicines and their role in adherence in chronic physical illness. Journal of Psychosomatic Research 1999; 47: Beecham J, Knapp M Costing psychiatric interventions. In: Thornicroft G (ed). Measuring mental health needs (2nd Edition). Gaskell, London. 52. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16: Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 2006; 166: Horne R, Weinman J, Hankins M. The beliefs about medicines questionnaire: The development and evaluation of a new method for assessing the cognitive representation of medication. Psychol Health 1999; 14: Broadbent E, Petrie KJ, Main J, Weinman J. The brief illness perception questionnaire. J Psychosom Res 2006; 60: Deighton C, Hyrich K, Ding T, Ledingham J, Lunt M, Luqmani R, Kiely P, Bukhari M, Abernethy R, Ostor A, Bosworth A, Gadsby K, McKenna F, Finney D, Dixey J; BSR Clinical Affairs Committee & Standards, Audit and Guidelines Working Group and the BHPR. BSR and BHPR rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy. Rheumatology 2010; 49: Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010; 69: Senior M Deprivation indicators. In: Rees P, Martin D and Williamson P (Eds.). The Census Data System. Wiley: Chichester. 59. Rubbert-Roth A. Assessing the safety of biologic agents in patients with rheumatoid arthritis. Rheumatology 2012; 51 Suppl 5: Chakravarty K, McDonald H, Pullar T, Taggart A, Chalmers R, Oliver S, Mooney J, Somerville M, Bosworth A, Kennedy T; British Society for Rheumatology, British Health Professionals in Rheumatology Standards, Guidelines and Audit Working Group; British Association of Dermatologists (BAD). BSR/BHPR guideline for disease-modifying antirheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology 2008; 47: Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, Kincaid W, Porter D. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004; 364: Choy EH, Smith CM, Farewell V, Walker D, Hassell A, Chau L, Scott DL; CARDERA (Combination Anti-Rheumatic Drugs in Early Rheumatoid Arthritis) Trial Group. Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis. Ann Rheum Dis 2008; 67: Diggle P, Farewell D, Henderson R. Analysis of longitudinal data with drop-out: objectives, assumptions and a proposal. J R Stat Soc C-Appl 2007; 56: National Institute for Health and Care Excellence Guide to the methods of technology appraisal. Page 34 of 36

35 65. Tosh J, Brennan A, Wailoo A, Bansback N. The Sheffield rheumatoid arthritis health economic model. Rheumatology (Oxford, England) 2011; 50 Suppl4: iv Doi: /rheumatology/ker243. Page 35 of 36

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