Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Ramanan AV, Dick AD, Jones AP, et al. Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med 2017;376: DOI: /NEJMoa

2 This supplement contains the following items: 1. Original protocol, final protocol, summary of changes 2. Original statistical analysis plan, final statistical analysis plan, summary of changes

3 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: A Randomised Controlled Trial of the Clinical Effectiveness, SafetY and Cost Effectiveness of Adalimumab in Combination with MethOtRExate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis (SYCAMORE) Version 1.0, 25 February Study Sponsor: University Hospitals Bristol NHS Foundation Trust UH Bristol Education Centre, Level 3, Upper Maudlin Street, Bristol, BS2 8AE EudraCT number: Funding reference Numbers: HTA 09/51/01 / ARUK Sponsor Reference: CH/2008/3061

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5 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: General Information This document describes the SYCAMORE trial and provides information about procedures for entering patients into it. The protocol should not be used as an aide-memoir or guide for the treatment of other patients; every care was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to the registered investigators in the trial, but centres entering patients for the first time are advised to contact the coordinating centre (Medicines for Children Clinical Trials Unit or Liverpool Cancer Trials Unit) to confirm they have the most up to date version. Clinical problems relating to this trial should be referred to the relevant Chief Investigator via the CTU. This protocol defines the participant characteristics required for study entry and the schedule of treatment and follow-up. Participant recruitment will be undertaken in compliance with this document and applicable regulatory and governance requirements and waivers to authorise non-compliance are not permitted. Incidence of protocol non-compliance, whether reported prospectively (e.g. where a treatment cannot be administered on a scheduled date as a result of public holidays) or retrospectively noted (e.g. as a result of central monitoring) are recorded as protocol deviations, the incidence of which are monitored and reported to trial oversight committees. Statement of Compliance This study will be carried out in accordance with the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989) and South Africa (1996) amendments and will be conducted in compliance with the protocol, CTU Standard Operating Procedures and EU Directive 2001/20/EC, transposed into UK law as the UK Statutory Instrument 2004 No 1031: Medicines for Human Use (Clinical Trials) Regulations 2004 as amended. Relationship Statements The UK Clinical Research Collaboration (UKCRC; is a partnership organisation working to establish the UK as a world leader in clinical research. Following a review by an international panel, the Clinical Trials Research Centre (CTRC) at the University of Liverpool has been assessed as reaching the highest quality standard required by the UKCRC and achieved full UKCRC registration. The CTRC encompasses clinical trials activity in areas including medicines for children (The Medicines for Children Research Network Clinical Trials Unit; MCRN CTU), cancer (The Liverpool Cancer Trials Unit; LCTU), epilepsy, oral health and obstetrics and gynaecology ( All CTRC activities are underpinned by methodological rigour, a modern data management system, similar technical requirements and a common set of standard operating procedures. The NIHR Medicines for Children Research Network and National Cancer Research Network is part of the National Institute for Health Research Clinical Research Network. Page 3 of 76

6 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: CONTACT DETAILS Contact Details: Institutions Sponsor: University Hospitals Bristol NHS Foundation Trust UH Bristol Education Centre, Level 3, Upper Maudlin Street, Bristol, BS2 8AE Tel: Fax: Trial Management and Monitoring: Medicines for Children Clinical Trials Unit Institute of Child Health Alder Hey Children s NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: mcrnctu@liverpool.ac.uk Clinical Laboratory: Dr Jennifer Oliver Research Coordinator Infection & Immunity Division Level 6, UBHT Education Centre Upper Maudlin Street Bristol, BS2 8AE Tel: Fax: Jennifer.Oliver@bristol.ac.uk Contact Details: Individuals Individual authorised to sign the protocol and protocol amendments on behalf of the Sponsor: Dr Diana Benton University Hospitals Bristol NHS Foundation Trust UH Bristol Education Centre, Level 3, Upper Maudlin Street, Bristol, BS2 8AE Tel: Fax: Diana.Benton@UHBristol.nhs.uk Co-Chief Investigator (Co-CI): Dr. Athimalaipet Vaidyanathan Ramanan Consultant Paediatric Rheumatologist Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol, BS2 8BJ Tel: Fax: avramanan@hotmail.com Co-Chief Investigator (Co-CI): Professor Michael Beresford Senior Lecturer Paediatric Medicine Paediatric Rheumatology Institute of Child Health Alder Hey Children s NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: m.w.beresford@liverpool.ac.uk Page 4 of 76

7 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Medical expert who will advise on protocol ophthalmology related clinical queries: Professor Andrew Dick Professor of Ophthalmology Academic Department of Ophthalmology Department of Clinical Sciences University of Bristol Tel: Fax: Medical Expert who will Advise on Protocol Rheumatology Related Clinical Queries: Dr. Athimalaipet Vaidyanathan Ramanan Consultant Paediatric Rheumatologist Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ Tel: Fax: Medical experts who will evaluate SAE reports: Dr. Athimalaipet Vaidyanathan Ramanan Consultant Paediatric Rheumatologist Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ Tel: Fax: Dr Clive Edelsten Consultant Ophthalmologist Department of Paediatric Rheumatology Great Ormond Street Hospital for Children London WC1N 3JH Tel: ext 7887 Fax: Professor Michael Beresford Senior Lecturer Paediatric Medicine Paediatric Rheumatology Institute of Child Health Alder Hey Children s NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: m.w.beresford@liverpool.ac.uk Professor Michael Beresford Senior Lecturer Paediatric Medicine Paediatric Rheumatology Institute of Child Health Alder Hey Children s NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: m.w.beresford@liverpool.ac.uk Professor Andrew Dick Professor of Ophthalmology Academic Department of Ophthalmology Department of Clinical Sciences University of Bristol Tel: Fax: a.dick@bristol.ac.uk Page 5 of 76

8 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: IMP Management Head of Health Economics: Head of Trial Management: Dr Utpal Shah Cheshire, Merseyside & North Wales LRN Medicines for Children Research Network 1st Floor, Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: Professor Dyfrig Hughes Professor of Pharmacoeconomics Centre for Economics and Policy in Health Bangor University Institute of Medical and Social Care Research Dean Street Gwynedd Wales LL57 1UT Tel: Fax: Ms Helen Hickey Medicines for Children Clinical Trials Unit Institute of Child Health Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: Head of Statistics: Trial Statistician: Trial Manager: Mr Ashley Jones Senior Statistician Medicines for Children Clinical Trials Unit Institute of Child Health Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: Miss Lynne Cresswell Medicines for Children Clinical Trials Unit Institute of Child Health Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: Mr Ben Hardwick Medicines for Children Clinical Trials Unit Institute of Child Health Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: Data Manager: Health Economist: Pharmacy Guidance Miss Jo Eatock Senior Data Manager Medicines for Children Clinical Trials Unit Institute of Child Health Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: Dr. Colin H Ridyard Centre for Economics and Policy in Health Institute for Medical and Social Care Research Bangor University Dean Street Bangor LL57 1UT Tel: Fax: c.h.ridyard@bangor.ac.uk Sarah Hanby/Amy Williams Pharmacy Department Bristol Eye Hospital Lower Maudline Street Bristol BS1 2LX Tel: Fax: Page 6 of 76

9 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Independent Oversight Committees Independent Data and Safety Monitoring Committee Mr John Sparrow Consultant Ophthalmologist Bristol Eye Hospital Bristol Eye Hospital Lower Maudlin Street Bristol BS1 2LX Tel: Dr Steff Lewis Deputy Director, Edinburgh MRC Clinical Trials Unit Methadology Hub Public Health Sciences section Centre for Population Health Sciences The University of Edinburgh Medical School, Teviot Place Edinburgh EH8 9AG Tel: (Mon)/ (Tue, Wed, Thur) Fax: Dr Justine Smith Ophthalmologist Casey Eye Institute Oregon Health Sciences University 3181 SW Sam Jackson Pk Rd MC L467AD Portland, OR UNITED STATES Tel. (503) Fax. (503) Dr Nico Wulffraat Paediatric Rheumatologist UMC Utrecht Department of Paediatrics Utrecht Netherlands 3508AB Tel. (31) Independent members of the Trial Steering Committee* Professor Ian Bruce Professor of Rheumatology The University of Manchester School of Translational Medicine Stopford Building Oxford Road Manchester M13 9PT Tel Professor Simon Harding Consultant Opthalmologist The Royal Liverpool and Broadgreen University Hospitals NHS Trust Spire Liverpool Hospital Greenbank Road Liverpool L18 1HQ Tel *Non independent Members are listed in Appendix A Dr Janine Gray Principal Medical Statistician Clinical Trials Research Unit University of Leeds Leeds LS2 9JT Tel Fax: j.c.gray@leeds.ac.uk Page 7 of 76

10 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: CONTENTS 1 Contact details Contents Protocol Summary Background Information Introduction Rationale Objectives Primary objective: Secondary objectives: Potential Risks and Benefits Potential Risks Known Potential Benefits Selection of Centres/Clinicians Centre/Clinician Inclusion Criteria Centre/Clinician Exclusion Criteria Trial design Primary Endpoint Secondary Endpoint(s) Study Population Inclusion Criteria Exclusion Criteria Co-enrolment Guidelines Patient Transfer and Withdrawal Patient Transfers Withdrawal from Trial Intervention Withdrawal from Trial Completely screening, Enrolment and Randomisation Patient Identification, Provision of Information and Pre-screening Consent and Screening Randomisation and Treatment Commencement Requests for Randomisation Trial Treatments Introduction Randomisation Delivery and storage of IMP at trial sites Dispensing, Dosage and Administration of Study Treatments Dispensing Dose Modifications (Adalimumab and placebo) Dosage and Administration Formulation and Packaging: Adalimumab solution for subcutaneous injection: Placebo solution for subcutaneous injection: Packaging: Labelling, Storage and Stability Expired and unused IMP stock Concomitant Medications/Treatments Medications Permitted Page 8 of 76

11 Page 9 of 76 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Medications Not Permitted Assessment of Compliance with Study Treatments Early withdrawal of treatment Unblinding Unblinding of Individual Participants During Trial Conduct Procedure Accidental Unblinding Unblinding at Trial Closure Non-Investigational medicinal Product (NIMP) - Methotrexate Dose range Dose modifications - Methotrexate Assessments and Procedures Schedule for Follow-up Procedures for Assessing Efficacy Ophthalmic Assessments Physical Examination Rheumatology Assessments: American College of Rheumatology Pedi Core Set Criteria and related outcomes Procedures for Assessing Safety Adverse Events Screening for Tuberculosis Urinalysis Serum pregnancy test Tanner Score Haematological Laboratory Assessments Biochemical laboratory Assessments Compliance with Study Treatment Quality of Life Child Health Assessment Questionnaire Childhood Health Questionnaire Health Economics Health Utilities Index Hospital Episode Statistics Client Service Receipt Inventory Other Assessments Special Assays or Procedures Establishment of JIA-associated Biobank Loss to Follow-up Trial Closure Statistical Considerations Method of Randomisation Outcome Measures Primary Secondary Endpoint(s) Sample Size Interim Monitoring Reports Analysis Plan Economic Analysis Plan Pharmacovigilance Terms and Definitions Notes on Adverse Event Inclusions and Exclusions Include Do Not Include... 49

12 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Reporting of Pregnancy Notes Severity / Grading of Adverse Events Relationship to Trial Treatment Expectedness Follow-up After Adverse Events Reporting Procedures Non serious ARs/AEs Serious ARs/AEs/SUSARs Responsibilities Investigator Maintenance of Blinding Responsibilities CTU SAE reporting Abbott Safety reports Ethical Considerations Ethical Considerations Ethical Approval Informed Consent Process General Competent Adults (aged years at time of consent) Minors (aged <16 years at time of consent) Minors reaching 16 years during trial participation Regulatory Approval Trial Monitoring Risk Assessment Source Documents Data Capture Methods Confidentiality Direct access to data Quality Assurance and Control Records Retention Indemnity Financial Arrangements Participant Payment Collaborating Centre Payments Research Team Pharmacy Department Trial Committees Trial Management Group (TMG) Trial Steering Committee (TSC) Independent Data and Safety Monitoring Committee (IDSMC) Publication Protocol Amendments Version 1 (25/Feb/2011) References Appendices Appendix A: Trial Management Group Composition Appendix B: LOCS III grading adapted from Chylack et al Page 10 of 76

13 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Glossary ACR American College of Rheumatology AE Adverse Event AR Adverse Reaction CHAQ Childhood Health Assessment Questionnaire CHQ Childhood Health Questionnaire CI Chief Investigator CMO Cystoid Macular Oedema CRF Case Report Form CTRC Clinical Trials Research Centre CTU Clinical Trials Unit DMARD Disease Modifying Anti-Rheumatic Drugs GP General Practitioner HUI2 Health Utilities Index 2 IB Investigator s Brochure IDSMC Independent Data and Safety and Monitoring Committee IEC Independent Ethical Committee IMP Investigational Medicinal Product LREC Local Research Ethics Committee MCRN CTU Medicines for Children Research Network Clinical Trials Unit MREC Main Research Ethics Committee NIHR CRN National Institute for Health Research Clinical Research Network OCT optical coherence tomography PI Principal Investigator R&D Research & Development S/C MTX Subcutaneous Methotrexate SAE Serious Adverse Event SAR Serious Adverse Reaction SDV Source Data Verification SPC Summary of product characteristics SUN Standardisation of the Uveitis Nomenclature SUSAR Suspected Unexpected Serious Adverse Reaction TMG Trial Management Group TSC Trial Steering Committee UAR Unexpected Adverse Reaction ULN Upper Limit of Normal Page 11 of 76

14 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: PROTOCOL SUMMARY Title of Study: Randomised controlled trial of the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis Study Design: Randomised, double-blind, placebo-controlled, multicentre, trial of adalimumab in combination with methotrexate (MTX) in patients with active uveitis in association with JIA refractory to MTX monotherapy. Participants will be randomised applying a ratio of 2:1 (in favour of adalimumab). Population Number of Sites 154 patients with persistently active JIA-associated uveitis (despite optimised methotrexate (MTX) treatment for at least 12 weeks) The study will be carried out in at least 14 tertiary care centres throughout the UK Study Duration All participants will be treated for 18 months, with follow up for a total of 3 years from randomisation (continuing on MTX throughout) Description of Agent/Intervention Primary Objective Secondary Objectives Adalimumab. All participants will receive a stable dose of MTX and in addition either adalimumab (20mg/0.8ml for patients <30kg or 40mg/0.8ml for patients weighing 30kg, s/c injection every 2 weeks based on body weight), or placebo ( 0.8ml as appropriate according to body weight) s/c injection every 2 weeks. To compare the clinical effectiveness of adalimumab in combination with MTX versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with juvenile idiopathic arthritis (JIA) To evaluate short term safety and tolerability of adalimumab in combination with MTX versus MTX alone, with regards ocular complications of treatment, adverse events and laboratory assessments To determine quality of life and cost effectiveness of adalimumab in combination with MTX versus MTX alone in severe uveitis associated with JIA To determine the clinical effectiveness of adalimumab in combination with MTX versus MTX alone, with regard underlying JIA disease activity To determine the durability and magnitude of adalimumab efficacy response in sustaining inactive disease and achieving complete clinical remission To determine the long term safety of adalimumab in combination with MTX versus MTX alone To assess the efficacy of treatment with adalimumab to permit concomitant medication reduction, in particular regional and parenteral steroids To assess clinical implications of anti-adalimumab antibody (HAHA) development in relation to efficacy / hypersensitivity To develop a fully consented, trial-related biobank for subsequent investigation Page 12 of 76

15 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Protocol Summary - continued Schematic of Study Design: Participant fulfilling eligibility criteria and providing fully informed written consent RANDOMISE (2:1 in favour of active) 2 weekly s/c injections adalumimab, plus MTX n = weekly s/c injections placebo plus MTX n = 52 Treatment Months 1 to 3 Monthly OPD review: completion of QoL and Health Economic questionnaires, AE review, ophthalmology and rheumatology review: Treatment failure? No Treatment Months 4 to 18 Three Monthly OPD review: completion of QoL and Health Economic questionnaires, AE review, ophthalmology and rheumatology review: Treatment failure? Yes No Post-treatment Follow-up Three Monthly OPD review: completion of QoL and Health Economic questionnaires, AE review, ophthalmology and rheumatology review. Any additional treatment administered at discretion of treating physician and recorded on CRF Cease trial treatment Page 13 of 76

16 4 BACKGROUND INFORMATION SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Introduction Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA also are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20-25% of all paediatric uveitis is associated with JIA 1,2 but a greater proportion are seen in referral cohorts. The major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity 3. In the initial stages of mild to moderate inflammation the uveitis is entirely asymptomatic. This has led to the current practice of screening all children with JIA regularly for uveitis. Approximately 12-38% of patients with JIA will develop uveitis in the seven years following the onset of arthritis 4,5. In 30-50% of children with JIA associated uveitis structural complications are present at diagnosis 6. Furthermore about 50-75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract, glaucoma, band keratopathy and macular pathology 7-9. Defining the severity of inflammation and structural complications in uveitis patients can now be more consistently described following Standardised Uveitis Nomenclature (SUN) guidelines, allowing their incorporation into design of randomised controlled trials (RCT) and cohort studies 10. Significant poor prognosticators of poor visual acuity include structural changes at presentation; the need for intraocular surgery, posterior segment inflammation, abnormal intraocular pressure and the failure to maintain long-term disease control as marked by persistent AC cell scores <1+ 6-8,11. Despite current screening and therapeutic options (prebiologics) % of children with JIA associated uveitis may eventually develop bilateral visual impairment and are certified legally blind 12,13. It is therefore critical to find more effective therapeutic interventions. 4.2 Rationale Methotrexate (MTX) is well established as the first-line disease modifying agent in the management of JIA 14,15. The current approaches to treatment of mild JIA-associated uveitis include use of topical steroids. MTX is also thought to be effective for JIA-associated uveitis in children with moderate-to-severe uveitis 16-18, but there have been no prospective randomised placebo-controlled trials of MTX or steroid regimens in JIA-associated uveitis. Systematic review of the evidence of MTX in JIA is restricted to joint involvement 14 but not in paediatric uveitis. Despite the scarce evidence, MTX has become the mainstay of treatment for JIA-uveitis 19. However, up to 15-50% of children will have refractory uveitis in spite of optimal therapy with methotrexate De Boer found that 30% of patients started on MTX will not achieve control during the first year of therapy and even when remission is achieved on MTX 9/13 will later relapse suggesting only 4/22[18%] patients achieve total remission.in the GOS cohort a similarly low proportion of 12% were found to be in total remission five years after starting MTX 74. Several agents including ciclosporin and mycophenolate mofetil (MMF) have been shown to be of benefit in controlling JIA-uveitis in retrospective small case series 20,21. However their use remains restricted due to intolerability due to adverse reactions and little evidence that they rescue methotrexate-refractory patients. In addition, neither ciclosporin nor MMF are very effective in controlling joint manifestations in the children 19. More recently, animal models and corroborative human evidence 22, supports the role of tumor necrosis alpha (TNF- ) in the aetiopathogenesis of uveitis, and moreover the potential value of its inhibition as a therapeutic intervention 23. Studies on experimental models of autoimmune uveitis have demonstrated that TNF plays a pivotal role in pathogenesis of intraocular inflammation 22, which has been borne out in Page 14 of 76

17 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: treatment of adult uveitis 23. In mouse models of anterior uveitis, deleting p55 receptor as well as combined TNFR p55 and p75 knockout animals, results in reduced disease 24, more significantly than the effect of TNFR p55 fusion protein 25. Furthermore, in an animal model of uveitis, infliximab reduced disease severity 26, albeit at doses of 20mg/kg. Translating this to humans, several case series have been published demonstrating the efficacy of infliximab and adalimumab in treatment of severe refractory uveitis in adults and children In contrast, etanercept has been reported not to halt onset of uveitis or be more effective than placebo 33,34, and less effective than infliximab in treating JIA-uveitis 30,35,36. There are a number of reports of new-onset uveitis associated with etanercept use in JIA 37. An adverse events register-based study examining these cases determined that whilst the frequency was greater for etanercept than for infliximab or adalimumab (n=20, 4 and 2 cases respectively), causality could not be established 38. Etanercept is not considered to be effective in treating intraocular inflammation 30. Adalimumab is a fully human monoclonal antibody engineered by gene technology that uses site-directed mutagenesis to enhance its binding efficiency to TNF. It does not contain nonhuman or artificial protein sequences. Adalimumab binds only to TNF-α and has a half life of approximately two weeks. The antibody has been extensively studied in vitro as well as in vivo and is non-toxic in animal toxicology experiments. Clinical trial of adalimumab as monotherapy or in combination with MTX in adult subjects with rheumatoid arthritis showed a significant clinical response 39. In children with JIA, a multicenter randomised, double blind stratified parallel group trial has shown a significant benefit in children with active arthritis 40. Studies in paediatric non-infectious uveitis have shown very promising results with adalimumab, with 21 out of 26 eyes from 14 children with JIA- or idiopathic-uveitis showing improvement in inflammation 41. In another retrospective case series of 18 paediatric patients with uveitis, 88% had a substantial decrease in ocular inflammation and adalimumab showed corticosteroid-sparing potential 27. There are no prospective studies of efficacy and safety of anti-tnf agents in JIA-associated uveitis. In the randomised controlled trial of adalimumab in JIA that demonstrated safety and efficacy, the most commonly reported adverse events were infections and injection-site reactions 40. Serious adverse events considered possibly related to study drug by the investigator occurred in 14 patients. Seven of these included one case of: bronchopneumonia, herpes simplex infection, pharyngitis, and pneumonia, and two cases of herpes zoster infection. In this trial there were no deaths, malignant conditions, opportunistic infections, cases of tuberculosis, demyelinating diseases or lupus-like reactions 40. The fixed dose model of 20 mg for children < 30 kg and 40mg for children 30 kg selected for this trial is based on the data generated in the above trial using the same dosing regimen Objectives Primary objective: To compare the clinical effectiveness of adalimumab in combination with methotrexate (MTX) versus MTX alone, with regard to controlling disease activity in refractory uveitis associated with juvenile idiopathic arthritis (JIA) Secondary objectives: To evaluate short term safety and tolerability of adalimumab in combination with MTX versus MTX alone, with regards ocular complications of treatment, adverse events and laboratory assessments Page 15 of 76

18 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: To determine quality of life and cost effectiveness of adalimumab in combination with MTX versus MTX alone in severe uveitis associated with JIA To determine the clinical effectiveness of adalimumab in combination with MTX versus MTX alone, with regard underlying JIA disease activity To determine the durability and magnitude of adalimumab efficacy response in sustaining inactive disease and achieving complete clinical remission To determine the long term safety of adalimumab in combination with MTX versus MTX alone To assess the efficacy of treatment with adalimumab to permit concomitant medication reduction, in particular regional and parenteral steroids To assess clinical implications of anti-adalimumab antibody (HAHA) development in relation to efficacy / hypersensitivity To develop a fully consented, trial-related biobank for collection of serum, DNA and RNA for subsequent investigation 4.4 Potential Risks and Benefits JIA-associated uveitis is a severe, potentially sight-threatening condition, often inadequately treated using standard therapies. Advent of the biologic therapies offers significant anticipated benefits therefore to the patient. However, due care must be taken in determining the potential benefits of anti-tnf therapy, now being used in off-label manner in this condition, against the potential associated risks. Safety (short and long term) of the new biologic therapies in children and young people is of major importance, particularly in this study. The risk / benefit assessment of this intervention needs careful attention. Safety is therefore a key secondary outcome measure of the trial Potential Risks The long term follow up of children on etanercept and adalimumab from controlled studies have, to date, not shown any increased risk of malignancies. However the United States Federal Drug Administration (FDA) have recently issued an alert to healthcare professionals that their analysis has revealed that 48 children developed malignancies whilst on anti-tnf agents including eleven deaths 48. The data is mainly for children and adolescents on etanercept and infliximab on account of limited follow up data available on adalimumab. The analysis includes in particular children with Crohn s disease. 88% of the 48 children were also on concomitant immunosuppressive medication including azathioprine and methotrexate. The complete details of the FDA analysis are not currently available. Importantly, these data do not provide comparative information on long term malignancy rates in JIA patients treated with methotrexate alone, or untreated JIA. Subsequent data presented at the American College of Rheumatology (2009) of 1168 patients over patient years indicates no increased risk of anti-tnf therapy in JIA (Abstract: Bernatsky, Rosenberg & Kiem, ACR, 2009). Recent data presented at EULAR emphasises the importance of comparing anti-tnf safety data to untreated disease (EULAR 2010, McCroskey P) and that current data does not indicate a significant relative increase with respect to controls (Southwood T et al. EULAR 2010 Oral presentation). All these reports however emphasise the critical importance of making safety a major priority in this trial. This priority is both within the treatment and follow up duration of the trial, but also ensuring procedures are in place to continue this safety follow up longer term. The risk of increased malignancy with azathioprine in patients with Crohn s disease on infliximab is well recognised 49,50. As noted already, adverse events associated with the recent adalimumab trial in JIA was associated with minimal safety signals 40. A recent retrospective cohort study evaluated overall mortality and cancer mortality in relation to immunosuppressive drugs exposure in adult patients with ocular inflammatory diseases Page 16 of 76

19 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: including anti-tnf drugs 51. The study did show an increased overall and cancer mortality in adult patients exposed to anti-tnf agents. The authors acknowledge that this data needs interpreted with caution on account of the methodological issues associated with retrospective studies and prevalence of co-morbidity in patients on anti-tnf drugs. From adult data, but also the growing evidence base from published data of long term follow up in biologic registries, clinical trials and cohort studies, a number of important safety signals need to be considered in this trial, Patients taking TNF-blockers are more susceptible to serious infections. Patients must therefore be monitored closely for infections, including tuberculosis, before, during and after treatment with adalimumab. Because the elimination of adalimumab may take up to five months, monitoring should be continued throughout this period. Adverse events of the haematologic system, including medically significant cytopaenia (e.g. thrombocytopaenia, leucopaenia) have been reported with adalimumab. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor) while on adalimumab. Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant methotrexate. Antibody formation to the drug itself was lower when adalimumab was given together with methotrexate in comparison with use as monotherapy. Administration of adalimumab without methotrexate resulted in increased formation of antibodies, increased clearance and reduced efficacy of adalimumab (see section 5.1). In patients with polyarticular juvenile idiopathic arthritis, adalimumab antibodies were identified in 27/171 subjects (15.8%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 22/86 (25.6%), compared to 5/85 (5.9%) when adalimumab was used as add-on to methotrexate 40. Patients who develop a new infection while undergoing treatment with adalimumab, should be monitored closely and undergo a complete diagnostic evaluation. Administration of adalimumab should be discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled. Physicians should exercise caution when considering the use of adalimumab in patients with a history of recurring infection or with underlying conditions which may predispose patients to infections, including the use of concomitant immunosuppressive medications. Serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis and septicaemia Approximately 10-15% of participants can be expected to see injection site reactions at some time Known Potential Benefits In rheumatoid arthritis studies I-IV, all individual components of the adult ACR response criteria (number of tender and swollen joints, physician and patient assessment of disease activity and pain, disability index (HAQ) scores and CRP (mg/dl) values) improved at 24 or 26 weeks compared to placebo. In rheumatoid arthritis studies I-IV, Adalimumab-treated patients achieved statistically significant ACR 20 and 50 responses compared to placebo as early as one to two weeks after initiation of treatment. Page 17 of 76

20 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: In polyarticular course JIA, adalimumab has been shown to have a significant clinical benefit in JIA on core paediatric ACR response criteria 46. In the double-blind, withdrawal design phase of the trial of adamilumab in JIA 40, amongst patients not receiving MTX, there was significant increase in the number of disease flares in those subsequently receiving placebo compared to adalimumab (71% versus 43%, p=0.03) 75. In those patients receiving concomitant MTX, flares occurred in 65% on placebo, compared to 37% receiving adalimumab (p=0.02). At 48 weeks, the percentage of patients treated with MTX who had ACR Pedi30, Pedi50, Pedi70 and Pedi90 responses were significantly greater for those receiving adalimumab than those receiving placebo (ACR Pedi 30: 63% versus 38%, p=0.03; ACR Pedi 50: 63% versus 38%, p=0.03; ACR Pedi70: 63% versus 27%, p=0.002). Open label extension of the studies showed sustained responses for up to 104 weeks of treatment. As outlined in the Protocol Rationale, its reported use in JIA-associated Uveitis warrants an RCT trial to assess its clinical effectiveness and safety. Page 18 of 76

21 5 SELECTION OF CENTRES/CLINICIANS SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Study centres will be initiated once all their global (e.g. local R&D approval) and studyspecific conditions (e.g. training requirements) have been met, and all necessary documents have been returned to MCRN CTU. Initiation meetings will cover the requirements outlined in the Clinical Trials Research Centre s Standard Operating Procedures relating to site training and set up. 5.1 Centre/Clinician Inclusion Criteria a. Centres offering combined paediatric rheumatology/ophthalmology service b. It is essential that all recruits should have regular and emergency access to a paediatric rheumatologist / ophthalmologist c. Completion of calibration training in ophthalmology assessments d. Sufficient demonstrated capacity of staff to carry out study assessments e. Curriculum Vitae (CV) including a record of International Conference for Harmonisation (ICH) of GCP training Principal Investigator (PI) f. CV including a record of ICH GCP training Other personnel on the delegation log g. Completion and return of Signature and Delegation Log to CTU h. Positive SSI i. Local R&D approval j. Signed contract between site and sponsor k. Receipt of evidence of completion of (h) to (j) by CTU l. Sites must be able to perform Biochemical assessments as outlined in section All sites would be expected to demonstrate ability to run paediatric clinical trials in accordance with Good Clinical Practice, and as such demonstrate support and infrastructure for all aspects of trial delivery including integration of the clinical research teams with pharmacy, clinical laboratory, and research support services; all centres will be expected to work in collaboration with Research Network support where present, including the NIHR MCRN Local Research Networks, the Comprehensive Local Research Network, and equivalent in Scotland, Wales and Northern Ireland. 5.2 Centre/Clinician Exclusion Criteria Not meeting the inclusion criteria and expectations stated above Page 19 of 76

22 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: TRIAL DESIGN 6.1 Primary Endpoint The primary endpoint is time to treatment failure. Treatment failure is defined by ONE or more of the following: 1) Anterior segment inflammatory score grade (SUN criteria) a) Following at least 3 months of therapy: i) 2-Step increase in SUN cell activity score (AC Cells) over 2 consecutive readings ii) Sustained non-improvement with entry grade of 3 or greater for 2 consecutive readings iii) Only partial improvement (1 grade) with sustained development of other ocular co-morbidity* iv) Sustained scores as recorded at entry grade measured over 2 consecutive readings (grades 0.5 to 2) still present after 6 months of therapy. v) Worsening of existing (on enrolment) ocular co-morbidity after 3 months 2) Use of Concomitant Medications: At any time, requirement to use concomitant medications in manner out with pre-defined acceptable criteria (see section 9.8.1), or any of the concomitant medications not allowed (see section 9.8.2) * Ocular co-morbidities are defined as: i) Disc swelling and/or Cystoid Macular Oedema (CMO) as gauged clinically and where possible by OCT evidence; and/or: ii) Sustained raised intraocular pressure (<25mm Hg) over 1 month not responding to single ocular hypotensive agent, and/or: iii) Sustained hypotony (<6 mm Hg) over 1 month, and/or iv) Development of unexplained reduction in vision (LogMar) of 15 letters (in the event of cataract participants will remain in trial, also if cataract surgery is required. Failure will still remain as described in endpoints above). 6.2 Secondary Endpoint(s) 1) Number of participants failing treatment 2) Incremental cost-effectiveness and cost-utility of adalimumab added to MTX compared with MTX alone 3) Health status according to the multi-attribute health utility index, HUI2 4) Safety, tolerability and compliance a. Adverse events (AEs) and serious adverse events (SAEs) b. Laboratory parameters (haematological and biochemical analysis and urinalysis c. Development of anti-adalimumab antibody (HAHA) will be determined with samples collected at months 1, 6 and 18 d. Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period 5) Use of Corticosteroids over duration of study period and throughout follow up, including: a. Total oral corticosteroid dose b. Reduction in and rate of systemic corticosteroid dose from entry dose c. Topical corticosteroid use (frequency) compared to entry usage Page 20 of 76

23 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: d. Need for pulsed corticosteroid 6) Optic and ocular a. Number of participants having disease flares (as defined by worsening on SUN criteria) following minimum 3 months disease control b. Number of participants having disease flares within the first 3 months. c. Visual acuity measured by Age-appropriate LogMar assessment d. Visual angle improvement: defined as number of participants halving visual angle e. Visual angle worsening: defined as number of participants doubling visual angle f. Number of participants with resolution of associated optic nerve or macular oedema (as assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) (where available). g. Number of participants with disease control (defined as zero cells, with topical treatment for 3 and 6 months) h. Number of participants entering disease remission (defined as zero cells, without topical treatment for 3 and 6 months) i. Duration and magnitude in sustaining inactive disease (zero cells, with or without topical treatment) 7) Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ)) 8) American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels (see section 8.2) 9) Number of participants undergoing disease flare, in remission on and off medication 54 of their JIA and with minimum disease activity 55 10) Number participants requiring change in biologic / Disease-modifying anti-rheumatic drugs (DMARDs) therapy due to failure to respond from arthritis Page 21 of 76

24 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: STUDY POPULATION 7.1 Inclusion Criteria A participant is eligible for the trial based upon at least one eye fulfilling the eligibility criteria 1) Children and young people aged 2 and 18 years fulfilling ILAR diagnostic criteria for JIA (all subgroups that have uveitis). 2) At the time of trial screening the participant must have active anterior uveitis, defined as a sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade >1+ or more during the preceding 12 weeks therapy despite MTX and corticosteroid (both systemic and topical) therapy 3) They must have failed MTX (minimum dose of 10-15mg/m 2, with a maximum dose of 25mgs). The participant must have been on MTX for at least 12 weeks* and have been on a stable dose for 4 weeks prior to screening visit. 4) Disease modifying immunosuppressive drugs, other than MTX, discontinued at least 4 weeks before receiving the first dose of adalimumab. 5) Written informed consent of participant or parent/legal guardian, and assent where appropriate. 6) Participant and parent/legal guardian willing and able to comply with protocol requirements. 7) For participants of reproductive potential (males and females), use of a reliable means of contraception throughout their trial participation. Post pubertal females must have a negative serum pregnancy test within 10 days before the first dose of trial drug. 8) Able to be randomised and commence trial treatment within 2 weeks of the screening visit. * Omission of a maximum of 2 weeks methotrexate treatment within the 12 weeks is acceptable and will not render the patient ineligible unless they have been missed in the 4 weeks prior to the screening visit. 7.2 Exclusion Criteria 1) Uveitis without a diagnosis of JIA 2) Currently on adalimumab or has previously failed on adalimumab. 3) Have been on other biologic agent within previous 5 half-lives of agent (For other biologic agents and their wash out periods, (refer to protocol supplementary document #10) 4) More than 6 topical steroid eye drops per day at randomisation (this dose must have been stable for at least 4 weeks prior to screening visit) 5) For patients on Prednisone or Prednisone equivalent, change of dose within 30 days prior to randomisation 6) For patients on Prednisone or Prednisone equivalent with a dose >0.2mg/kg per day 7) Intra-articular joint injections within four weeks prior to randomisation 8) Any ongoing chronic or active infection (including infective uveitis) or any major episode of infection requiring hospitalisation or treatment with intravenous antibiotics within 30 days or oral antibiotics within 14 days prior to the screening evaluation 9) History of active tuberculosis of less than 6 months treatment or untreated latent TB 10) Participant has history of central nervous system (CNS) neoplasm, active CNS infection, demyelinating disease, or any progressive or degenerative neurological disease Page 22 of 76

25 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: ) Poorly controlled diabetes or persistently poorly controlled severe hypertension (>95 th percentile for height / age) as deemed by the treating physician 12) Previous history of malignancy 13) Intraocular surgery within the 3 months prior to screening (cataract/ glaucoma/ vitrectomy) 14) Intra-ocular or peri-ocular corticosteroids within 30 days prior to randomisation. 15) History of ocular herpetic disease 16) Pregnant or nursing female 17) Demonstrations of clinically significant deviations in any of the following laboratory parameters: a. Platelet count < 100,000/mm 3 b. Total white cell count < 4000 cells/mm 3 c. Neutrophils < 1000 cells/mm 3 d. AST or ALT > 2 x upper limit of normal (ULN) or serum bilirubin > 2x the ULN e. Glomerular filtration rate (GFR) of < 90 ml/min/1.73m 2 [GFR (ml.min/1.73 m 2 BSA) = 0.55 x height (cm)/plasma creatinine (mg/dl)] f. Hematocrit <24% 18) Having been administered a live or attenuated vaccine within three months prior to screening 19) Previous randomisation into the SYCAMORE trial to either arm of the trial. 7.3 Co-enrolment Guidelines To avoid potentially confounding issues, patients should not be recruited into other interventional IMP trials. Individuals who have participated in previous trial testing of an IMP should will not be eligible for this trial until the appropriate washout period has outlined within Exclusion Criteria (Section 7.2) or in accordance with the respective half-life of the previous IMP. Where recruitment into another trial or study is considered to be appropriate and without having any detrimental effect on either trial this must first be discussed with the coordinating centre (MCRN CTU) who will contact the Chief Investigator (Dr Athimalaipet Vaidyanathan Ramanan). All patients however are eligible to be considered for recruitment to non-interventional studies relevant to their disorder or treatment, in accordance with the respective study protocols. In particular, longitudinal observational cohort, pharmacovigilance and efficacy, quality of life and mechanism of disease studies. 7.4 Patient Transfer and Withdrawal Patient Transfers For patients moving from the area, every effort should be made for the patient to be followed-up at another participating trial centre and for this trial centre to take over responsibility for the patient or for follow-up via GP. A copy of the patient CRFs should be provided to the new site. The patient (or parent/legal representative) will have to sign a new consent form at the new site, and until this occurs, the patient remains the responsibility of the original centre. The CTU should be notified in writing of patient transfers. Page 23 of 76

26 7.4.2 Withdrawal from Trial Intervention SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Patients may be withdrawn from treatment for any of the following reasons: a. Parent/ legal representative (or, where applicable, the patient) withdraws consent. b. Unacceptable adverse effects/ toxicity as determined by the treating clinician. c. Intercurrent illness preventing further treatment. d. Development of serious disease or any change in the patient s condition that justifies the discontinuation of treatment in the clinician s opinion. If a patient wishes to withdraw from trial treatment, centres should nevertheless explain the importance of remaining on trial follow-up, or failing this, of allowing routine follow-up data to be used for trial purposes. Generally, follow-up will continue unless the patient explicitly also withdraws consent for follow-up (see section 7.4). Upon discontinuation of trial intervention participants will be treated in accordance with usual local clinical practice Withdrawal from Trial Completely Patients are free to withdraw consent at any time without providing a reason. In consenting to the trial, patients are consented to trial treatment, follow-up and data collection. If voluntary withdrawal occurs, the patient (or parent/legal representative, where applicable) should be asked to allow continuation of scheduled evaluations, complete an end-of-study evaluation, and be given appropriate care under medical supervision until the symptoms of any adverse event resolve or the subject s condition becomes stable. If consent is withdrawn completely then the reasons for withdrawal of consent will be collected (if possible) and reported for both groups. Participants who wish to withdraw consent for the trial will have anonymised data collected up to the point of that withdrawal of consent included in the analyses unless the patient explicitly states that this is not their wish. The patient will not contribute further data to the study and the CTU should be informed in writing by the responsible physician and a withdrawal CRF should be completed. Page 24 of 76

27 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: SCREENING, ENROLMENT AND RANDOMISATION Several assessments are required to be undertaken as part of the research activity in order to establish eligibility, requiring that written informed consent (or proxy consent in the case of minors) is obtained prior to formal trial screening. For this reason, centres are encouraged to adopt a pre-screening procedure in order to identify potentially eligible patients prior to their attending clinic review. 8.1 Patient Identification, Provision of Information and Prescreening All teams will review on a regular and timely basis potentially eligible patients from within their clinical cohort(s). Potential recruits identified via these pre-screening exercises will be provided with an ethically approved summary of the trial prior to attending for clinical review. At the time of clinical review the treating consultant and / or other designated individual (as identified on the site signature and delegation log) will subsequently ratify that they potentially meet these criteria and will approach identified patients to discuss the study further. If they wish to know more about the trial and to be considered for entry they will be supplied with a copy of the Patient Information Sheet and Consent form (PISC). The time taken from initial contact and provision of information to obtaining written consent should be sufficient to enable appropriate discussions with the patient / family about the trial, explanation of the protocol and procedures, and seeking formal consent. Generally this will be a minimum period of 24 hours, although it is acknowledged that some patients / families may come to this decision sooner A screening log will be maintained at each trial centre, recording all individuals considered and screened for the trial, assigning each a unique screening number, and recording the eventual outcome. Reasons for non-consideration of pre-screened patients, and nonrecruitment of screened patients will be documented (e.g. not eligible, declined consent, etc.) and the information will be used for monitoring purposes. 8.2 Consent and Screening Formal screening involves the collection of baseline data. All patients considered for the trial will be recorded on the screening log and have a unique screening number that will be used on trial documents until the randomisation number is allocated. Assessments for consideration of trial entry which are not undertaken as part of routine care should only be undertaken following provision of written consent. All screening assessments should be completed, and results collated to verify eligibility in a timely manner to ensure that randomisation and treatment can be commenced within 2 weeks of obtaining written consent. Assessment activities are summarised here and detailed descriptions of assessments are provided in section 10. During screening you should: 1) Obtain or verify that written informed consent has been obtained from non-minors (aged years inclusive) or proxy consent for minors (aged <16 years), with assent of minors, where appropriate. 2) Carry out assessments to confirm eligibility and determine baseline parameters: Page 25 of 76

28 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: a. Demographics / medical/ ophthalmic/ surgical history and past medical history b. Detailed rheumatology assessments c. Detailed ophthalmology assessments d. Review concurrent medication and medication history in relation to eligibility e. Detailed Systems Physical examination f. Haematological laboratory assessments g. Biochemical laboratory assessments h. Tanner score i. Height, weight and vital signs (heart & respiratory rate, temperature and blood pressure) j. Standard ACR Pedi Core Set outcome variables k. Urinalysis (microscopy) l. Serum Pregnancy Test m. PPD Tuberculin skin test or local equivalent n. Completion of CHQ/CHAQ, HUI2 and CSRI 3) Eligible patients can now be randomised (Sections 8.4 and 9.2) 4) Consent/assent forms and the Baseline CRF of eligible patients should be submitted to the CTU within 7 days of the visit occurring 5) The outcome for patients found to be ineligible after completing assessments will be recorded on screening logs (CRFs do not require to forwarded to the CTU) 6) Patient s who fail screening may be re-screened after a minimum period of 1 week after their last screening. Patients who fail screening on three occasions are considered to be ineligible for the trial and should not be screened again. 8.3 Randomisation and Treatment Commencement 8.4 Requests for Randomisation Randomisation and treatment commencement should occur within 2 weeks of the screening visit. N.B. All screening assessments should be completed prior to randomising and commencing allocated treatment 1) Complete the appropriate documents to confirm eligibility, request randomisation and prescribe trial treatment. All documentation will carry the trial participants screening number 2) Trial prescriptions will detail the appropriate dose for the participants weight and will indicate that Adalimumab or placebo are to be dispensed according to the treatment allocated at randomisation. 3) Deliver these documents to the pharmacy department in order that pharmacy can proceed with the randomisation (see Section 9.2). 4) Randomisations will be undertaken during normal working hours (Monday Friday ). Randomisation requests received outside of these times will be actioned on the next working day. 5) Commence allocated treatment Page 26 of 76

29 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: TRIAL TREATMENTS 9.1 Introduction This is a randomised, double-blind, placebo controlled trial. The investigational medicinal products (IMPs) in this trial are adalimumab and placebo. Participants will be randomised to one of the following treatment arms: Active arm: Adalimumab subcutaneous injection every 2 weeks for 18 months. The dose will be based on body weight (20mg for participants weighing <30kg or 40mg for participants weighing 30kg). Dose modifications are NOT permitted in participants whose bodyweight changes from less than 30 kg to greater than 30 kg or from greater than 30 kg to less than 30 kg during the 18 month treatment period. Placebo arm: Placebo subcutaneous injection every 2 weeks for 18 months All patients in both arms will continue to receive a stable dose of Methotrexate at a minimum dose of 10-15mg/m 2 and a maximum dose of 25mgs as a non-investigational medicinal product (NIMP) throughout the 18 month treatment period (refer to section 9.12). After the 18 month treatment period participants will be followed up for a further 18 months to determine sustained effectiveness (remission) and safety over and above ongoing MTX therapy. 9.2 Randomisation Randomisation will be undertaken during normal working hours (Monday Friday ) by the pharmacy departments of participating centres upon receipt of a randomisation request form and prescription from authorised clinicians. Pharmacy personnel will verify that these documents are appropriately completed before proceeding. It is the responsibility of the PI or delegated research staff to: 1) Notify pharmacy of potential randomisations so that pharmacy can ensure adequate drug supplies are at site and 2) Complete the appropriate trial documents and deliver these to the pharmacy department at their centre in order that pharmacy can proceed with a randomisation. Participants will be randomised using a secure (24-hour) web based randomisation programme. Randomisation lists will be generated in a 2:1 ratio in favour of the active therapy. The lists will incorporate random elements and the web randomisation programme will controlled centrally by the MCRN CTU; both measures to ensure allocation concealment. Participant treatment allocation will be displayed on a secure webpage and an automated confirmation sent to the authorised randomiser. In the event of an internet connection failure between the centre and the randomisation system, the centre should contact the MCRN CTU immediately to try to resolve the problem. If this is not possible at the time MCRN CTU will provide the treatment allocation. Page 27 of 76

30 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Randomisation: web access If there are any problems with web randomisation please contact the MCRN CTU helpdesk on: Designated pharmacy staff will be trained to use the web randomisation system during the initiation process. After pharmacy staff are trained they will be issued with personal login and password details. 9.3 Delivery and storage of IMP at trial sites Clinical trial supplies will only be delivered to an investigator site once the site has been initiated by MCRN CTU, acting on behalf of sponsor to ensure full ethical and regulatory approvals have been granted. The size of the shipments to each site will be pre-determined based on the participant recruitment target for that individual site. Recruitment will be monitored centrally and drug shipment dates will be tailored accordingly to ensure that pharmacies hold adequate supplies of trial treatment. Pharmacies must document all shipment receipts and will provide copies of this documentation to the MCRN CTU. IMP stock must be received by a designated member of the pharmacy department and must be stored at 2-8 C with temperature monitoring and in accordance with IMP regulations. Records of all shipments must be kept in the drug accountability log. If IMP stock received from the distributor is unexpected, wrong, damaged or out of temperature range, the stock should be quarantined and MCRN CTU contacted for further actions. 9.4 Dispensing, Dosage and Administration of Study Treatments Dispensing IMPs will be supplied as bulk stock from the distributor to pharmacy in kits containing 2 vials. Authorised, trial trained pharmacy staff should select adalimumab or placebo vials (identified by corresponding kit numbers) according to the randomisation instruction, prescription and participant s body weight (20mg for participants weighing <30kg or 40mg for participants weighing 30kg). The number of vials to besupplied at each dispensing will be determined by the date of the next clinic visit, up to a maximum of three months supply (i.e. 6 vials). Pharmacy must enter the site and trial participant identifiers onto the vial and carton labels of each kit at dispensing, (refer to section 9.6) and must complete, sign and date their accountability log. A second member of the pharmacy team must counter-sign and date the log to document the dispensing. Pharmacy must ensure that the participant and the researcher remain blinded to the treatment allocation. At each subsequent dispensing, the patient s randomised treatment allocation should be ascertained by pharmacy (adalimumab or placebo) and a corresponding kit dispensed on production of a valid trial prescription. Drug accountability logs must be maintained throughout. Page 28 of 76

31 9.4.2 Dose Modifications (Adalimumab and placebo) SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: The dose of Adalimumab should remain the same as at trial entry, regardless of minor fluctuations in weight which may cause a participant to cross the 30kg threshold for the upper and lower doses Dosage and Administration The allocated treatment (adalimumab or placebo) must be administered by subcutaneous injection as per local policy every 2 weeks based on the participant s body weight (20mg/0.8mL for participants <30kg or 40mg/0.8mL for participants weighing 30kg) The first dose will be administered by the research / clinical team looking after the patient. All participants or a family member will be invited to self-administer the study treatment after the first dose and taught as such to do this under procedures in place within each participating centre for teaching this. The first dose they administer will also be under supervision of the clinical team, who will ensure they are confident and able to carry out all parts of the procedure appropriately and accurately. If they do not want to do this, then arrangements will be put in place on an individual basis for ensuring trial medication is administered as prescribed. The exact date and time (24-hour clock) of all doses administered must be recorded on the administration record of the CRF. For participants who are self-administering this must be recorded in their trial medication diary. 9.5 Formulation and Packaging: Two strengths of adalimumab and matching placebo will be manufactured by Abbott Laboratories Ltd and supplied in bulk to the distributor for distribution to trial centres. Shipment requests will be authorised by the MCRN CTU Adalimumab solution for subcutaneous injection: Adalimumab 20 milligrams/0.8ml is a clear, colourless solution presented in a singleuse glass vial for subcutaneous injection. Adalimumab 40 milligrams/0.8ml is a clear, colourless solution presented in a singleuse glass vial for subcutaneous injection. Excipients: Mannitol, Citric acid monohydrate, Sodium citrate, Disodium phosphate dehydrate, Sodium dihydrogen phosphate dehydrate, Sodium Chloride, Polysorbate 80, Water for injections, Sodium hydroxide added as necessary to adjust ph. Each vial is intended for a single dose to a single patient. Discard any remaining solution in vials Placebo solution for subcutaneous injection: The matching placebo solution is a clear, colourless solutions presented in a singleuse vial for subcutaneous injection in volumes of 0.8mL. The composition and ph of the placebo is identical to that of the active vials but without adalimumab. Page 29 of 76

32 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Each vial is intended for a single dose to a single patient. Discard any remaining solution in vials Packaging: Contents: Each kit will consist of 2 vials of adalimumab or placebo in an outer carton. Both vials and outer carton will be labelled. 9.6 Labelling, Storage and Stability Labelling: IMPs will be labelled in accordance with regulation 46 SI2004/1031 and the detailed guidance provided in annex 13 of the EU Good Manufacturing Practice (GMP) guide. Each kit will be identified by a kit number on the labelling. Blank sections will be provided on the vial label and outer label for site and patient specific details to be filled in by pharmacy during dispensing. Storage and shelf life: The IMPs should be stored in a refrigerator at 2-8 C. Do not freeze. Keep the vials in the outer carton. The product has a shelf life of 24 months, cool bags with cool blocks will be provided to transport vials home by patients. Temperature excursions: In the event of storage temperatures falling outside the range permitted, stock should be quarantined and the trial coordinator at the MCRN CTU notified for further instructions (see section 1 for trial coordinator contact details). 9.7 Expired and unused IMP stock Any stock that has expired at the trial site during the trial and any stock remaining at trial closedown must be notified to the MCRN CTU who will authorise destruction. Stock will be destroyed locally according to site policy and records made in the drug accountability log. Any unused vials remaining at the patient s home at the end of the trial or on early withdrawal should be returned to the dispensing pharmacy at the participating trial site. 9.8 Concomitant Medications/Treatments Any medication (including over the counter medicines such as paracetamol, antacids, mineral supplements, NSAIDs, anti-inflammatory eye drops and herbal preparations) that the participant is receiving at the time of enrolment, or receives during the study, must be recorded on the appropriate case report form (CRF) along with the reason for use, dates of administration, dosage form, dose and dose frequency Medications Permitted Methotrexate participants must be receiving at least 10-15mgs/m 2 with a maximum dose of 25mgs Low dose of steroids ( 0.2mg/kg/day of prednisone or prednisolone equivalent medication orally) are permitted prior to randomisation and during the active phase of the trial. Prednisone or prednisone equivalent dose must be unchanged for at least Page 30 of 76

33 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: days prior to enrolment. Weaning of systemic steroids whilst enrolled in the trial is at the discretion of the treating clinician. Topical steroid eye drops with maximum of 6 drops/ day at randomisation (this dose must have been stable for at least 4 weeks prior to screening visit). o Either within the first 3 months of being in the trial, or at the 3 month assessment visit, the drops should be reduced to a maximum of 2 drops/day (the rate at which the drops are reduced within the 3 month period will be determined by the treating clinician). o Failure to reduce eye drops to 2 drops/ day by or at the 3 month visit will be considered a treatment failure and the participant should be withdrawn from trial treatment. o After the 3 month time point the dose cannot be changed for the duration of the trial treatment phase. Maxidex, Predforte or equivalent preparation to be stipulated at screening and to remain unchanged for individual throughout treatment-phase of trial Intra-articular joint injections- the participant must not receive more than two intraarticular joint injections in a single session and no more than a total of eight injections per year; no joint injections within 4 weeks of randomisation. Depot peri-ocular steroid injection but not within 30 days prior to screening Medications Not Permitted Intra-ocular or peri-ocular corticosteroids The introduction of oral steroids, or increase in oral steroids, is not permitted at any time during the trial. Intravenous methylprednisolone at any time Other biologic therapies, including: etanercept, infliximab, gonilumimab; rituximab, abatacept, anakinra, tocilizumab Ciclosporine, Mycophenolate Mofetil, Azathioprine, Lefunamide, Sulfazalazine, hydroxychloroquine, any other disease modifying, anti-rheumatic drug 9.9 Assessment of Compliance with Study Treatments Participant diaries and dosing records will determine tolerability and compliance throughout the trial period (see section 10). The parent/guardian of a participant will maintain a diary for all trial and other medications that are administered outside of the trial visit (i.e. at home). In the diary, the date and time the drug is administered will be recorded. The dosing records will be reviewed and verified for compliance at each visit by the research personnel at the trial centre, and all relevant dosing information will be transcribed onto the CRF at each visit. Additionally, any discernible departure from the protocol regarding trial drug administration will also be recorded onto the CRF Early withdrawal of treatment Patients meeting the criteria for treatment failure (section 6.1) or failing to comply with criteria of permitted and non-permitted medicines will be withdrawn from the trial. The decision to discontinue trial therapy is at the discretion of the treating physician. Doses may be discontinued at any point during the trial period for reasons such as unacceptable adverse effects, serious adverse events, intercurrent illness, development of serious disease or any change in the participant s condition that the physician believes warrants a change in medication. Any changes must be documented in the CRF along with the justification for those changes. Page 31 of 76

34 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Unblinding Treatment allocation will be concealed unless knowledge is essential for ongoing care. Should knowledge of treatment allocation be required by the responsible investigator this shall be obtained via their pharmacy department who will complete an unblinding CRF and submit this to the MCRN CTU. All children participating in this study during the active treatment phase of the study are immunosuppressed, in view of their concomitant MTX therapy and / or potentially corticosteroid therapy, irrespective of them being on IMP or placebo. Additionally, for the purpose of out-of-hours management of the patient, all patients should be presumed to be on anti-tnf therapy, and managed as such. In this way, in the event of an AE or SAE, such as an inter-current infection, the treating clinician should manage as patients presumed to be on anti-tnf therapy. For this reason, should unblinding be deemed necessary, this would be carried out via the local pharmacy department following the procedure described below. If out of hours unblinding is required, this will be accessed via the local pharmacy department on-call service Unblinding of Individual Participants During Trial Conduct Upon completion of 18 months treatment Although discouraged, it is acceptable to unblind participants upon completion of their trial treatment (18 months) if this is necessary to enable appropriate ongoing treatment Early withdrawal from treatment Upon early withdrawal from trial therapy, breaking the statistical blind should generally be considered only when knowledge of the treatment assignment is deemed essential for the subject s care by the subject s physician or a regulatory body as it is considered that it may not always be necessary to know the allocation of these patients. N.B. If simply ceasing study treatment is a viable option for the patient s care, it should not be necessary for unblinding to occur Procedure a. The decision to unblind a single case should be made when knowledge of an individuals allocated treatment is essential to: i. Enable treatment of severe adverse event/s, or ii. Enable administration of another therapy that is contraindicated by the trial treatment iii. Enable appropriate ongoing care upon cessation of allocated trial therapy b. Where possible (during office hours), consent for individual unblinding should be made via the trial coordinator at MCRN CTU who will seek agreement of one of the lead investigators (Ramanan and Beresford) c. Pharmacy departments will be unblinded to the treatment allocations of patients within their centre. The PI should ensure that all research personnel are aware of contact details for obtaining details of treatment allocation should this be necessary. d. The request for the allocated treatment should be made to the local pharmacy department e. Only the individual patient is to be unblinded and the following is to be documented by pharmacy on the unblinding CRF: i. Date information needed ii. Detailed reason for unblinding Page 32 of 76

35 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: iii. Identity of recipients of the unblinding information f. The local investigator will ensure all necessary CRFs to time of unblinding are completed and submitted to MCRN CTU (if possible, completed before unblinding is performed) g. All instances of unblinding should be recorded and reported in writing to the MCRN CTU by the local investigator, including the identity of all recipients of the unblinding information. h. Allocation should not routinely be revealed to MCRN CTU personnel Accidental Unblinding All instances of inadvertent unblinding should be recorded and reported in writing to the MCRN CTU by the local investigator. Reports to include: a. Date of unblinding b. Detailed explanation of circumstances c. Recipients of the unblinding information d. Action to prevent further occurrence e. Allocation should not be routinely revealed to MCRN CTU personnel Unblinding at Trial Closure The end of the trial will be considered as the date of the final database lock. In the event that the trial is closed prematurely by the Trial Steering Committee, on the recommendation of the Independent Data and Safety Monitoring Committee, for reasons such as clear differences between safety of trial treatments, the end of the trial will still be considered as the date of the final database lock. Upon trial closure the criteria for unblinding will remain in effect. Pharmacy departments will not disclose treatment allocations on an individual basis. Each participating pharmacy department will return unblinding codes, without breaking the seals to reveal allocation codes, to the MCRN CTU. MCRN CTU will notify local investigators in writing of unblinding information for patients under their care. A copy of this notification should be placed in the medical records and a copy retained in the site file. It is the responsibility of the local investigator to notify trial participants of their allocated treatment Non-Investigational medicinal Product (NIMP) - Methotrexate All participants will be prescribed methotrexate in conjunction with their allocated trial treatment Dose range All participants should, at trial entry, be on a stable dose of methotrexate, which should be in the dose range of 10-15mg/m 2, with a maximum dose of 25mgs. The participant must have been on a stable dose for at least 4 weeks prior to the screening visit. Treatment with MTX will continue for the duration of participants continuing with randomised treatment Dose modifications - Methotrexate Upon randomisation, all participants are to remain on a stable dose of MTX in combination with their allocated trial treatment. The MTX dose/route should remain within the parameters Page 33 of 76

36 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: mg/m 2 (maximum dose of 25mgs) No dose reduction or change in route of administration is allowed after randomisation. A dose increase is acceptable for growth (at same dose/m 2 as at trial entry) but must not be increased on clinical grounds. Methotrexate treatment may be suspended for clinical reasons, however this can only be for up to a maximum cumulative period of 4 weeks throughout the duration of the protocol treatment phase. Patients requiring intermittent or continuous suspension of methotrexate treatment for a cumulative period longer than 4 weeks will be considered a treatment failure and should be withdrawn from trial treatment. Page 34 of 76

37 10 ASSESSMENTS AND PROCEDURES SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: After obtaining written consent (and assent where appropriate) from the parent or legal guardian, or from the trial participant, a medical/ophthalmic history will be taken and recorded on the appropriate CRF with particular emphasis on other disorders of relevance and allergies. Separate sections on the CRF will be provided to record the JIA and uveitisspecific medical/ophthalmic history and the participant s other medical/surgical history. Medication (prescription, over-the-counter, and herbal supplements) use over the four weeks prior to the screening visit will also be recorded. Physical examination, measures of disease activity and complications, medication history, surgical history and laboratory tests (haematological and biochemical analysis and urinalysis) will be performed at the screening visit and will be repeated at each subsequent trial visit Schedule for Follow-up Table 1 summarises study visits and assessments: Page 35 of 76

38 Screening* Randomisation & commence treatment End of treatment End of trial Premature withdrawal SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Table 1: Study visits and assessments: Time (months) 0^ Written informed consent X Confirm consent (verbal) X X X X X X X X X X X X X X Assessment of Eligibility Criteria X X Review of Medical/ Opthalmic/ X Surgical History Review of Concomitant Medications X X X X X X X X X X X X X X X X X Pregnancy test (serum) X (X) X X X X X X X Purified protein derivative (PPD) X Tuberculin Skin Test 1,2 / Test for latent TB as locally performed Urinalysis 3 X X X X X X X X X X X X X X X X Randomisation X Study Intervention X X X X X X X X X Compliance with study intervention X X X X X X X X X Physical Exam - Complete X X X X X X X X X X X X X X X X Vital Signs (heart & Respiratory rate, X X X X X X X X X X X X X X X X temperature and blood pressure) Height X X X X X X X X X X X X X X X X Weight X X X X X X X X X X X X X X X X Childhood Health Questionnaire (CHQ) X X X X X X X X X Childhood Health Assessment Questionnaire (CHAQ) X X X X X X X X X Health Utilities Index 2 Questionnaire X X X X X X X X X Client Service Receipt Inventory (CSRI) X X X X X X X X X Sample for DNA collection (X) RNA and Serum/plasma (X) X X Haematological analysis X X X X X X X X X X X X X X X X X Biochemical analysis X X X X X X X X X X X X X X X X X Samples for HAHA analyses ** X X ANA, dsdna and ENA X X Opthalmic assessments: Vision assessment X X X X X X X X X X X X X X X X Optical coherence tomography (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (optional) Assessment of vitritis X X X X X X X X X X X X X X X X Slit lamp bio-microscopy X X X X X X X X X X X X X X X X Cataract scoring X X X X X X X X X X X X X X X X Goldmann tonometry or tonopen X X X X X X X X X X X X X X X X Standard ACR Pedi Core Set outcome X X X X X X X X X X X X X X X X variables Tanner Score X X X X X X X X X X Review of Participant Diaries X X X X X X X X X X X X X X X (X) Assessment of Adverse Events X X X X X X X X X X X X X X X X ^ Visit 0 must be completed and treatment commenced within 14 days of the screening visit (10 days for pregnancy test) * all procedures should be done before study intervention. ** to be done also as required if anaphylaxis occurs during trial. (X) - As applicable/indicated/appropriate 1 Participants who are PPD positive at screening will require a chest x-ray. Treatment of participants who have a positive PPD skin test and/or abnormal chest x-ray should be in accordance with regional/national guidelines, and initiated at least 4 weeks prior to receiving the first dose of trial medication 2 Participants with recent (within 6 months of trial entry screen) positive PPD ( 5 mm) who are being treated with appropriate prophylaxis may request a waiver for a screening PPD from the MCRN CTU. Documentation of the positive PPD should be available as well as chest x-ray report from the date of the positive PPD and treatment/prophylaxis history from near the time of the participant s conversion. 3 Microscopic urinalysis will be obtained at baseline and for other visits only if relevant abnormalities greater than trace are noted on the dipstick analysis. Page 36 of 76

39 10.2 Procedures for Assessing Efficacy Ophthalmic Assessments SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Ophthalmic assessment of disease activity and ocular complications will take place by slit lamp bio-microscopy for uveitis activity (at maximum illumination), including cells and flare in anterior and posterior chambers, using SUN criteria SUN Criteria SUN Criteria is a quantitative assessment of cell number in the anterior chamber which is graded 0-4 (see table below adapted from Jabs et al 10 ). With no fully validated measures in paediatric uveitis, SUN criteria are the most robust currently available; the investigators are currently engaged in international collaborative efforts to reach consensus on their use and complete their validation in paediatric uveitis. The SUN Working Group Grading Scheme for Anterior Chamber Cells Grade Cells in Field 0 < > 50 SUN = Standardisation of Uveitis Nomenclature Field size is a 1mm by 1mm slit beam Sun Working Group Grading Scheme for criteria for grading presence of AC flare: Grade Description 0 None 1+ Faint 2+ Moderate (iris and lens details clear) 3+ Marked (iris and lens details hazy) 4+ Intense (fibrin or plastic aqueous) Vision Using age-appropriate LogMar visual acuity (Kays pictures and standard LogMar) Fundoscopy Fundoscopy to assess: Disc swelling, or macular oedema and other structural changes in macular (epiretinal membrane) and optic nerve (neovascularisation, glaucomatous neuropathy) and retina (neovascularisation, retinal detachment) Fundoscopy is to be assessed at trial entry and then at trial exit. Additional dilated fundoscopy can be done in between if clinically indicated, if the participant is in anterior remission, then it is not mandatory to undertake this assessment for the purposes of the trial. Page 37 of 76

40 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Optical coherence tomography (OCT) Optical coherence tomography (OCT; at least stratus II) for macular oedema; where units available to do so (non invasive). Within units - same OCT to be used throughout study. Vitritis Assessment of vitritis and vitreous haze. Gadin be assessed through the binocular indirect ophthalmoscope (BIO SCORE) Cataract Score Cataract score (LOCS III grading) Adapted from Chylack et al 45 (see Appendix B) Intraocular pressure Intraocular pressure by Goldmann tonometry or tonopen as clinically deemed appropriate at the clinical trial setting Other structural Changes Presence or absence of other structural changes including extent of band keratopathy, synechiae, iris bombe, membrane formation and neovascularisation Physical Examination A full musculoskeletal and systems physical examination will be performed at each trial visit including detailed joint count. If the full examination is completed at baseline then it does not need to be completed again at first treatment visit as little time will have elapsed between visits. Vital Signs will also be measured including resting blood pressure and heart rate, with the participant in the sitting position, respiratory rate and oral body temperature. Body weight and height: will be measured at screening and at each trial visit Rheumatology Assessments: American College of Rheumatology Pedi Core Set Criteria and related outcomes Standard ACR Paediatric Core Set outcome variables 46 will be assessed at each study visit. The table below (adapted from Giannini et al 46 ) summarises the 6 core set variables.. Paediatric Core Set Criteria Physician global assessment of disease activity (10 cm visual analogue scale) Parent/patient assessment of overall well-being (10 cm visual analogue scale) Functional ability (Childhood Health Assessment Questionnaire, CHAQ) [34] Number of joints with active arthritis Number of joints with limited range of movement Erythrocyte sedimentation rate, normalised to a 0-10 scale From these core outcome variables, the following rheumatology outcome variables will be determined during data analysis, according to published methodology, namely: Page 38 of 76

41 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: The ACR Paediatric 30, 50, 70, 90 and 100 levels. These are defined as 30%, 50%, 70%, 90% and 100% improvement respectively in a minimum of three variables in the core set with worsening of one variable by no more than 30% as defined in the ACR criteria (see reference 46 ). Episode(s) of disease flare, defined as a minimum of 40% worsening in at least 2 out of 6 components, with no more than one component improving by >30% 75 Ability to achieve clinical remission as defined by standardised definitions of inactive disease, remission on medication and remission off medication 54 and with minimum disease activity 55 (see references) The Juvenile Arthritis Disease Activity Score, or JADAS 76. The JADAS comprises four components: (1) physician global assessment of disease activity (2) parent/patient global assessment of well-being (3) active joint count, in 27, 71 or 10 joints; and (4) erythrocyte sedimentation rate (ESR). The JADAS is calculated as a sum of scores from its four components, giving global scores of 0-57, and 0-40 for the JADAS-27, JADAS-71 and JADAS-10 respectively Procedures for Assessing Safety Adverse Events An assessment of adverse events will be undertaken at each study visit from baseline to study completion. These reviews will be carried out by the PI or other delegated staff member conducting the visit. Requirements for adverse event reporting is detailed fully in Section 12 (Pharmacovigilance) Screening for Tuberculosis A test for latent tuberculosis infection (LTBI) must be performed within four weeks prior to the baseline visit according to local practice guidelines, including those with a prior history of BCG administration. Multiple puncture tests such as the Tine and Heaf tests are not acceptable. The purified protein derivative (PPD) tuberculin skin test and the QuantiFERON -TB Gold (QFT-G) (or local equivalent) are acceptable screening assays for latent TB in this study. The TB test results should be interpreted according to local guidelines for immunocompromised patients, even though the patients entering this study may or may not be immunocompromised at baseline. The purpose of using this definition is to maximize the likelihood of detecting latent TB. Participants who are PPD / QFT-G (or local equivalent) positive according to local guidelines at screening will require a chest x-ray. Participants with recent (within 6 months of screening visit) positive PPD ( 5 mm) who are being treated with prophylaxis may be eligible for trial entry. In these circumstances, documentation of: o The positive PPD o A chest x-ray report from the date of the positive PPD o Documentation of treatment detail and duration Treatment of participants who have a positive PPD skin test / QFT-G (or local equivalent) and/or abnormal chest x-ray should be managed in accordance with regional/national guidelines, and initiated at least 4 weeks prior to receiving the first dose of trial medication Page 39 of 76

42 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Treatment for latent tuberculosis must be started with anti-tuberculosis therapy in accordance with local/national recommendations. Those with positive PPD at screen must have been treated with anti-tuberculosis therapy for at least 4 weeks prior to receiving study medication and chest radiograph is negative for active tuberculosis Urinalysis Urinalysis will also be carried out at each study visit, a fresh aliquot of urine will be tested for protein, glucose, blood, leukocyte esterase, specific gravity, and ph by dipstick. A microscopic urinalysis will be obtained at screening and the results recorded on the CRF. Subsequently, microscopic urinalysis will be obtained only if relevant abnormalities greater than trace are noted on the dipstick analysis Serum pregnancy test Designated trial personnel will perform a serum pregnancy test for all post-pubertal female participants at the screening visit. There must be evidence of a negative serum pregnancy test for all post pubertal females within 10 days before their first dose of trial drug. Subsequently, serum pregnancy tests will be undertaken three monthly for the duration of treatment and a final test three months after their final dose of trial drug Tanner Score Secondary sexual development will be measured at baseline and at weeks 12 and 48 during receipt of treatment. This will be done either by self- assessment or by clinical examination. The Tanner score 77 will also be assessed at early withdrawal from trial treatment and three monthly at post treatment follow visits. This will be done on participants of ALL ages, if the participant has reached full sexual maturity then this assessment will only take place at screening Haematological Laboratory Assessments Routine haematological assessments of full blood count will be required for the study (to include haematocrit, haemoglobin, red blood cell count, white blood cell count, neutrophils, bands, lymphocytes, monocytes, basophils, eosinophils, platelet count and ESR), which will be analysed in local laboratories. If ESR is unable to be tested then plasma viscosity may be accepted. For safety purposes, an auto- antibody screen (ANA, dsdna and ENA) should also be carried out at the baseline and 12 month visits Biochemical laboratory Assessments Routine biochemical assessments of renal and liver function tests) are required for the study (to include C- Reactive protein (CRP), urea, creatinine, sodium, potassium, calcium, inorganic phosphate, glucose, chloride, bicarbonate, total bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST]), which will be assessed in local laboratories Compliance with Study Treatment Participant Diaries: The participant or the parent/guardian of a participant will maintain a diary for all trial and other medications that are administered outside of the trial visit (i.e. at home). Page 40 of 76

43 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: For trial allocated treatment the diary will collect information on: (i) Vial number (ii) Time/ date of administration (iii) Volume/dose (iv) Any problems with administration/ protocol adherence For other prescribed medications the diary will record: (i) Medicine name (ii) Dose prescribed (iii) Number of times per day medicine was taken (iv) Number of days/ weeks supplied For over the counter medicines, the diary will record: (i) Name of medicine (ii) Cost Pharmacy/ Clinical accountability Any discernible departure from the protocol regarding trial drug administration will be recorded onto the CRF (see section 9 for IMP accountability) 10.4 Quality of Life Quality of, Life will be measured by the use of Childhood Health Questionnaire (CHQ) 78 and Childhood Health Assessment Questionnaire (CHAQ) 47. Data collection will take place on a monthly basis for the first 3 months, then 3 monthly until withdrawal from the active phase of trial treatment Child Health Assessment Questionnaire Childhood Health Assessment Questionnaire (CHAQ) is the most widely used functional measure of disability in JIA both in routine clinical practice throughout the UK and clinical trials. Translated into many languages and validated in respective cultures and countries, it is easily completed and scored. It consists of eight domains, enquiring about the child / young person s ability to manage a range of activities of daily living on a 5 point scale. Completion of the questionnaire will be checked by staff Childhood Health Questionnaire The Child Health Questionnaire (CHQ) is a generic measure of quality of life used in JIA. It explores a number of important domains including self esteem, emotional and behavioural difficulties, and family impact. Completion of the questionnaire will be checked by staff 10.5 Health Economics The primary health outcome measure for the economic evaluation will be quality-adjusted life-years (QALY). Page 41 of 76

44 Health Utilities Index 2 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Health Utilities Index 2 (HUI2) questionnaire will be administered to participants or their parents (guardians) where appropriate 59 for self completion. Health utilities will be assessed at baseline and at 3, 6, 9, 12, 18, 27 and 36-months post randomisation (or at early trial withdrawal). The HUI2 is the only validated utility measure for children with UK preferences, and is specified as NICE s preferred method for this purpose 60. The 6 attributes of the HUI2 (sensation, mobility, emotion, cognition, self-care, and pain) will be summarized into a single UK-derived preference-based utility score 61. HUI2 is more likely to be sensitive to the quality of life decrement attributable to sensory (vision) loss than alternative generic measures of utility Hospital Episode Statistics Patients use of secondary care resources in English sites will be measured from routine hospital information systems via the NHS Information Centre (bespoke Hospital Episode Statistics (HES) Extract Service). Requests for anonymised extracts will be made according to standardised procedures at 18 and 36 months Client Service Receipt Inventory Patients use of primary care services, personal social services, non-scheduled clinic attendance and out-of-pocket expenditures will be collected at baseline and at 3, 6, 9, 12, 18, 27 and 36-months post randomisation by administering a specifically designed questionnaire (based on a modified Client Service Receipt Inventory) 56 to parents (guardians). Data on patients use of medicines will be collected within patients diaries Other Assessments Special Assays or Procedures To assess clinical implications of anti-adalimumab antibody (HAHA) development in relation to efficacy / hypersensitivity Establishment of JIA-associated Biobank A Biobank will be developed, integral to the trial, in accordance with Arthritis Research UK's guidelines on detailed clinical and related material banks ( Written information will be provided to families for this part of the study and written informed consent (with assent where appropriate) obtained. All blood samples will be gifted to the University of Bristol under the care of Professor Adam Finn and kept for a minimum of ten years. The Trial Management Committee will have first call on their use. The BioBank will include all children enrolled in this trial and will be under strict governance control according to Good Clinical Practice, and adherence to HTA licences where applicable. Samples will be identifiable by identifying number only and stored in a locked freezer. The laboratory has alarm systems and backups for all freezers containing samples and there is a high level of security for access to the building. The Biobank will be a resource open to all, UK-wide, through application and approval for use through the Trial Steering Committee. Application will need to be made to the Steering Page 42 of 76

45 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Committee for access to parallel clinical data such that combined analysis would be possible. The Biobank will serve as a resource to investigate the pharmacogenetics, aetiopathogenesis and identification of biomarkers of JIA-associated uveitis. Understanding the genetic basis of age-specific disease processes allows consideration of the unique and rapid period of human development through to adulthood. Pharmacologic modulation of developing gene networks may have unintended and unanticipated consequences that do not become apparent or relevant until later in life. Early predictors of response allow future personalised treatment prescription in children. The Biobank of DNA alongside the clinical data collection will make this a very real possibility in the near future. In addition, understanding the aetiopathogenesis of JIA-associated uveitis will offer insight and opportunity into novel therapeutic targets, especially in the new era of biologic therapies. Blood samples will be collected pre and post treatment (at 2 months, 6 months and 18 months). Samples will be collected for DNA and RNA extraction, acdna synthesis, serum and PBLs frozen for future analysis. Separate funding and ethical approval will be sought to support future pharmacogenetic and molecular biological investigations. A range of state-of-the-art technologies will be adopted to interrogate the mechanisms and biomarker search and assessment. These will employ the ability to elaborate both epigenetic, genetic, transcriptomic and proteomic analyses as well as functional assays where appropriate or indicated.. For example, 560gene-array analysis looking for candidate cytokine polymorphisms (e.g. IL-17, IL-10 and steroid resistance ) and epigenetic control of cytokine responses ; investigation using qpcr and Western Blotting of RNA control of TNF translation via FxR1P to assess activation in population of responders or nonresponders in the trial and thus validate possibilities of responsiveness to therapy Loss to Follow-up If any of the trial participants are lost to follow up contact will initially be attempted through the PI or designated research staff at each centre. If the lead investigator at the trial centre is not the participants usual clinician responsible for their specialist care then follow up will also be attempted through this latter clinician. Where these attempts are unsuccessful, the participants GP will be asked to contact the patient or the participants family to provide follow up information to the recruiting centre. This information will be included on the Patient Information Sheet. Wherever possible, information on the reason for loss to follow up will be recorded Trial Closure The end of the trial will be considered as the date of the final database lock. However, the trial may be closed prematurely by the Trial Steering Committee (TSC), on the recommendation of the Independent Data and Safety Monitoring Committee (ISDMC). Should the trial be closed prematurely, all active participants (receiving treatment or in follow-up) will be called in for a final follow-up visit and assessments will be undertaken as per schedule (section 8). Ongoing care will be at the discretion of the treating clinician. Page 43 of 76

46 11 STATISTICAL CONSIDERATIONS SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Method of Randomisation Randomisation lists will be generated in STATA using simple block randomisation with random variable block length. Randomisation will be stratified by centre Outcome Measures Primary The primary endpoint is time to treatment failure. Treatment failure is defined by ONE or more of the following: 3) Anterior segment inflammatory score grade (SUN criteria) a) Following at least 3 months of therapy: i) 2-Step increase in SUN cell activity score (AC Cells) over 2 consecutive readings ii) Sustained non-improvement with entry grade of 3 or greater for 2 consecutive readings iii) Only partial improvement (1 grade) with sustained development of other ocular co-morbidity* iv) Sustained scores as recorded at entry grade measured over 2 consecutive readings (grades 0.5 to 2) still present after 6 months of therapy. v) Worsening of existing (on enrolment) ocular co-morbidity after 3 months 4) Use of Concomitant Medications: At any time, requirement to use concomitant medications in manner out with pre-defined acceptable criteria section 9.8.1), or any of the concomitant medications not allowed (see section 9.8.2) * Ocular co-morbidities are defined as: v) Disc swelling and/or Cystoid Macular Oedema (CMO) as gauged clinically and where possible by OCT evidence; and/or: vi) Sustained raised intraocular pressure (<25mm Hg) over 1 month not responding to single ocular hypotensive agent, and/or: vii) Sustained hypotony (<6 mm Hg) over 1 month, and/or viii) Development of unexplained reduction in vision (LogMar) of 15 letters (in the event of cataract participants will remain in trial, also if cataract surgery is required. Failure will still remain as described in endpoints above) Secondary Endpoint(s) 11) Number of participants failing treatment 12) Incremental cost-effectiveness and cost-utility of adalimumab added to MTX compared with MTX alone 13) Health status according to the multi-attribute health utility index, HUI2 14) Safety, tolerability and compliance e. Adverse events (AEs) and serious adverse events (SAEs) f. Laboratory parameters (haematological and biochemical analysis and urinalysis Page 44 of 76

47 Page 45 of 76 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: g. Development of anti-adalimumab antibody (HAHA) will be determined with samples collected at months 1, 6 and 18 h. Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period 15) Use of Corticosteroids over duration of study period and throughout follow up, including: e. Total oral corticosteroid dose f. Reduction in and rate of systemic corticosteroid dose from entry dose g. Topical corticosteroid use (frequency) compared to entry usage h. Need for pulsed corticosteroid 16) Optic and ocular j. Number of participants having disease flares (as defined by worsening on SUN criteria) following minimum 3 months disease control k. Number of participants having disease flares within the first 3 months. l. Visual acuity measured by Age-appropriate LogMar assessment m. Visual angle improvement: defined as number of participants halving visual angle n. Visual angle worsening: defined as number of participants doubling visual angle o. Number of participants with resolution of associated optic nerve or macular oedema (as assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) (where available). p. Number of participants with disease control (defined as zero cells, with topical treatment for 3 and 6 months) q. Number of participants entering disease remission (defined as zero cells, without topical treatment for 3 and 6 months) r. Duration and magnitude in sustaining inactive disease (zero cells, with or without topical treatment) 17) Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ)) 18) American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels (see section 8.2) 19) Number of participants undergoing disease flare, in remission on and off medication 54 of their JIA and with minimum disease activity 55 20) Number participants requiring change in biologic / Disease-modifying anti-rheumatic drugs (DMARDs) therapy due to failure to respond from arthritis Sample Size The sample size was based on data on failure rates from 62 patients on MTX in a comparable population provided by Dr C Edelsten, Great Ormond Street Hospital. After three months 11 patients had disease control based on Grade 0 SUN criteria (18%) and therefore based on the trial inclusion criteria would not be eligible for the trial. At 15 months following the start of treatment with MTX, 23 patients of the 51 who had failed at 3 months had achieved disease control (45%), leaving 28 (55%) who had not. To detect a relative reduction of 50% between a failure rate of 60% to 30% with 90% power (there is unlikely to be a trial of this nature again in the near future and therefore we have increased the power to 90% from the conventional power of 80% to optimise the detection of a significant difference between treatment regimes if one truly exists)at a 5% significance level, using a 2:1 randomisation a total of 140 patients (93 adalimumab, 47 placebo) are required. A trial of adalimumab in JIA with or without MTX powered the study using a 40% absolute (57% relative) difference in the rate of flare between the placebo and the adalimumab groups 40. The advent of biological therapies in JIA has led international investigators to a paradigm shift in the treatment of JIA and its related complications, leading to significantly more

48 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: ambitious outcomes in clinical trials, including elimination of inflammation and normalisation of short-term and long-term function 15,52. To this end, in JIA, instead of previously accepted clinical outcomes of 30% absolute difference in outcome between active agent and placebo 53, increasingly significant differences are being expected and regarded as significant, with new definitions of response being established for use in clinical trials such as clinical remission and minimal disease activity 54,55. Indeed, 40% of patients in the adalimumab-jia trial were reported as showing an ACR Pedi 100% response (100% response rate) at 2 years 40. The clinically relevant outcomes of JIA-uveitis may take years to develop and the relationship between isolated measures of clinical activity and long term outcomes remains ill defined. Recent studies do suggest that the length of continuously controlled activity is likely to be of more clinical relevance than short term improvements in levels of activity. In view of these factors, as well as the expectation expressed unanimously through consumer consultation in the development of this trial protocol, we have set a minimum 50% relative difference in failure rate between interventions. Based on the nature of the disease resulting potentially in loss of vision and a meeting of investigators representing participating centres, as well as consumer representatives, and their experience of compliance from current usage of biologic therapies in JIA-uveitis, it is estimated that loss to follow up will be approximately 10%. Therefore we have increased the sample size by approximately 10% to allow for this, giving a total number of patients 154 (102 adalimumab, 52 placebo). The null hypothesis underlying this trial is that there is no significant difference between adalimumab and placebo in controlling disease activity of JIA-associated uveitis unresponsive to MTX therapy Interim Monitoring Reports Interim monitoring reports of the accumulating data will be performed at regular intervals (at least annually) for review by an Independent Data Monitoring and Safety Committee (IDSMC). The IDSMC will be asked to give advice on whether the accumulated data from the trial, together with results from other relevant trials, justifies continuing recruitment of further patients or further follow-up. A decision to discontinue recruitment, in all patients or in selected subgroups will be made only if the result is likely to convince a broad range of clinicians including participants in the trial and the general clinical community. If a decision is made to continue, the IDSMC will advise on the frequency of future reviews of the data on the basis of accrual and event rates. The IDSMC will make recommendations to the Trial Steering Committee (TSC, see section 16) as to the continuation of the trial Analysis Plan A comprehensive statistical analysis plan will be developed before any formal statistical analyses will be carried out. The primary analysis will use the principle of intention to treat based on all the randomised participants, as far as is practically possible. If consent for treatment is withdrawn but the participant is happy to remain in the study for follow-up, they will be followed up until completion. However if they decide to withdraw consent completely then the reasons for withdrawal of consent will be collected (if possible) and reported for both groups. Page 46 of 76

49 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: The primary outcome is time to failure with detailed criteria as to what constitutes a treatment failure described in section A participant is eligible for the trial based upon at least one eye fulfilling the eligibility criteria (see section 3.5). At baseline and all subsequent assessment visits both eyes will be assessed and decisions with regards to treatment failure will be based on the worst eye, irrespective as to whether this was the original failing eye used to determine eligibility. Analysis of time to treatment failure will be summarised by Kaplan-Meier curves for each treatment group and compared overall using the logrank test and survival regression methods. For secondary outcomes continuous data will be reported as a difference in means and binary data will be reported in terms of the relative risk each with 95% confidence intervals. Missing data will be monitored and strategies developed to minimise its occurrence. Missing data will be handled by considering the robustness of the complete case analysis to sensitivity analyses using various imputation assumptions; however these will be informed by data collected on the reasons for missing data Economic Analysis Plan The analysis will adopt the perspectives of the NHS and personal social service providers and patients, which approximates a societal perspective. Each item of resource use (see section 8) will be multiplied by the unit cost specific to that item. Unit cost data will be obtained from appropriate sources, including routine hospital data (NHS reference costs, published annually by the Department of Health) 57, the British National Formulary and nationally published data, e.g. Unit costs of health and social care published annually by the PSSRU, University of Kent 58. Total costs per patient will be calculated. Two analytic approaches will be used: a within trial analysis and an economic model. Trialbased estimates of cost-effectiveness will be calculated based on standard methods 63. Uncertainty in parameter estimates being addressed through the application of nonparametric bootstrapping and the estimation of cost-effectiveness acceptability curves 63. We will also apply regression (GLM) models of cost and outcomes, with age, baseline active anterior uveitis grade score and other covariates as deemed appropriate, to minimise bias in the ICER estimates. A model-based extrapolation of the trial results will be performed to explore the impact of a longer analytic time horizon, and consideration of health outcomes on the treatment costeffectiveness 64. The impact of adalimumab on the development of cataract, glaucoma and blindness will be estimated by constructing risk equations based on epidemiological data 65,66. Costs and health state utilities, derived from published sources, will be attached to these states for the development of a Markov model to assess the long-term costs and benefits of the two treatment arms. Incremental cost-utility ratios will be estimated based on QALY estimates. Costs and benefits exceeding 1-year will be discounted at 3.5% per annum, according to NICE s current rate 60. Estimates of ICERs will be compared with the 20,000 to 30,000 per QALY threshold for cost-effectiveness 60, and a range of uni- and multi-variate, as well as probabilistic sensitivity analyses will be conducted to assess the robustness of the analysis. Page 47 of 76

50 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: PHARMACOVIGILANCE 12.1 Terms and Definitions The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) definitions: Adverse Event (AE) Any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product. Adverse Reaction (AR) Any untoward and unintended response in a subject to an investigational medicinal product which is related to any dose administered to that subject. Unexpected Adverse Reaction (UAR) An adverse reaction the nature and severity of which is not consistent with the information about the medicinal product in question set out in: In the case of a product with a marketing authorization, in the summary of product characteristics for that product In the case of any other investigational medicinal product, in the investigator's brochure relating to the trial in question. Serious Adverse Event (SAE), Serious Adverse Reaction (SAR) or Suspected Unexpected Serious Adverse Reaction (SUSAR) Any adverse event, adverse reaction or unexpected adverse reaction, respectively, that: results in death is life-threatening* (subject at immediate risk of death) requires in-patient hospitalisation or prolongation of existing hospitalisation** results in persistent or significant disability or incapacity, or consists of a congenital anomaly or birth defect Other important medical events * life-threatening in the definition of serious refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. **Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the hospitalisation is a precautionary measure for continued observation. Hospitalisations for a pre-existing condition, including elective procedures that have not worsened, do not constitute an SAE. ***Other important medical events that may not result in death, be life-threatening, or require hospitalisation may be considered a serious adverse event/experience when, based upon appropriate medical judgment, they may jeopardise the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition Page 48 of 76

51 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Notes on Adverse Event Inclusions and Exclusions Include An exacerbation of a pre-existing illness An increase in frequency or intensity of a pre-existing episodic event/condition A condition (even though it may have been present prior to the start of the trial) detected after trial drug administration Continuous persistent disease or symptoms present at baseline that worsens following the administration of the study/trial treatment Laboratory abnormalities that require clinical intervention or further investigation (unless they are associated with an already reported clinical event). Abnormalities in physiological testing or physical examination that require further investigation or clinical intervention Injury or accidents Do Not Include Medical or surgical procedures- the condition which leads to the procedure is the adverse event Pre-existing disease or conditions present before treatment that do not worsen Situations where an untoward medical occurrence has occurred e.g. cosmetic elective surgery Overdose of medication without signs or symptoms The disease being treated or associated symptoms/signs unless more severe than expected for the patient s condition Reporting of Pregnancy Designated trial personnel will perform a serum pregnancy test at the screening visit for all post-pubertal female participants. This will be repeated three monthly for the duration of treatment administration and a further test three months after administration of the last dose of study drug. Any pregnancy which does occur during the course of the study should be reported to the MCRN CTU immediately as an SAE. The investigator should discuss the risks of continuing with the pregnancy with the participant and the possible effects on the foetus if they continue on trial treatment. It is at the investigator s discretion to decide whether the individual should be instructed to stop taking study drugs. All pregnancies that occur during trial treatment, or within 3 months of finishing treatment, need to be followed up until delivery and neonatal outcome (defined as 4 weeks from delivery) and reported separately Notes Severity / Grading of Adverse Events The assignment of the severity/grading should be made by the investigator responsible for the care of the participant using the definitions below. Regardless of the classification of an AE as serious or not, its severity must be assessed according to medical criteria alone using the following categories: Page 49 of 76

52 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Mild: does not interfere with routine activities Moderate: interferes with routine activities Severe: impossible to perform routine activities A distinction is drawn between serious and severe AEs. Severity is a measure of intensity (see above) whereas seriousness is defined using the criteria in section 10.1, hence, a severe AE need not necessarily be a Serious Adverse Event Relationship to Trial Treatment The assignment of the causality should be made by the investigator responsible for the care of the participant using the definitions in table 2. If any doubt about the causality exists the local investigator should inform the study coordination centre who will notify the Chief Investigators. In the case of discrepant views on causality between the investigator and others, the MHRA will be informed of both points of view. Table 2: Definitions of Causality Relationship Description Unrelated There is no evidence of any causal relationship. N.B. An alternative cause for the AE should be given Unlikely There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within a reasonable time after administration of the trial medication). There is another reasonable explanation for the event (e.g. the participant s clinical condition, other concomitant treatment). Possibly There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable time after administration of the trial medication). However, the influence of other factors may have contributed to the event (e.g. the participant s clinical condition, other concomitant treatments). Probably There is evidence to suggest a causal relationship and the influence of other factors is unlikely. Almost certainly There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out Expectedness An AE whose causal relationship to the study drug is assessed by the investigator as possible, probable, or definite is an Adverse Drug Reaction. All events judged by the investigator to be possibly, probably, or almost certainly related to the IMP, graded as serious and unexpected (see section 10.2 and SPC for list of Expected Adverse Events) should be reported as a SUSAR. Page 50 of 76

53 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Follow-up After Adverse Events All adverse events should be followed until satisfactory resolution or until the investigator responsible for the care of the participant deems the event to be chronic or the patient to be stable. When reporting SAEs and SUSARs the investigator responsible for the care of the participant should apply the following criteria to provide information relating to event outcomes: resolved; resolved with sequelae (specifying with additional narrative); not resolved/ongoing; ongoing at final follow-up; fatal or unknown Reporting Procedures All adverse events fulfilling reporting criteria should be recorded on the CRF and submitted to the MCRN CTU within the defined timelines, beginning from the time that written informed consent is obtained (i.e. prior to to undergoing any study-related procedure and/or receiving investigational medicinal product) and continuing for 30 calendar days after cessation of the investigational medicinal product. Depending on the nature of the event the reporting procedures below should be followed. Any questions concerning adverse event reporting should be directed to the CTU in the first instance. A flowchart is given overpage to aid in determining reporting requirements Non serious ARs/AEs All such events, whether expected or not, should be recorded on an Adverse Event Form, which should be transmitted to the CTU within seven days of the form being due Serious ARs/AEs/SUSARs SARs, SAEs and SUSARs should be reported within 24 hours of the local site becoming aware of the event. The SAE form asks for the nature of event, date of onset, severity, corrective therapies given, outcome and causality. The responsible investigator should sign the causality of the event. Additional information should be sent within 5 days if the reaction has not resolved at the time of reporting. The CTU will notify the MHRA and main REC of all SUSARs occurring during the study according to the following timelines; fatal and life-threatening within 7 days of notification and non-life threatening within 15 days. All investigators will be informed of all SUSARs occurring throughout the study. Local investigators should report any SUSARs and /or SAEs as required locally. Page 51 of 76

54 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Adverse event Unrelated Possibly/Probably/Almost Certainly related Serious Not serious Serious Not serious Unexpected Expected Unexpected Expected Unexpected Expected Unexpected Expected Unexpected Expected Complete AE CRF and SUSAR SAR Unexpected Expected AR. SAE report to CTRC within 24 hours SAE report to CTRC within 24 hours submit as per routine schedule report to CTRC within 24 hours report to CTRC within 24 hours AR. Report on AE CRF and submit as per routine schedule Report on AE CRF and submit as per routine schedule 12.8 Responsibilities Investigator The Investigator is responsible for reporting all AEs that are observed or reported during the study, regardless of their relationship to study product. All SAEs must be reported immediately by the investigator to the CTU on an SAE form unless the SAE is specified in the protocol as not requiring immediate reporting. All other adverse events should be reported on the regular progress/follow-up reports. Minimum information required for reporting: Study identifier Study centre Patient number A description of the event Date of onset Current status Whether study treatment was discontinued The reason why the event is classified as serious Investigator assessment of the association between the event and study treatment i. The SAE form should be completed by a designated investigator, a physician named on the signature list and delegation of responsibilities log as responsible for reporting SAEs and making trial related medical decisions. The investigator should assess the SAE for the likelihood that it is a response to the investigational medicinal product. In the absence of the designated investigator the form should be completed and signed by an alternative member of the research site trial team and submitted to the CTRC. As soon as possible thereafter the responsible investigator should check Page 52 of 76

55 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: ii. iii. the SAE form, make amendments as appropriate, sign and re-send to the CTRC. The initial report shall be followed by detailed reports as appropriate. When submitting an SAE to the CTRC research sites should also telephone the appropriate trial co-ordinator/data manager on telephone number to advise that an SAE report has been submitted. Send the SAE form by fax (within 24 hours or next working day) to the CTU: Fax Number: iv. The responsible investigator must notify their R&D department of the event (as per standard local governance procedures). v. In the case of an SAE the subject must be followed-up until clinical recovery is complete and laboratory results have returned to normal, or until the event has stabilised. Follow-up may continue after completion of protocol treatment if necessary. vi. Follow-up information is noted on another SAE form by ticking the box marked follow-up and faxing to the CTU as information becomes available. Extra, annotated information and/or copies of test results may be provided separately. vii. The patient must be identified by trial number, date of birth and initials only. The patient s name should not be used on any correspondence Maintenance of Blinding Systems for SUSAR and SAR reporting should, as far as possible, maintain blinding of individual clinicians and of trials staff involved in the day-to-day running of the trial. Unblinding clinicians may be unavoidable if the information is necessary for the medical management of particular patients. The safety of patients in the trial always takes priority. In each report, seriousness, causality and expectedness will be evaluated for active and excipents in placebo. Cases that are considered serious, unexpected and possibly, probably or almost certainly related to one of the trial therapies (i.e. possible SUSARs) would have to be unblinded at the clinical trials unit prior to reporting to the regulator Responsibilities CTU The CTU is undertaking duties delegated by the trial sponsor, University Hospitals Bristol NHS Foundation Trust, and is responsible for the reporting of SUSARs and other SARs to the regulatory authorities (MHRA, competent authorities of other European member states in which the trial is taking place and, if required, the research ethics committees) as follows: SUSARs which are fatal or life-threatening must be reported not later than 7 days after the CTU is first aware of the reaction. Any additional relevant information must be reported within a further 8 days. SUSARs that are not fatal or life-threatening must be reported within 15 days of the CTU first becoming aware of the reaction. A list of all SARs (expected and unexpected) must be reported annually. Page 53 of 76

56 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: It is recommended that the following safety issues should also be reported in an expedited fashion An increase in the rate of occurrence or a qualitative change of an expected serious adverse reaction, which is judged to be clinically important; Post-study SUSARs that occur after the patient has completed a clinical trial and are notified by the investigator to the sponsor; New events related to the conduct of the trial or the development of the IMPs and likely to affect the safety of the subjects, such as: a. A serious adverse event which could be associated with the trial procedures and which could modify the conduct of the trial; b. A significant hazard to the subject population, such as lack of efficacy of an IMP used for the treatment of a life-threatening disease; c. A major safety finding from a newly completed animal study (such as carcinogenicity). d. Any anticipated end or temporary halt of a trial for safety reasons and conducted with the same IMP in another country by the same sponsor; Recommendations of the Data Monitoring Committee, if any, where relevant for the safety of the subjects. Staff at the CTU will liaise with the Chief Investigator (or designated other specified in the protocol) who will evaluate all SAEs received for seriousness, expectedness and causality. Investigator reports of suspected SARs will be reviewed immediately and those that are SUSARs identified and reported to regulatory authorities and MREC. The causality assessment given by the Local Investigator at the hospital cannot be overruled and in the case of disagreement, both opinions will be provided with the report. The CTU will also send an annual safety report containing a list of all SARs to regulatory authorities and MREC. Copies of the report will be sent to the Principal Investigator at all institutions participating in the trial Patient safety incidents that take place in the course of research should be reported to the National Patient Safety Agency (NPSA) by each participating NHS Trust in accordance with local reporting procedures SAE reporting Abbott In line with Abbott policies for the reporting of adverse events in connection with investigatorinitiated studies supported by Abbott Laboratories, UK, the CTU will notify Abbott UK Pharmacovigilance of all SAEs that occur during the trial. These reports will remain blinded Safety reports Safety reports will be generated during the course of the trial which allows for monitoring of SAE and ADR reporting rates across sites. The CTU will send annual safety reports containing a list of all SARS to regulatory authorities an MREC. Any concerns raised by the IDSMC or inconsistencies noted at a given site may prompt additional training at sites, with the potential for the CTU to carry out site visits if there is suspicion of unreported AEs in Page 54 of 76

57 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: patient case notes. Additional training will also be provided if unacceptable delay in safety reporting timelines. Page 55 of 76

58 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: ETHICAL CONSIDERATIONS 13.1 Ethical Considerations The study will abide by the principles of the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989) and South Africa (1996) Ethical Approval The trial protocol will not be initiated until it has received the favourable opinion of the a Main Research Ethics Committee (MREC). Subsequent to this it must also undergo review at the R&D offices at participating sites. The local R&D office should be sent the appropriate SSI form complete with the necessary authorisation signatures, plus any other documentation requested for review. A copy of local Research & Development (R&D) approval should be forwarded to CTU before the site is initiated and patients recruited Informed Consent Process General Informed consent is a process initiated prior to an individual agreeing to participate in a trial and continues throughout the individual s participation. Written informed consent is required for all trial participants. In obtaining and documenting informed consent, the investigator should comply with applicable regulatory requirements and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. This trial will be recruiting minors and young people over the age of 16 years and informed consent processes will reflect the legal and ethical requirements to obtain valid informed consent for trial participants. Information will be provided to potential participants and their families verbally and in writing. All will have the opportunity to discuss the project with the responsible investigator at site and/or a designated member of the research team. Discussions will be supported with detailed written and ethically approved Patient Information Sheets and Consent forms (PISC) provided directly to young people able to consent for themselves (defined in statutory instrument 2004 No.1031 as aged 16 years) and parents / legal guardian of minors (aged <16 years). Age and stage of development appropriate information leaflets will be provided to minors and their assent obtained, where appropriate. Careful presentation will be made of the known risks of the disease and trial medications, and possible benefits, as well as a detailed explanation of the trial procedures and protocol. All participants will be given opportunity to ask any questions that may arise, should have the opportunity to discuss the study with their surrogates and time to consider the information prior to agreeing to participate. A contact point where further information about the trial may be obtained will be provided. Page 56 of 76

59 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Minors and young people eligible for this trial will have JIA-associated uveitis refractory to treatment with MTX. They may therefore be anxious about available treatments and the ultimate outcome for their sight if inflammation persists. All of the recruiting investigators are experienced rheumatologists and ophthalmologists familiar with imparting information to families and young people. When potentially eligible minors and young people are identified, they/ their parent/ the person with parental responsibility will be approached by the investigator, or a designated member of the investigating team, during which an opportunity will be given to understand the objectives of the trial. The treatment schedule and trial visits are in line with standard clinical care, although they will be made aware that additional travel may be needed if the trial assessments require they be reviewed at their tertiary centre rather than their local hospital. The potential risks and benefits of the anti-tnf agent will be discussed, as will treatment failure criteria and what will happen if they choose not to enter the trial or have to withdraw from the trial for any reason. In addition, the rationale for the use of a placebo and the applied randomisation ratio will be explained. Consent from the patient, or proxy consent in the case of minors, should be obtained by a designated member of the research team prior to their participation in the trial, after a full explanation has been given of the treatment options, including the conventional and generally accepted methods of treatment. Verbal information should be reinforced with the implementation of the Patient Information and Consent Forms (PISC). The right of the patient (non-minors) or parent/ legal guardian (for minors) to refuse consent to participate in the trial without giving reasons must be respected. After the patient has entered the trial, the clinician remains free to give alternative treatment to that specified in the protocol, at any stage, if he/she feels it to be in the best interest of the patient. However, the reason for doing so should be recorded and the patient will remain within the trial for the purpose of follow-up and data analysis according to the treatment option to which they have been allocated. Similarly, the patient remains free to withdraw at any time from the protocol treatment and trial follow-up without giving reasons and without prejudicing their further treatment. Adequate time to consider trial entry (at least 24 hours) will be allowed before written consent of the participant/ parent/ lrgal representative will be obtained by the responsible clinician or other designated team member (recorded on the signature and delegation log). The right of the individual to refuse participation without giving reasons will be respected Competent Adults (aged years at time of consent) Upon completion of the above, the patient will then sign and date the informed consent document. Both the person obtaining consent and the participant must personally sign and date the form. A copy of the informed consent document will be given to the patient for their records. The original copy will be filed in the participant s medical notes and a further copy of the signed consent form will be filed in the Investigators Site File. One final copy of the consent form should be sent to the CTU. Page 57 of 76

60 Minors (aged <16 years at time of consent) SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: The Medicines for Human use (Clinical Trials) Regulations 2004 define a person under the age of 16 years to be a minor. The regulatons require that informed consent for minors be provided by a person with parental responsibility* or a legal representative. Upon completion of the above, proxy consent from the parent or legally acceptable representative should be obtained prior to each patient participating in the trial. Both the person obtaining consent and the parent/legal representative must personally sign and date the form. A copy of the informed consent document will be given to the parent/legal representative for their records. The original copy will be filed in the participant s medical notes and a further copy of the signed consent form will be filed in the Investigators Site File. One final copy of the consent form should be sent to the CTU. * A mother automatically has parental responsibility for her child from birth. However, this is not the case for fathers. Conditions for fathers gaining parental responsibility varies throughout the UK and is summarised below. Practitioners should verify that the consenting parent has parental responsibility to do so. For births registered in England and Wales In England and Wales, if the parents of a child are married to each other at the time of the birth, or if they have jointly adopted a child, then they both have parental responsibility. Parents do not lose parental responsibility if they divorce, and this applies to both the resident and the non-resident parent. This is not automatically the case for unmarried parents. According to current law, a mother always has parental responsibility for her child. A father, however, has this responsibility only if he is married to the mother when the child is born or has acquired legal responsibility for his child through one of these three routes: (from 1 December 2003) by jointly registering the birth of the child with the mother by a parental responsibility agreement with the mother by a parental responsibility order, made by a court For births registered in Scotland A father has parental responsibility if he is married to the mother when the child is conceived, or any time after that date. An unmarried father has parental responsibility if he is named on the child's birth certificate (from 4 May 2006). Alternatively, unmarried fathers can also be named following a re-registration of the birth. For births registered in Northern Ireland A father has parental responsibility if he is married to the mother at the time of the child's birth. However he does not have parental responsibility if he marries the mother after the birth. An unmarried father has parental responsibility if he is named on the child's birth certificate (from 15 April 2002). Alternatively, unmarried fathers can also be named following a re-registration of the birth. For births registered outside the UK If a child is born overseas and then comes to live in the UK, the parental responsibility rules apply for the UK country in which they live. Page 58 of 76

61 Assent in minors SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: If capable, and under appropriate circumstances, minors should approached to provide assent by a member of the research team experienced with minors. Age-and-state-ofdevelopment Patient information Sheet and Assent forms, approved by the independent ethical committee, describing (in simplified terms) the details of the trial intervention/product, trial procedures and risks should be used. The information leaflets will be developed in close collaboration with the consumer representatives on the trial team and with guidance from the MCRN young persons group. The minor should personally write their name and date the assent form, which is then signed by the parent/legal representative and the researcher and copies retained/disseminated as for consent forms. Assent should be obtained, where appropriate, and documented in the patient notes, however assent forms do not substitute for the consent form signed by the patient s legally acceptable representative. Whilst the absence of assent does not exclude the patient provided consent has been obtained from the parent/legal representative, the explicit wish of a minor who is capable of forming an opinion and assessing information in relation to the trial and who wishes to refuse participation in, or to be withdrawn from, the clinical trial at any time should be considered by the investigator. Reasons for absence of assent should therefore be recorded in the participant s medical notes Minors reaching 16 years during trial participation For a participant involved in the study who reaches the age of 16 (and is therefore deemed competent to provide consent), the minor should be re-consented at their next scheduled visit after their 16 th Birthday. The same process will be followed as for competent adults aged at the time of consent (refer to section 11) Page 59 of 76

62 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: REGULATORY APPROVAL This trial has been registered with the MHRA and will not be initiated until it has been granted a Clinical Trial Authorisation (CTA). The EUdraCT reference is Page 60 of 76

63 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: TRIAL MONITORING Trial monitoring is carried out to ensure that the rights and well-being of human participants are protected during the course of a clinical trial. A risk assessment is performed for each trial coordinated by the CTU to determine the level and type of monitoring required for specific hazards. The nature and extent of monitoring will be specific to the individual trial Risk Assessment In accordance with the CTRC Standard Operating Procedures this trial will undergo a risk assessment, completed in partnership between: Representative/s of the Trial Sponsor Chief Investigator Trial Coordinator and supervising Trial Manager Trial Statistician and supervising Statistician MCRN CTU Director In conducting this risk assessment, the contributors considered potential patient, organisational and study hazards, the likelihood of their occurrence and resulting impact should they occur. The outcome of the risk assessment is expressed as a percentage, assigned according to the following categories: Score 33% = Low risk Score 34 to 67% = Moderate risk Score 68 to 100% = High risk The outcome of the SYCAMORE trial risk assessment has defined this to be a low risk trial and the level and nature of monitoring has been determined accordingly Source Documents Source data: All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies). (ICH E6, 1.51). Source documents: Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial). (ICH E6, 1.52). In order to resolve possible discrepancies between information appearing in the CRF and any other patient related documents, it is important to know what constitutes the source document and therefore the source data for all information in the CRF. Page 61 of 76

64 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: The data that is to be recorded in the CRF and should be consistent and verifiable with source data in source documents other than the CRF (e.g. medical record, laboratory reports and nurses notes) and the data where no prior record exists and which is recorded directly in the CRF (i.e. where the CRF is considered the source document, unless otherwise indicated by the investigator) can be found in protocol supplementary document #6. In addition to the above, date(s) of conducting informed consent (plus assent, where appropriate) process including date of provision of patient information, screening number, randomisation number and the fact that the patient is participating in a clinical trial of adalimumab versus placebo should be added to the patient s medical record chronologically, i.e. when treatment is allocated to the patient. Further, study treatment allocation should also be noted in the patient s medical record after unblinding of the study Data Capture Methods The study case report form (CRF) is the primary data collection instrument for the study. All data requested on the CRF must be recorded. MCRN CTU will supply No Carbon Required Case Report Forms (NCR CRFs).and guidance on how the CRF should be completed (supplementary document #13). Data stored at CTU will be checked for missing or unusual values (range checks) and checked for consistency within participants over time. Any suspect data will be returned to the site in the form of data queries. Data query forms will be produced at the CTU from the trial database and sent either electronically or through the post to a named individual (as listed on the site delegation log). Sites will respond the queries providing an explanation/resolution to the discrepancies and return the data query forms to CTU. The forms will then be filed along with the appropriate CRFs and the appropriate corrections made on the database. There are a number of monitoring features in place at the CTU to ensure reliability and validity of the trial data, to be detailed in the trial monitoring plan Confidentiality Individual participant medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited with the exceptions noted below. Case report forms will be labelled with the participant s initials and unique trial screening and/or randomisation number. Medical information may be given to the participant s medical team and all appropriate medical personnel responsible for the participant s welfare. The CTU will be undertaking activities requiring the transfer of identifiable data: Verification that appropriate informed consent is obtained will be enabled by the provision of copies of participant s signed informed consent/assent forms being supplied to the CTU by recruiting centres, which requires that name data will be transferred to the CTU. This transfer of identifiable data is disclosed in the PISC. The CTU will preserve the confidentiality of participants taking part in the study and The University of Liverpool is registered as a Data Controller with the Information Commissioners Office. Page 62 of 76

65 Direct access to data SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: In order to perform their role effectively, monitors and persons involved in Quality Assurance and Inspection will need direct access to primary subject data, e.g. patient records, laboratory reports, appointment books, etc. Participants will consent to allow the research time access to their data Quality Assurance and Control QA includes all the planned and systematic actions established to ensure the study is performed and data generated, documented/recorded and reported in compliance with applicable regulatory requirements. QC includes the operational techniques and activities done within the QA system to verify that the requirements for quality of the trial-related activities are fulfilled. The level and nature of monitoring will be described in the trial monitoring plan, which will be fianlised upon completion of the trial risk assessment. To ensure the integrity of the data the following policies will be observed: The Principal Investigator, and designated staff from each centre will attend an initiation meeting, coordinated by CTU in conjunction with co-lead investigators to provide training in the trial protocol and procedures The trial coordinator will verify appropriate approvals are in place prior to the trial being initiated within the CTU The trial coordinator is to verify appropriate approvals are in place prior to the initiation of a site, and that the relevant personnel have attended study specific training The trial coordinator is to monitor screening, recruitment and withdrawal rates between sites and report to the TMG Regular QC checks will be performed on data already inputted to ensure data entered is of a high standard. Independent oversight of the study will be provided by the Independent Data and safety Monitoring Committee and the Trial Steering Committee Records Retention The investigator at each investigational site must make arrangements to store the essential trial documents, (as defined in Essential Documents for the Conduct of a Clinical Trial (ICH E6, Guideline for Good Clinical Practice)) including the Investigator Site File and Pharmacy Site File, until the Clinical Trials Unit informs the investigator that the documents are no longer to be retained, or for a maximum period of 15 years (whichever is soonest). In addition, the investigator is responsible for archiving of all relevant source documents so that the trial data can be compared against source data after completion of the trial (e.g. in case of inspection from authorities). The investigator is required to ensure the continued storage of the documents, even if the investigator, for example, leaves the clinic/practice or retires before the end of required storage period. Delegation must be documented in writing. The MCRN CTU undertakes to store originally completed CRFs and separate copies of the above documents for the same period, except for source documents pertaining to the individual investigational site, which are kept by the investigator only. Data will be boxed and transferred to specially renovated, secure, premises where unique reference numbers are applied to enable confidentiality, tracking and retrieval. The MCRN CTU will archive the documents in compliance with ICH GCP utilising the Records Management Service of the Page 63 of 76

66 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: University of Liverpool. All electronic CRFs and trial data will be archived onto an appropriate media for long term accessible storage. Hard copies of data will be boxed and transferred to specially renovated, secure, premises where unique reference numbers are applied to enable confidentiality, tracking and retrieval. Page 64 of 76

67 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: INDEMNITY The SYCAMORE trial is sponsored by University Hospitals Bristol NHS Foundation Trust and co-ordinated by the MCRN CTU in the University of Liverpool. The University Hospitals Bristol NHS Foundation Trust cover for negligent harm is in place through the Clinical Negligence Scheme for Trusts. For NHS sponsored research HSG(96)48 reference no.2 refers If there is any negligent harm during the study when the NHS body owes a duty of care to their person harmed, NHS indemnity covers NHS staff, medical academic staff with honorary contracts, and those conducting the trial. NHS indemnity does not offer no-fault compensation and is unable to agree in advance to pay compensation for non-negligent harm. Ex-gratia payments may be considered in the case of a claim. For the purposes of the study clinical negligence is defined as: A breach of duty of care by members of the health care professions employed by NHS bodies or by others consequent on decisions or judgments made by members of those professions acting in their professional capacity in the course of their employment, and which are admitted as negligent by the employer or are determined as such through the legal process. Page 65 of 76

68 17 FINANCIAL ARRANGEMENTS SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: This study is funded by a joint venture between Arthritis Research UK and the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme. Contractual agreements will be in place between the sponsor and collaborating sites that will describe financial arrangements. IMP and Placebo are to be supplied by Abbott Laboratories Participant Payment Participants and their parents / guardians will not be paid to participate in the trial and the schedule for study visits is in line with routine standard care where possible. There is provision for reimbursement of travel expenses in the event that participants are required to travel to a tertiary centre for assessment at a visit that would otherwise take place at a centre closer to their home Collaborating Centre Payments Research Team Some tasks are to be undertaken during routinely scheduled clinic appointments that are directly related to the research and will impose a time demand on clinic staff, which is in addition to their usual clinical work. Financial support for these activities are split between NHS Service Support Costs and Research Costs NHS Service Support This cost is estimated to be 1,738 per participant randomised and followed up as per protocol. This amount is calculated as a cost to the NHS, but is not necessarily reimbursed to the centre as such; resource to for NHS Service Support Costs can be accessed via the Local Comprehensive Research Network Research Support Additionally, a per patient payment of 871 pounds per participant randomised and followed up as per protocol is available. This has been calculated to cover research-associated costs for the time of personnel at collaborating centres. Payment schedule details are specified in the Research Site Agreement (paid quarterly in arrears upon receipt of valid invoice) Pharmacy Department The pharmacy costs are to support the additional workload associated with the clinical trial and have been included as NHS Service Support Costs. Page 66 of 76

69 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: TRIAL COMMITTEES 18.1 Trial Management Group (TMG) The composition of the Trial Management Group (TMG) is detailed in Appendix A The TMG is be responsible for the day-to-day running and management of the trial and will convene at least monthly in the first year and at least quarterly thereafter Trial Steering Committee (TSC) The TSC comprises three independent members (see section 1). The role of the TSC is to provide overall supervision for the trial and provide advice through its Chairperson, who will be one of the independent members of the committee. Additionally, the TSC will be composed of TMG members, a consumer representative appointed by the MCRN/ARC Paediatric Rheumatology Clinical Studies Group (CSG), a representative of the MCRN/ARC Paediatric Rheumatology CSG (as per Arthritis Research UK requirements) and a nursing representative. The TSC will convene to approve the protocol and then at least annually thereafter. The ultimate decision for the continuation of the trial lies with the TSC 18.3 Independent Data and Safety Monitoring Committee (IDSMC) The Independent Data and Safety Monitoring Committee (IDSMC) consists of three independent members (see section 1). The IDSMC will be responsible for reviewing and assessing recruitment, interim monitoring of safety, trial conduct and external data. They will first convene to approve the protocol, agree their charter and define frequency of subsequent meetings (at least annually). The IDSMC will provide a recommendation to the Trial Steering Committee concerning the continuation of the trial. Page 67 of 76

70 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: PUBLICATION The results from different centres will be analysed together and published as soon as possible. Individual Clinicians must undertake not to submit any part of their individual data for publication without the prior consent of the Trial Management Group. The Trial Management Group will form the basis of the Writing Committee and advise on the nature of publications. The Uniform Requirements for Manuscripts Submitted to Biomedical Journals ( will be respected. All publications shall include a list of participants, and if there are named authors, these should include the trial s Chief Investigator(s), Statistician(s) and Trial Manager(s) involved at least. If there are no named authors (i.e. group authorship) then a writing committee will be identified that would usually include these people, at least. The ISRCTN allocated to this trial should be attached to any publications resulting from this trial. The members of the TSC and IDSMC should be listed with their affiliations in the Acknowledgements/Appendix of the main publication. Page 68 of 76

71 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: PROTOCOL AMENDMENTS 20.1 Version 1 (25/Feb/2011) Original submitted version. Page 69 of 76

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73 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Diaz-Llopis M, Garcia-Delpech S, Salom D, Udaondo P, Bosch-Morell F, Quijada A, Romero FJ, Amselem L. High-dose infliximab prophylaxis in endotoxin-induced uveitis. J Ocul Pharmacol Ther 2007;23: Biester S, Deuter C, Michels H, Haefner R, Kuemmerle-Deschner J, Doycheva D, Zierhut M. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol 2007;91: Foeldvari I, Nielsen S, Kummerle-Deschner J, Espada G, Horneff G, Bica B, Olivieri AN, Wierk A, Saurenmann RK. Tumor necrosis factor-alpha blocker in treatment of juvenile idiopathic arthritisassociated uveitis refractory to second-line agents: results of a multinational survey. J Rheumatol 2007;34: Gallagher M, Quinones K, Cervantes-Castaneda RA, Yilmaz T, Foster CS. Biological response modifier therapy for refractory childhood uveitis. Br J Ophthalmol 2007;91: Saurenmann RK, Levin AV, Rose JB, Parker S, Rabinovitch T, Tyrrell PN, Feldman BM, Laxer RM, Schneider R, Silverman ED. Tumour necrosis factor alpha inhibitors in the treatment of childhood uveitis. Rheumatology (Oxford) 2006;45: Sharma SM, Ramanan AV, Riley P, Dick AD. Use of infliximab in juvenile onset rheumatological disease-associated refractory uveitis: efficacy in joint and ocular disease. Ann Rheum Dis 2007;66: Tynjala P, Kotaniemi K, Lindahl P, Latva K, Aalto K, Honkanen V, Lahdenne P. Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis. Rheumatology (Oxford) 2008;47: Schmeling H, Horneff G. Etanercept and uveitis in patients with juvenile idiopathic arthritis. Rheumatology (Oxford) 2005;44: Smith JA, Thompson DJ, Whitcup SM, Suhler E, Clarke G, Smith S, Robinson M, Kim J, Barron KS. A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum 2005;53: Hale S, Lightman S. Anti-TNF therapies in the management of acute and chronic uveitis. Cytokine 2006;33: Saurenmann RK, Levin AV, Feldman BM, Laxer RM, Schneider R, Silverman ED. Risk of newonset uveitis in patients with juvenile idiopathic arthritis treated with anti-tnfalpha agents. J Pediatr 2006;149: Taban M, Dupps WJ, Mandell B, Perez VL. Etanercept (enbrel)-associated inflammatory eye disease: case report and review of the literature. Ocul Immunol Inflamm 2006;14: Lim LL, Fraunfelder FW, Rosenbaum JT. Do tumor necrosis factor inhibitors cause uveitis? A registry-based study. Arthritis Rheum 2007;56: Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human antitumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004;50: Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, Mouy R, Sandborg C, Bohnsack J, Elewaut D, Foeldvari I, Gerloni V, Rovensky J, Minden K, Vehe RK, Weiner LW, Horneff G, Huppertz HI, Olson NY, Medich JR, Carcereri-De-Prati R, McIlraith MJ, Giannini EH, Martini A. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med 2008;359: Vazquez-Cobian LB, Flynn T, Lehman TJ. Adalimumab therapy for childhood uveitis. J Pediatr 2006;149: Thornton J, Lunt M, Ashcroft DM, Baildam E, Foster H, Davidson J, Gardner-Medwin J, Beresford MW, Symmons D, Thomson W, Elliott RA. Costing juvenile idiopathic arthritis: examining patientbased costs during the first year after diagnosis. Rheumatology (Oxford) 2008;47: BSPAR Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology 1985;92: Chylack LT, Jr., Wolfe JK, Singer DM, Leske MC, Bullimore MA, Bailey IL, Friend J, McCarthy D, Wu SY. The Lens Opacities Classification System III. The Longitudinal Study of Cataract Study Group. Arch Ophthalmol 1993;111: Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40: Page 71 of 76

74 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Nugent J, Ruperto N, Grainger J, Machado C, Sawhney S, Baildam E, Davidson J. The British version of the childhood health questionnaire (CHAQ) and the child health questionnaire (CHQ). Clin Exp Rheumatol 2001;19 (Suppl 23):S163-S FDA. ugsafetyinformationforheathcareprofessionals/ucm htm Caspersen S, Elkjaer M, Riis L, Pedersen N, Mortensen C, Jess T, Sarto P, Hansen TS, Wewer V, Bendtsen F, Moesgaard F, Munkholm P. Infliximab for inflammatory bowel disease in Denmark : clinical outcome and follow-up evaluation of malignancy and mortality. Clin Gastroenterol Hepatol 2008;6: de Vries HS, van Oijen MG, de Jong DJ. Serious events with infliximab in patients with inflammatory bowel disease: a 9-year cohort study in the Netherlands. Drug Saf 2008;31: Kempen JH, Daniel E, Dunn JP, Foster CS, Gangaputra S, Hanish A, Helzlsouer KJ, Jabs DA, Kacmaz RO, Levy-Clarke GA, Liesegang TL, Newcomb CW, Nussenblatt RB, Pujari SS, Rosenbaum JT, Suhler EB, Thorne JE. Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs: retrospective cohort study. BMJ 2009;339:b Ilowite NT. Update on biologics in juvenile idiopathic arthritis. Curr Opin Rheumatol 2008;20: Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, Wouters C, Silverman ED, Balogh Z, Henrickson M, Apaz MT, Baildam E, Fasth A, Gerloni V, Lahdenne P, Prieur AM, Ravelli A, Saurenmann RK, Gamir ML, Wulffraat N, Marodi L, Petty RE, Joos R, Zulian F, McCurdy D, Myones BL, Nagy K, Reuman P, Szer I, Travers S, Beutler A, Keenan G, Clark J, Visvanathan S, Fasanmade A, Raychaudhuri A, Mendelsohn A, Martini A, Giannini EH. A randomized, placebocontrolled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 2007;56: Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004;31: Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, Cugno C, Bozzola E, Martini A, Ravelli A. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Rheum 2008;59: Beecham J, Knapp M. Costing psychiatric interventions. In: Thornicroft, Graham, (ed.) Measuring mental health needs. Gaskell, London, UK, pp ISBN Department of Health. NHS reference costs _ Curtis L. Costs of Health and Social Care Personal Social Services Research Unit, University of Kent Sung L, Petrou S, Ungar W. Measuring health utilities in children and their parents. In: Ungar W, ed. Economic Evaluation in Child Health. Oxford University Press National Institute for Health and Clinical Excellence (NICE). Guide to the Methods of Technology Appraisal McCabe CJ, Stevens KJ, Brazier JE. Utility scores for the Health Utilities Index Mark 2: an empirical assessment of alternative mapping functions. Med Care 2005;43: Espallargues M, Czoski-Murray CJ, Bansback NJ, Carlton J, Lewis GM, Hughes LA, Brand CS, Brazier JE. The impact of age-related macular degeneration on health status utility values. Invest Ophthalmol Vis Sci 2005;46: Glick H, Doshi JA, Sonnad SS, Polsky D. Economic evaluation in clinical trials. Oxford: Oxford University Press Briggs A, Sculpher M, Claxton K. Decision Modelling for Health Economic Evaluation. pp. 256 Oxford: Oxford University Press Kotaniemi K, rkela-kautiainen M, Haapasaari J, Leirisalo-Repo M. Uveitis in young adults with juvenile idiopathic arthritis: a clinical evaluation of 123 patients. Ann Rheum Dis 2005;64: Carvounis PE, Herman DC, Cha S, Burke JP. Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefes Arch Clin Exp Ophthalmol 2006;244: ICH. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting Page 72 of 76

75 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Murphy CC, Greiner K, Plskova J, Frost NA, Forrester JV, Dick AD. Validity of using vision-related quality of life as a treatment end point in intermediate and posterior uveitis. Br J Ophthalmol 2007;91: Murphy CC, Hughes EH, Frost NA, Dick AD. Quality of life and visual function in patients with intermediate uveitis. Br J Ophthalmol 2005;89: Lee RW, Creed TJ, Schewitz LP, Newcomb PV, Nicholson LB, Dick AD, Dayan CM. CD4+CD25(int) T cells in inflammatory diseases refractory to treatment with glucocorticoids. J Immunol 2007;179: Lee RW, Schewitz LP, Nicholson LB, Dayan CM, Dick AD. Steroid refractory CD4+ T cells in patients with sight-threatening uveitis. Invest Ophthalmol Vis Sci 2009;50: Schewitz LP, Lee RW, Dayan CM, Dick AD. Glucocorticoids and the emerging importance of T cell subsets in steroid refractory diseases. Immunopharmacol Immunotoxicol 2009;31: Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 1999;10: V. Kalinina Ayuso, Evelyne Leonce van de Winkel, Aniki Rothova, Joke Helena de Boer. Relapse Rate of Uveitis Post-Methotrexate Treatment in Juvenile Idiopathic Arthritis. American Journal of Opthamology; DOI: /j.ajo Brunner HI, Lovell DJ, Finck BK, Giannini EH. Preliminary definition of disease flare in juvenile rheumatoid arthritis. J Rheumatol 2002; 29(5): Consolaro A, Ruperto N, Bazso A et al. Development and validation of a composite disease activity score for juvenile idiopathic arthritis. Arthritis Rheum 2009; 61(5): Tanner Score: Blondell, Roster and dave, Disorders of Puberty. Am Fam Physician; 60(1): , Oliveira S, Ravelli A, Pistorio A, Castell E, Malattia C, Prieur AM et al. Proxy-reported health related quality of life of patients with juvenile idiopathic arthritis: the Paediatric Rheumatology International Trials Organisation multinational quality of life cohort study. Arthritis Rheum 2007; (1): Page 73 of 76

76 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: APPENDICES Appendix A: Trial Management Group Composition Dr. Athimalaipet Vaidyanathan* Ramanan Consultant Paediatric Rheumatologist Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ Tel: Fax: Professor Michael Beresford* Senior Lecturer Paediatric Medicine Paediatric Rheumatology Institute of Child Health Alder Hey Children s NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: m.w.beresford@liverpool.ac.uk Professor Andrew Dick* Professor of Ophthalmology Academic Department of Ophthalmology Department of Clinical Sciences University of Bristol Tel: Fax: a.dick@bristol.ac.uk Dr Clive Edelsten* Consultant Ophthalmologist Department of Paediatric Rheumatology Great Ormond Street Hospital for Children London WC1N 3JH Tel: ext 7887 Fax: edelsten@easynet.co.uk Professor Dyfrig Hughes* Professor of Pharmacoeconomics Centre for Economics and Policy in Health Bangor University Institute of Medical and Social Care Research Dean Street Gwynedd Wales LL57 1UT Tel: Fax: d.a.hughes@bangor.ac.uk Mr Ashley Jones* Senior Statistician Medicines for Children Clinical Trials Unit Institute of Child Health Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: apjones@liverpool.ac.uk Ms Helen Hickey Medicines for Children Clinical Trials Unit Institute of Child Health Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: H.Hickey@liverpool.ac.uk Dr Utpal Shah Cheshire, Merseyside & North Wales LRN Medicines for Children Research Network 1st Floor, Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: utpal.shah@alderheyrlc.nhs.uk Miss Lynne Cresswell* Medicines for Children Clinical Trials Unit Institute of Child Health Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: lynne.cresswell@liv.ac.uk Page 74 of 76

77 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Mr Ben Hardwick* Medicines for Children Clinical Trials Unit Institute of Child Health Alder Hey Children's NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: Dr Diana Benton University Hospitals Bristol NHS Foundation Trust UH Bristol Education Centre, Level 3, Upper Maudlin Street, Bristol, BS2 8AE Tel: Fax: Arthritis Research UK/ CSG representative: Professor Helen Foster* Professor of Paediatric Rheumatology Newcastle University c/o Rheumatology (ICM) Catherine Cookson Building Medical School Framlington Place Newcastle upon Tyne NE2 4HH Tel Fax Professor Pat Woo* Professor of Paediatric Rheumatology Great Ormond Street Hospital Great Ormond Street London WC1N 3JH Tel Fax * Non-independent members of Trial Steering Committee Page 75 of 76

78 SYCAMORE Protocol V1.0, 25 February 2011 EudraCT number: Appendix B: LOCS III grading adapted from Chylack et al 45 Page 76 of 76

79 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: A Randomised Controlled Trial of the Clinical Effectiveness, SafetY and Cost Effectiveness of Adalimumab in Combination with MethOtRExate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis (SYCAMORE) Version /07/2016. Study Sponsor: University Hospitals Bristol NHS Foundation Trust UH Bristol Education Centre, Level 3, Upper Maudlin Street, Bristol, BS2 8AE EudraCT number: Funding reference Numbers: HTA 09/51/01 / ARUK Sponsor Reference: CH/2008/3061 ISRCTN

80 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: April 2015 update and amendments to protocol As per section 11.4, an interim analysis of SYCAMORE primary outcome data was requested by the Independent Data and Safety Monitoring Committee (IDSMC). Following this the SYCAMORE Trial Management Group received the unanimous decision and recommendation of the SYCAMORE Trial Steering Committee (TSC) after they had received a unanimous recommendation from the IDSMC. The decision and recommendations of the indepenedendent members is based on a clear positive signal of efficacy of the IMP vs placebo that exceeded the pre-specified P value of P<0.001 as laid down in the Statistical Analysis Plan. The recommendations of the Independent Oversight Committees have been incorporated into the current version of the protocol. The recommendations have been incorporated by leaving original text intact, but noting amendments at the start of affected sections 2

81

82 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: General Information This document describes the SYCAMORE trial and provides information about procedures for entering patients into it. The protocol should not be used as an aide-memoir or guide for the treatment of other patients; every care was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to the registered investigators in the trial, but centres entering patients for the first time are advised to contact the coordinating centre (Medicines for Children Clinical Trials Unit or Liverpool Cancer Trials Unit) to confirm they have the most up to date version. Clinical problems relating to this trial should be referred to the relevant Chief Investigator via the CTU. This protocol defines the participant characteristics required for study entry and the schedule of treatment and follow-up. Participant recruitment will be undertaken in compliance with this document and applicable regulatory and governance requirements and waivers to authorise non-compliance are not permitted. Incidence of protocol non-compliance, whether reported prospectively (e.g. where a treatment cannot be administered on a scheduled date as a result of public holidays) or retrospectively noted (e.g. as a result of central monitoring) are recorded as protocol deviations, the incidence of which are monitored and reported to trial oversight committees. Statement of Compliance This study will be carried out in accordance with the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989) and South Africa (1996) amendments and will be conducted in compliance with the protocol, CTU Standard Operating Procedures and EU Directive 2001/20/EC, transposed into UK law as the UK Statutory Instrument 2004 No 1031: Medicines for Human Use (Clinical Trials) Regulations 2004 as amended. Relationship Statements The UK Clinical Research Collaboration (UKCRC; is a partnership organisation working to establish the UK as a world leader in clinical research. Following a review by an international panel, the Clinical Trials Research Centre (CTRC) at the University of Liverpool has been assessed as reaching the highest quality standard required by the UKCRC and achieved full UKCRC registration. The CTRC encompasses clinical trials activity in areas including medicines for children (The Medicines for Children Research Network Clinical Trials Unit; MCRN CTU), cancer (The Liverpool Cancer Trials Unit; LCTU), epilepsy, oral health and obstetrics and gynaecology ( All CTRC activities are underpinned by methodological rigour, a modern data management system, similar technical requirements and a common set of standard operating procedures. The NIHR Medicines for Children Research Network and National Cancer Research Network is part of the National Institute for Health Research Clinical Research Network. 4

83 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: CONTACT DETAILS Contact Details: Institutions Sponsor: University Hospitals Bristol NHS Foundation Trust UH Bristol Education Centre, Level 3, Upper Maudlin Street, Bristol, BS2 8AE Tel: Fax: Trial Management and Monitoring: Medicines for Children Clinical Trials Unit University of Liverpool 1st Floor Duncan Building Department of Biostatistics Daulby Street Liverpool L69 3GA Tel: Fax: uveitis@liv.ac.uk Tissue Bank: Dr Jennifer Oliver Research Coordinator Infection & Immunity Division Level 6, UBHT Education Centre Upper Maudlin Street Bristol, BS2 8AE Tel: Fax: Jennifer.Oliver@bristol.ac.uk Contact Details: Individuals Individual authorised to sign the protocol and protocol amendments on behalf of the Sponsor: Diana Benton Head of Research & Innovation University Hospitals Bristol NHS Foundation Trust UH Bristol Education Centre, Level 3, Upper Maudlin Street, Bristol, BS2 8AE Tel: Fax: Diana.Benton@UHBristol.nhs.uk Co-Chief Investigator (Co-CI): Professor. Athimalaipet Vaidyanathan Ramanan Consultant Paediatric Rheumatologist Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol, BS2 8BJ Tel: Fax: avramanan@hotmail.com Co-Chief Investigator (Co-CI): Professor Michael Beresford Senior Lecturer Paediatric Medicine Paediatric Rheumatology Institute of Child Health Alder Hey Children s NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: m.w.beresford@liverpool.ac.uk 5

84 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Medical expert who will advise on protocol ophthalmology related clinical queries: Professor Andrew Dick Professor of Ophthalmology Academic Department of Ophthalmology Department of Clinical Sciences University of Bristol Tel: Fax: Medical Expert who will Advise on Protocol Rheumatology Related Clinical Queries: Professor. Athimalaipet Vaidyanathan Ramanan Consultant Paediatric Rheumatologist Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ Tel: Fax: Medical experts who will evaluate SAE reports: Professor. Athimalaipet Vaidyanathan Ramanan Consultant Paediatric Rheumatologist Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ Tel: Fax: Dr Clive Edelsten Consultant Ophthalmologist Department of Paediatric Rheumatology Great Ormond Street Hospital for Children London WC1N 3JH Tel: ext 7887 Fax: Professor Michael Beresford Senior Lecturer Paediatric Medicine Paediatric Rheumatology Institute of Child Health Alder Hey Children s NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: m.w.beresford@liverpool.ac.uk Professor Michael Beresford Senior Lecturer Paediatric Medicine Paediatric Rheumatology Institute of Child Health Alder Hey Children s NHS Foundation Trust Eaton Road Liverpool L12 2AP Tel: Fax: m.w.beresford@liverpool.ac.uk Professor Andrew Dick Professor of Ophthalmology Academic Department of Ophthalmology Department of Clinical Sciences University of Bristol Tel: Fax: a.dick@bristol.ac.uk 6

85 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: CONTENTS 1 Contact details Contents Protocol Summary Background Information Introduction Rationale Objectives Primary objective: Secondary objectives: Potential Risks and Benefits Potential Risks Known Potential Benefits Selection of Centres/Clinicians Centre/Clinician Inclusion Criteria Centre/Clinician Exclusion Criteria Trial design Primary Endpoint Secondary Endpoint(s) Study Population Inclusion Criteria Exclusion Criteria Co-enrolment Guidelines Patient Transfer and Withdrawal Patient Transfers Withdrawal from Trial Intervention Withdrawal from Trial Completely screening, Enrolment and Randomisation Patient Identification, Provision of Information and Pre-screening Consent and Screening Randomisation and Treatment Commencement Requests for Randomisation Trial Treatments Introduction Randomisation Delivery and storage of IMP at trial sites Dispensing, Dosage and Administration of Study Treatments Dispensing Dose Modifications (Adalimumab and placebo) Dosage and Administration Formulation and Packaging Adalimumab solution for subcutaneous injection Placebo solution for subcutaneous injection Packaging Labelling, Storage and Stability Expired and unused IMP stock Concomitant Medications/Treatments Medications Permitted Medications Not Permitted

86 8 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Assessment of Compliance with Study Treatments Early withdrawal of treatment Unblinding Procedure Accidental Unblinding Unblinding at Trial Closure Non-Investigational medicinal Product (NIMP) - Methotrexate Dose range Dose modifications - Methotrexate Assessments and Procedures Schedule for Follow-up Procedures for Assessing Efficacy Ophthalmic Assessments Physical Examination Rheumatology Assessments: American College of Rheumatology Pedi Core Set Criteria and related outcomes Procedures for Assessing Safety Adverse Events Screening for Tuberculosis Urinalysis Serum pregnancy test Tanner Score Haematological Laboratory Assessments Biochemical laboratory Assessments Compliance with Study Treatment Quality of Life Child Health Assessment Questionnaire Childhood Health Questionnaire Health Economics Health Utilities Index Hospital Episode Statistics Client Service Receipt Inventory Establishment of JIA-associated Tissue Bank Sample Collection Loss to Follow-up Trial Closure Statistical Considerations Method of Randomisation Outcome Measures Primary Secondary Endpoint(s) Sample Size Interim Monitoring Reports Analysis Plan Economic Analysis Plan Pharmacovigilance Terms and Definitions Notes on Adverse Event Inclusions and Exclusions Include Do Not Include Reporting of Pregnancy Notes Severity / Grading of Adverse Events Relationship to Trial Treatment Expectedness Follow-up After Adverse Events... 51

87 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Reporting Procedures Non serious ARs/AEs Serious ARs/AEs/SUSARs Responsibilities Investigator Maintenance of Blinding Responsibilities CTU SAE reporting AbbVie Safety reports Ethical Considerations Ethical Considerations Ethical Approval Informed Consent Process General Competent Adults (aged years at time of consent) Minors (aged <16 years at time of consent) Minors reaching 16 years during trial participation Regulatory Approval Trial Monitoring Risk Assessment Source Documents Data Capture Methods Confidentiality Direct access to data Quality Assurance and Control Records Retention Indemnity Financial Arrangements Participant Payment Collaborating Centre Payments Research Team Pharmacy Department Trial Committees Trial Management Group (TMG) Trial Steering Committee (TSC) Independent Data and Safety Monitoring Committee (IDSMC) Publication Protocol Amendments References Appendices...75 Appendix A: LOCS III grading adapted from Chylack et al

88 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Glossary AE Adverse Event AR Adverse Reaction CHAQ Childhood Health Assessment Questionnaire CHQ Childhood Health Questionnaire CI Chief Investigator CMO Cystoid Macular Oedema CRF Case Report Form CTRC Clinical Trials Research Centre CTU Clinical Trials Unit DMARD Disease Modifying Anti-Rheumatic Drugs GP General Practitioner HUI2 Health Utilities Index 2 IB Investigator s Brochure IDSMC Independent Data and Safety and Monitoring Committee IEC Independent Ethical Committee IMP Investigational Medicinal Product LREC Local Research Ethics Committee MCRN CTU Medicines for Children Research Network Clinical Trials Unit MREC Main Research Ethics Committee NIHR CRN National Institute for Health Research Clinical Research Network OCT optical coherence tomography PI Principal Investigator R&D Research & Development S/C MTX Subcutaneous Methotrexate SAE Serious Adverse Event SAR Serious Adverse Reaction SDV Source Data Verification SPC Summary of product characteristics SUN Standardisation of the Uveitis Nomenclature SUSAR Suspected Unexpected Serious Adverse Reaction TMG Trial Management Group TSC Trial Steering Committee UAR Unexpected Adverse Reaction ULN Upper Limit of Normal 9

89 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: PROTOCOL SUMMARY Title of Study: Study Design: Population Number of Sites Randomised controlled trial of the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis Amendment: Design revised following interim analysis April See sections 8 and 9 for revised design Randomised, double-blind, placebo-controlled, multicentre, trial of adalimumab in combination with methotrexate (MTX) in patients with active uveitis in association with JIA refractory to MTX monotherapy. Participants will be randomised applying a ratio of 2:1 (in favour of adalimumab). Patients with persistently active JIA-associated uveitis (despite optimised methotrexate (MTX) treatment for at least 12 weeks) The study will be carried out in at least 16 tertiary care centres throughout the UK Study Duration All participants will be treated for 18 months, with follow up for a total of 2 years from randomisation (continuing on MTX throughout) Description of Agent/Intervention Primary Objective Secondary Objectives Amendment: Design revised following interim analysis April See section 9 for revised design Adalimumab. All participants will receive a stable dose of MTX and in addition either adalimumab (20mg/0.8ml for patients <30kg or 40mg/0.8ml for patients weighing 30kg, s/c injection every 2 weeks based on body weight), or placebo ( 0.8ml as appropriate according to body weight) s/c injection every 2 weeks. To compare the clinical effectiveness of adalimumab in combination with MTX versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with juvenile idiopathic arthritis (JIA) To evaluate short term safety and tolerability of adalimumab in combination with MTX versus MTX alone, with regards ocular complications of treatment, adverse events and laboratory assessments To determine quality of life and cost effectiveness of adalimumab in combination with MTX versus MTX alone in severe uveitis associated with JIA To determine the clinical effectiveness of adalimumab in combination with MTX versus MTX alone, with regard underlying JIA disease activity To determine the durability and magnitude of adalimumab efficacy response in sustaining inactive disease and achieving complete clinical remission To determine the long term safety of adalimumab in combination with MTX versus MTX alone To assess the efficacy of treatment with adalimumab to permit concomitant medication reduction, in particular regional and parenteral steroids To develop a fully consented, trial-related Tissue Bank for subsequent investigation 10

90 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Protocol Summary - continued Schematic of Original Study Design: Participant fulfilling eligibility criteria and providing fully informed consent RANDOMISE (2:1 in favour of active) 2 weekly s/c injections Adalimumab, plus MTX N = 76 2 weekly s/c injections placebo, plus MTX N = 38 Treatment Months 1 to 3 Monthly OPD review: completion of QoL and Health Economic questionnaires, AE review, ophthalmology and rheumatology review: Treatment failure? No Treatment Months 4 to 18 Three Monthly OPD review: completion of QoL and Health Economic questionnaires, AE review, ophthalmology and rheumatology review: Treatment failure? Yes No Post-treatment Follow-up Three Monthly OPD review: completion of QoL and Health Economic questionnaires, AE review, ophthalmology and rheumatology review. Any additional treatment administered at discretion of treating physician and recorded on CRF Cease trial treatment 11

91 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: BACKGROUND INFORMATION 4.1 Introduction Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA also are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20-25% of all paediatric uveitis is associated with JIA 1,2 but a greater proportion are seen in referral cohorts. The major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity 3. In the initial stages of mild to moderate inflammation the uveitis is entirely asymptomatic. This has led to the current practice of screening all children with JIA regularly for uveitis. Approximately 12-38% of patients with JIA will develop uveitis in the seven years following the onset of arthritis 4,5. In 30-50% of children with JIA associated uveitis structural complications are present at diagnosis 6. Furthermore about 50-75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract, glaucoma, band keratopathy and macular pathology 7-9. Defining the severity of inflammation and structural complications in uveitis patients can now be more consistently described following Standardised Uveitis Nomenclature (SUN) guidelines, allowing their incorporation into design of randomised controlled trials (RCT) and cohort studies 10. Significant poor prognosticators of poor visual acuity include structural changes at presentation; the need for intraocular surgery, posterior segment inflammation, abnormal intraocular pressure and the failure to maintain long-term disease control as marked by persistent AC cell scores >/= ,11. Despite current screening and therapeutic options (pre-biologics) % of children with JIA associated uveitis may eventually develop bilateral visual impairment and are certified legally blind 12,13. It is therefore critical to find more effective therapeutic interventions. 4.2 Rationale Methotrexate (MTX) is well established as the first-line disease modifying agent in the management of JIA 14,15. The current approaches to treatment of mild JIA-associated uveitis include use of topical steroids. MTX is also thought to be effective for JIA-associated uveitis in children with moderate-to-severe uveitis 16-18, but there have been no prospective randomised placebo-controlled trials of MTX or steroid regimens in JIA-associated uveitis. Systematic review of the evidence of MTX in JIA is restricted to joint involvement 14 but not in paediatric uveitis. Despite the scarce evidence, MTX has become the mainstay of treatment for JIA-uveitis 19. However, up to 15-50% of children will have refractory uveitis in spite of optimal therapy with methotrexate De Boer found that 30% of patients started on MTX will not achieve control during the first year of therapy and even when remission is achieved on MTX 9/13 will later relapse suggesting only 4/22[18%] patients achieve total remission.in the GOS cohort a similarly low proportion of 12% were found to be in total remission five years after starting MTX 75. Several agents including ciclosporin and mycophenolate mofetil (MMF) have been shown to be of benefit in controlling JIA-uveitis in retrospective small case series 20,21. However their use remains restricted due to intolerability due to adverse reactions and little evidence that they rescue methotrexate-refractory patients. In addition, neither ciclosporin nor MMF are very effective in controlling joint manifestations in the children 19. More recently, animal models and corroborative human evidence 22, supports the role of tumor necrosis alpha (TNF-α) in the aetiopathogenesis of uveitis, and moreover the potential value of its inhibition as a therapeutic intervention 23. Studies on experimental models of autoimmune uveitis have demonstrated that TNF plays a pivotal role in pathogenesis of intraocular inflammation 22, which has been borne out in treatment of adult uveitis 23. In mouse models of anterior uveitis, deleting p55 receptor as 12

92 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: well as combined TNFR p55 and p75 knockout animals, results in reduced disease 24, more significantly than the effect of TNFR p55 fusion protein 25. Furthermore, in an animal model of uveitis, infliximab reduced disease severity 26, albeit at doses of 20mg/kg. Translating this to humans, several case series have been published demonstrating the efficacy of infliximab and adalimumab in treatment of severe refractory uveitis in adults and children In contrast, etanercept has been reported not to halt onset of uveitis or be more effective than placebo 33,34, and less effective than infliximab in treating JIA-uveitis 30,35,36. There are a number of reports of new-onset uveitis associated with etanercept use in JIA 37. An adverse events register-based study examining these cases determined that whilst the frequency was greater for etanercept than for infliximab or adalimumab (n=20, 4 and 2 cases respectively), causality could not be established 38. Etanercept is not considered to be effective in treating intraocular inflammation 30. Adalimumab is a fully human monoclonal antibody engineered by gene technology that uses site-directed mutagenesis to enhance its binding efficiency to TNF. It does not contain nonhuman or artificial protein sequences. Adalimumab binds only to TNF-α and has a half life of approximately two weeks. The antibody has been extensively studied in vitro as well as in vivo and is non-toxic in animal toxicology experiments. Clinical trial of adalimumab as monotherapy or in combination with MTX in adult subjects with rheumatoid arthritis showed a significant clinical response 39. In children with JIA, a multicenter randomised, double blind stratified parallel group trial has shown a significant benefit in children with active arthritis 40. Studies in paediatric non-infectious uveitis have shown very promising results with adalimumab, with 21 out of 26 eyes from 14 children with JIA- or idiopathic-uveitis showing improvement in inflammation 41. In another retrospective case series of 18 paediatric patients with uveitis, 88% had a substantial decrease in ocular inflammation and adalimumab showed corticosteroid-sparing potential 27. There are no prospective studies of efficacy and safety of anti-tnf agents in JIA-associated uveitis. In the randomised controlled trial of adalimumab in JIA that demonstrated safety and efficacy, the most commonly reported adverse events were infections and injection-site reactions 40. Serious adverse events considered possibly related to study drug by the investigator occurred in 14 patients. Seven of these included one case of: bronchopneumonia, herpes simplex infection, pharyngitis, and pneumonia, and two cases of herpes zoster infection. In this trial there were no deaths, malignant conditions, opportunistic infections, cases of tuberculosis, demyelinating diseases or lupus-like reactions 40. The fixed dose model of 20 mg for children < 30 kg and 40mg for children 30 kg selected for this trial is based on the data generated in the above trial using the same dosing regimen Objectives Primary objective: To compare the clinical effectiveness of adalimumab in combination with methotrexate (MTX) versus MTX alone, with regard to controlling disease activity in refractory uveitis associated with juvenile idiopathic arthritis (JIA) Secondary objectives: To evaluate short term safety and tolerability of adalimumab in combination with MTX versus MTX alone, with regards ocular complications of treatment, adverse events and laboratory assessments To determine quality of life and cost effectiveness of adalimumab in combination with MTX versus MTX alone in severe uveitis associated with JIA 13

93 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: To determine the clinical effectiveness of adalimumab in combination with MTX versus MTX alone, with regard underlying JIA disease activity To determine the durability and magnitude of adalimumab efficacy response in sustaining inactive disease and achieving complete clinical remission To determine the long term safety of adalimumab in combination with MTX versus MTX alone To assess the efficacy of treatment with adalimumab to permit concomitant medication reduction, in particular regional and parenteral steroids To develop a fully consented, trial-related Tissue Bank for collection of serum, DNA and RNA for subsequent investigation 4.4 Potential Risks and Benefits JIA-associated uveitis is a severe, potentially sight-threatening condition, often inadequately treated using standard therapies. Advent of the biologic therapies offers significant anticipated benefits therefore to the patient. However, due care must be taken in determining the potential benefits of anti-tnf therapy, now being used in off-label manner in this condition, against the potential associated risks. Safety (short and long term) of the new biologic therapies in children and young people is of major importance, particularly in this study. The risk / benefit assessment of this intervention needs careful attention. Safety is therefore a key secondary outcome measure of the trial Potential Risks The long term follow up of children on etanercept and adalimumab from controlled studies have, to date, not shown any increased risk of malignancies. However the United States Federal Drug Administration (FDA) have recently issued an alert to healthcare professionals that their analysis has revealed that 48 children developed malignancies whilst on anti-tnf agents including eleven deaths 48. The data is mainly for children and adolescents on etanercept and infliximab on account of limited follow up data available on adalimumab. The analysis includes in particular children with Crohn s disease. 88% of the 48 children were also on concomitant immunosuppressive medication including azathioprine and methotrexate. The complete details of the FDA analysis are not currently available. Importantly, these data do not provide comparative information on long term malignancy rates in JIA patients treated with methotrexate alone, or untreated JIA. Subsequent data presented at the American College of Rheumatology (2009) of 1168 patients over patient years indicates no increased risk of anti-tnf therapy in JIA (Abstract: Bernatsky, Rosenberg & Kiem, ACR, 2009). Recent data presented at EULAR emphasises the importance of comparing anti-tnf safety data to untreated disease (EULAR 2010, McCroskey P) and that current data does not indicate a significant relative increase with respect to controls (Southwood T et al. EULAR 2010 Oral presentation). All these reports however emphasise the critical importance of making safety a major priority in this trial. This priority is both within the treatment and follow up duration of the trial, but also ensuring procedures are in place to continue this safety follow up longer term. The risk of increased malignancy with azathioprine in patients with Crohn s disease on infliximab is well recognised 49,50. As noted already, adverse events associated with the recent adalimumab trial in JIA was associated with minimal safety signals 40. A recent retrospective cohort study evaluated overall mortality and cancer mortality in relation to immunosuppressive drugs exposure in adult patients with ocular inflammatory diseases including anti-tnf drugs 51. The study did show an increased overall and cancer mortality in adult patients exposed to anti-tnf agents. The authors acknowledge that this data needs interpreted with caution on account of the methodological issues associated with retrospective studies and prevalence of co-morbidity in patients on anti-tnf drugs. 14

94 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: From adult data, but also the growing evidence base from published data of long term follow up in biologic registries, clinical trials and cohort studies, a number of important safety signals need to be considered in this trial, Patients taking TNF-blockers are more susceptible to serious infections. Patients must therefore be monitored closely for infections, including tuberculosis, before, during and after treatment with adalimumab. Because the elimination of adalimumab may take up to five months, monitoring should be continued throughout this period. Adverse events of the haematologic system, including medically significant cytopaenia (e.g. thrombocytopaenia, leucopaenia) have been reported with adalimumab. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor) while on adalimumab. Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant methotrexate. Antibody formation to the drug itself was lower when adalimumab was given together with methotrexate in comparison with use as monotherapy. Administration of adalimumab without methotrexate resulted in increased formation of antibodies, increased clearance and reduced efficacy of adalimumab (see section 4.1). In patients with polyarticular juvenile idiopathic arthritis, adalimumab antibodies were identified in 27/171 subjects (15.8%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 22/86 (25.6%), compared to 5/85 (5.9%) when adalimumab was used as add-on to methotrexate 40. Patients who develop a new infection while undergoing treatment with adalimumab, should be monitored closely and undergo a complete diagnostic evaluation. Administration of adalimumab should be discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled. Physicians should exercise caution when considering the use of adalimumab in patients with a history of recurring infection or with underlying conditions which may predispose patients to infections, including the use of concomitant immunosuppressive medications. Serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis and septicaemia Approximately 10-15% of participants can be expected to see injection site reactions at some time Known Potential Benefits In rheumatoid arthritis studies I-IV, all individual components of the adult ACR response criteria (number of tender and swollen joints, physician and patient assessment of disease activity and pain, disability index (HAQ) scores and CRP (mg/dl) values) improved at 24 or 26 weeks compared to placebo. In rheumatoid arthritis studies I-IV, Adalimumab-treated patients achieved statistically significant ACR 20 and 50 responses compared to placebo as early as one to two weeks after initiation of treatment. In polyarticular course JIA, adalimumab has been shown to have a significant clinical benefit in JIA on core paediatric ACR response criteria 46. In the double-blind, withdrawal design phase of the trial of adamilumab in JIA 40, amongst patients not receiving MTX, there was significant increase in the number of disease flares in those subsequently receiving placebo compared to adalimumab (71% versus 43%, p=0.03) 76. In those patients receiving concomitant MTX, flares occurred in 65% on placebo, compared to 37% receiving 16

95 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: adalimumab (p=0.02). At 48 weeks, the percentage of patients treated with MTX who had ACR Pedi30, Pedi50, Pedi70 and Pedi90 responses were significantly greater for those receiving adalimumab than those receiving placebo (ACR Pedi 30: 63% versus 38%, p=0.03; ACR Pedi 50: 63% versus 38%, p=0.03; ACR Pedi70: 63% versus 27%, p=0.002). Open label extension of the studies showed sustained responses for up to 104 weeks of treatment. As outlined in the Protocol Rationale, its reported use in JIA-associated Uveitis warrants an RCT trial to assess its clinical effectiveness and safety. 17

96 5 SELECTION OF CENTRES/CLINICIANS SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Study centres will be initiated once all their global (e.g. local R&D approval) and studyspecific conditions (e.g. training requirements) have been met, and all necessary documents have been returned to MCRN CTU. Initiation meetings will cover the requirements outlined in the Clinical Trials Research Centre s Standard Operating Procedures relating to site training and set up. 5.1 Centre/Clinician Inclusion Criteria a. Centres offering combined paediatric rheumatology/ophthalmology service b. It is essential that all recruits should have regular and emergency access to a paediatric rheumatologist / ophthalmologist c. Completion of calibration training in ophthalmology assessments d. Sufficient demonstrated capacity of staff to carry out study assessments e. Curriculum Vitae (CV) including a record of International Conference for Harmonisation (ICH) of GCP training Principal Investigator (PI) f. CV including a record of ICH GCP training Other personnel on the delegation log g. Completion and return of Signature and Delegation Log to CTU h. Positive SSI i. Local R&D approval j. Signed contract between site and sponsor k. Receipt of evidence of completion of (h) to (j) by CTU l. Sites must be able to perform Biochemical assessments as outlined in section All sites would be expected to demonstrate ability to run paediatric clinical trials in accordance with Good Clinical Practice, and as such demonstrate support and infrastructure for all aspects of trial delivery including integration of the clinical research teams with pharmacy, clinical laboratory, and research support services; all centres will be expected to work in collaboration with Research Network support where present, including the NIHR MCRN Local Research Networks, the Comprehensive Local Research Network, and equivalent in Scotland, Wales and Northern Ireland. 5.2 Centre/Clinician Exclusion Criteria Not meeting the inclusion criteria and expectations stated above 18

97 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: TRIAL DESIGN 6.1 Primary Endpoint The primary endpoint is time to treatment failure. Treatment failure is defined by ONE or more of the following: 1) Anterior segment inflammatory score grade (SUN criteria) Following at least 3 months of therapy: i) 2-Step increase from baseline in SUN cell activity score (AC Cells) over 2 consecutive readings ii) Sustained non-improvement with entry grade of 3 or greater for 2 consecutive readings iii) Only partial improvement (1 grade) or no improvement, from baseline, with development of other ocular co-morbidity* which is sustained iv) Worsening of existing (on enrolment) ocular co-morbidity* after 3 months v) Sustained scores as recorded at entry grade measured over 2 consecutive readings (grades 1 to 2) still present after 6 months of therapy. 2) Use of Concomitant Medications: At any time, requirement to use concomitant medications in manner out with pre-defined acceptable criteria (see section 9.8.1), or any of the concomitant medications not allowed (see section 9.8.2) 3) Intermittent or continuous suspension of study treatment (adalimumab/placebo) for a cumulative period longer than 4 weeks * Ocular co-morbidities are defined as: i) Disc swelling and/or Cystoid Macular Oedema (CMO) as gauged clinically and where possible by OCT evidence; and/or: ii) Raised intraocular pressure (>25mm Hg) sustained over 2 consecutive visits not responding to single ocular hypotensive agent, and/or: iii) Hypotony (<6 mm Hg) sustained over 2 consecutive visits, and/or iv) Development of unexplained reduction in vision (LogMar) over two consecutive visits of 0.3 LogMar units(in the event of cataract participants will remain in trial, also if cataract surgery is required. Failure will still remain as described in endpoints above). N.B> Intraocular pressure >= 25 mmhg or < 6 mmhg are exclusion criteria at baseline and ocular co-morbidities i-iv can be developed during follow up only, i may worsen based on the existing (on enrolment) ocular co-morbidity. Where a reading is required to be sustained over two consecutive visits to define treatment failure the time of treatment failure will be taken as the second of these readings. For determining treatment failure there should be in interval of at least four weeks between assessments. 6.2 Secondary Endpoint(s) 1) Number of participants failing treatment 2) Incremental cost-effectiveness and cost-utility of adalimumab added to MTX compared with MTX alone 3) Health status according to the multi-attribute health utility index, HUI2 19

98 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: ) Safety, tolerability and compliance a. Adverse events (AEs) and serious adverse events (SAEs) b. Laboratory parameters (haematological and biochemical analysis and urinalysis c. Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period 5) Use of Corticosteroids over duration of study period and throughout follow up, including: a. Total oral corticosteroid dose b. Reduction in and rate of systemic corticosteroid dose from entry dose c. Topical corticosteroid use (frequency) compared to entry usage d. Need for pulsed corticosteroid 6) Optic and ocular a. Number of participants having disease flares (as defined by worsening on SUN criteria) following minimum 3 months disease control b. Number of participants having disease flares within the first 3 months. c. Visual acuity measured by Age-appropriate LogMar assessment d. Number of participants with resolution of associated optic nerve or macular oedema (as assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) (where available). e. Number of participants with disease control (defined as zero cells, with topical treatment for 3 and 6 months) f. Number of participants entering disease remission (defined as zero cells, without topical treatment for 3 and 6 months) g. Duration of sustaining inactive disease (zero cells, with or without topical treatment) 7) Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ)) 8) American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels (see section ) 9) Number of participants undergoing disease flare, in remission on and off medication 54 of their JIA and with minimum disease activity 55 10) Number participants requiring change in biologic / Disease-modifying anti-rheumatic drugs (DMARDs) therapy due to failure to respond from arthritis 11) Participants score of the Juvenile Arthritis Disease Activity Score (JADAS). The JADAS comprises four components: (1) physician global assessment of disease activity (2) parent/patient global assessment of well-being (3) active joint count, in 27, 71 or 10 joints; and (4) erythrocyte sedimentation rate (ESR). 20

99 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: STUDY POPULATION 7.1 Inclusion Criteria Screening, enrolment and randomisation of new participants into SYCAMORE has ceased based upon the recommendations of the Independent Data and Safety Monitoring Committee and Trial Steering Committee. 1) Children and young people aged 2 and <18 years fulfilling ILAR diagnostic criteria for JIA (all subgroups that have uveitis). 2) At the time of trial screening the participant must have active anterior uveitis, defined as a sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade >1+ or more during the preceding 12 weeks therapy despite MTX and corticosteroid (both systemic and topical) therapy. The latest date of SUN grade score must be the date of the screening visit. 3) They must have failed MTX (minimum dose of 10-20mg/m 2, with a maximum dose of 25mg/participant). The participant must have been on MTX for at least 12 weeks* and have been on a stable dose for 4 weeks prior to screening visit. 4) No Disease modifying immunosuppressive drugs, other than MTX, in the 4 weeks prior to screening 5) Written informed consent of participant or parent/legal guardian, and assent where appropriate. 6) Participant and parent/legal guardian willing and able to comply with protocol requirements. 7) For participants of reproductive potential (males and females), use of a reliable means of contraception throughout their trial participation. Post pubertal females must have a negative serum pregnancy test within 10 days before the first dose of trial drug. 8) Able to be randomised and commence trial treatment within 2 weeks of the screening visit. * Omission of a maximum of 2 weeks methotrexate treatment within the 12 weeks is acceptable and will not render the patient ineligible unless they have been missed in the 4 weeks prior to the screening visit. 7.2 Exclusion Criteria Screening, enrolment and randomisation of new participants into SYCAMORE has ceased based upon the recommendations of the Independent Data and Safety Monitoring Committee and Trial Steering Committee. 1) Uveitis without a diagnosis of JIA 2) Currently on adalimumab or has previously received adalimumab. 3) Have been on other biologic agent within previous 5 half-lives of agent (For other biologic agents and their was out periods, (refer to protocol supplementary document #10) 4) More than 6 topical steroid eye drops per eye, per day prior to screening (this dose must have been stable for at least 4 weeks prior to screening visit) 5) For patients on Prednisone or Prednisone equivalent, change of dose within 30 days prior to screening 6) For patients on Prednisone or Prednisone equivalent with a dose >0.2mg/kg per day 7) Intra-articular joint injections within four weeks prior to screening 8) Any ongoing chronic or active infection (including infective uveitis) or any major episode of infection requiring hospitalisation or treatment with intravenous antibiotics within 30 days or oral antibiotics within 14 days prior to the screening evaluation 21

100 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: ) History of active tuberculosis of less than 6 months treatment or untreated latent TB 10) Participant has history of central nervous system (CNS) neoplasm, active CNS infection, demyelinating disease, or any progressive or degenerative neurological disease 11) Poorly controlled diabetes or persistently poorly controlled severe hypertension (>95 th percentile for height / age) as deemed by the treating physician 12) Previous history of malignancy 13) Intraocular surgery within the 3 months prior to screening (cataract/ glaucoma/ vitrectomy) 14) Intra-ocular or peri-ocular corticosteroids within 30 days prior to screening. 15) History of ocular herpetic disease 16) Pregnant or nursing female 17) Demonstrations of clinically significant deviations in any of the following laboratory parameters: a. Platelet count < 100,000/mm 3 b. Total white cell count < 4000 cells/mm 3 c. Neutrophils < 1000 cells/mm 3 d. AST or ALT > 2 x upper limit of normal (ULN) or serum bilirubin > 2x the ULN e. Glomerular filtration rate (GFR) of < 90 ml/min/1.73m 2 [GFR (ml.min/1.73 m 2 BSA) = 0.55 x height (cm)/plasma creatinine (mg/dl)] f. Hematocrit <24% 18) Having been administered a live or attenuated vaccine within three months prior to screening 19) Previous randomisation into the SYCAMORE trial to either arm of the trial. 20) Intra-ocular pressure <6mm Hg or Intra-ocular pressure > 25mm Hg 21) Intra-ocular pressure control requiring more than one topical pressure lowering therapy or requiring systemic acetazolamide 7.3 Co-enrolment Guidelines To avoid potentially confounding issues, patients should not be recruited into other interventional IMP trials. Individuals who have participated in previous trial testing of an IMP should will not be eligible for this trial until the appropriate washout period has outlined within Exclusion Criteria (Section 7.2) or in accordance with the respective half-life of the previous IMP. Where recruitment into another trial or study is considered to be appropriate and without having any detrimental effect on either trial this must first be discussed with the coordinating centre (MCRN CTU) who will contact the Chief Investigator (Prof Athimalaipet Vaidyanathan Ramanan). All patients however are eligible to be considered for recruitment to non-interventional studies relevant to their disorder or treatment, in accordance with the respective study protocols. In particular, longitudinal observational cohort, pharmacovigilance and efficacy, quality of life and mechanism of disease studies. 7.4 Patient Transfer and Withdrawal Patient Transfers For patients moving from the area, every effort should be made for the patient to be followed-up at another participating trial centre and for this trial centre to take over responsibility for the patient or for follow-up via GP. A copy of the patient CRFs should be provided to the new site. The patient (or parent/legal representative) will have to sign a new consent form at the new site, and until this occurs, 22

101 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: the patient remains the responsibility of the original centre. The CTU should be notified in writing of patient transfers Withdrawal from Trial Intervention Patients may be withdrawn from treatment for any of the following reasons: a. Parent/ legal representative (or, where applicable, the patient) withdraws consent. b. Unacceptable adverse effects/ toxicity as determined by the treating clinician. c. Intercurrent illness preventing further treatment. d. Development of serious disease or any change in the patient s condition that justifies the discontinuation of treatment in the clinician s opinion. If a patient wishes to withdraw from trial treatment, centres should nevertheless explain the importance of remaining on trial follow-up, or failing this, of allowing routine follow-up data to be used for trial purposes. Generally, follow-up will continue unless the patient explicitly also withdraws consent for follow-up (see section 7.4). Upon discontinuation of trial intervention participants will be treated in accordance with usual local clinical practice and followed up for 18 months Withdrawal from Trial Completely Patients are free to withdraw consent at any time without providing a reason. In consenting to the trial, patients are consented to trial treatment, follow-up and data collection. If voluntary withdrawal occurs, the patient (or parent/legal representative, where applicable) should be asked to allow continuation of scheduled evaluations, complete an end-of-study evaluation, and be given appropriate care under medical supervision until the symptoms of any adverse event resolve or the subject s condition becomes stable. If consent is withdrawn completely then the reasons for withdrawal of consent will be collected (if possible) and reported for both groups. Participants who wish to withdraw consent for the trial will have anonymised data collected up to the point of that withdrawal of consent included in the analyses unless the patient explicitly states that this is not their wish. The patient will not contribute further data to the study and the CTU should be informed in writing by the responsible physician and a withdrawal CRF should be completed. 23

102 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: SCREENING, ENROLMENT AND RANDOMISATION Screening, enrolment and randomisation of new participants into SYCAMORE has ceased based upon the recommendations of the Independent Data and Safety Monitoring Committee and Trial Steering Committee. Several assessments are required to be undertaken as part of the research activity in order to establish eligibility, requiring that written informed consent (or proxy consent in the case of minors) is obtained prior to formal trial screening. For this reason, centres are encouraged to adopt a pre-screening procedure in order to identify potentially eligible patients prior to their attending clinic review. 8.1 Patient Identification, Provision of Information and Prescreening All teams will review on a regular and timely basis potentially eligible patients from within their clinical cohort(s). Potential recruits identified via these pre-screening exercises will be provided with an ethically approved summary of the trial prior to attending for clinical review. At the time of clinical review the treating consultant and / or other designated individual (as identified on the site signature and delegation log) will subsequently ratify that they potentially meet these criteria and will approach identified patients to discuss the study further. If they wish to know more about the trial and to be considered for entry they will be supplied with a copy of the Patient Information Sheet and Consent form (PISC). The time taken from initial contact and provision of information to obtaining written consent should be sufficient to enable appropriate discussions with the patient / family about the trial, explanation of the protocol and procedures, and seeking formal consent. Generally this will be a minimum period of 24 hours, although it is acknowledged that some patients / families may come to this decision sooner A screening log will be maintained at each trial centre, recording all individuals considered and screened for the trial, assigning each a unique screening number, and recording the eventual outcome. Reasons for non-consideration of pre-screened patients, and nonrecruitment of screened patients will be documented (e.g. not eligible, declined consent, etc.) and the information will be used for monitoring purposes. 8.2 Consent and Screening Formal screening involves the collection of baseline data. All patients considered for the trial will be recorded on the screening log and have a unique screening number that will be used on trial documents until the randomisation number is allocated. Assessments for consideration of trial entry which are not undertaken as part of routine care should only be undertaken following provision of written consent. All screening assessments should be completed, and results collated to verify eligibility in a timely manner to ensure that randomisation and treatment can be commenced within 2 weeks of obtaining written consent. Assessment activities are summarised here and detailed descriptions of assessments are provided in section 9. During screening you should: 24

103 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: ) Obtain or verify that written informed consent has been obtained from non-minors (aged years inclusive) or proxy consent for minors (aged <16 years), with assent of minors, where appropriate. 2) Carry out assessments to confirm eligibility and determine baseline parameters: a. Demographics / medical/ ophthalmic/ surgical history and past medical history b. Detailed rheumatology assessments c. Detailed ophthalmology assessments d. Review concurrent medication and medication history in relation to eligibility e. Detailed Systems Physical examination f. Haematological laboratory assessments g. Biochemical laboratory assessments h. Tanner score i. Height, weight and vital signs (heart & respiratory rate, temperature and blood pressure) j. Standard ACR Pedi Core Set outcome variables k. Urinalysis (microscopy) l. Serum Pregnancy Test m. PPD Tuberculin skin test or local equivalent n. Completion of CHQ/CHAQ, HUI2 and CSRI 3) Eligible patients can now be randomised (Sections and 9.2) 4) Consent/assent forms and the Baseline CRF of eligible patients should be submitted to the CTU within 7 days of the visit occurring 5) The outcome for patients found to be ineligible after completing assessments will be recorded on screening logs (CRFs do not require to forwarded to the CTU) 6) Patient s who fail screening may be re-screened after a minimum period of 1 week after their last screening. 8.3 Randomisation and Treatment Commencement Requests for Randomisation Randomisation and treatment commencement should occur within 2 weeks of the screening visit. N.B. All screening assessments should be completed prior to randomising and commencing allocated treatment 1) Complete the appropriate documents to confirm eligibility, request randomisation and prescribe trial treatment. All documentation will carry the trial participants screening number 2) Trial prescriptions will detail the appropriate dose for the participants weight and will indicate that Adalimumab or placebo are to be dispensed according to the treatment allocated at randomisation. 3) Deliver these documents to the pharmacy department in order that pharmacy can proceed with the randomisation (see Section 9.2). 4) Randomisations will be undertaken during normal working hours (Monday Friday ). Randomisation requests received outside of these times will be actioned on the next working day. 5) Commence allocated treatment 25

104 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: TRIAL TREATMENTS Following the recommendations of the IDSMC and TSC, the SYCAMORE trial design has been amended. Screening, enrolment and randomisation of new participants into SYCAMORE has ceased and participants will no longer receive placebo treatment. All participants should invited to attend a blinded assessment at their earliest convenience. At this visit, before the patient is unblinded they will undergo study assessments as per protocol (section 10) and unblinded as described in section At this point, participants allocated placebo will cease trial treatment and subsequent treatment will be at the discretion of their local treating clinician. Participants allocated adalimumab will continue on trial treatment as per protocol. When the trial assessments have been completed the researcher should contact Ben Hardwick (Trial Co-ordinator) on , during this call the researcher should confirm that all Rheumatology, Ophthalmology, quality of life and general assessments have been completed as per protocol, following which permission to unblind the participant will be provided. Unblinding information will be provided by the local pharmacy department (section ). Please note that unblinding should not take place before the final blinded assessments have been completed. 9.1 Introduction This is a randomised, double-blind, placebo controlled trial. The investigational medicinal products (IMPs) in this trial are adalimumab and placebo. Participants will be randomised to one of the following treatment arms: Active arm: Adalimumab subcutaneous injection every 2 weeks for 18 months. The dose will be based on body weight (20mg for participants weighing <30kg or 40mg for participants weighing 30kg). Dose modifications are NOT permitted in participants whose bodyweight changes from less than 30 kg to greater than 30 kg or from greater than 30 kg to less than 30 kg during the 18 month treatment period. Placebo arm: Placebo subcutaneous injection every 2 weeks for 18 months All patients in both arms will continue to receive a stable dose of Methotrexate at a minimum dose of 10-20mg/m 2 and a maximum dose of 25mgs as a non-investigational medicinal product (NIMP) throughout the 18 month treatment period (refer to section 9.12). After the 18 month treatment period participants will be followed up for a further 6 months to determine sustained effectiveness (remission) and safety over and above ongoing MTX therapy. 9.2 Randomisation Randomisation will be undertaken during normal working hours (Monday Friday ) by the pharmacy departments of participating centres upon receipt of a randomisation 26

105 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: request form and prescription from authorised clinicians. Pharmacy personnel will verify that these documents are appropriately completed before proceeding. It is the responsibility of the PI or delegated research staff to: 1) Notify pharmacy of potential randomisations so that pharmacy can ensure adequate drug supplies are at site and 2) Complete the appropriate trial documents and deliver these to the pharmacy department at their centre in order that pharmacy can proceed with a randomisation. Participants will be randomised using a secure (24-hour) web based randomisation programme. Randomisation lists will be generated in a 2:1 ratio in favour of the active therapy. The lists will incorporate random elements and the web randomisation programme will be controlled centrally by the MCRN CTU; both measures to ensure allocation concealment. Participant treatment allocation will be displayed on a secure webpage and an automated confirmation sent to the authorised randomiser. In the event of an internet connection failure between the centre and the randomisation system, the centre should contact the MCRN CTU immediately to try to resolve the problem. If this is not possible within a reasonable time then the supplied back up randomisation envelopes should be used to provide the treatment allocation. Randomisation: web access If there are any problems with web randomisation please contact the MCRN CTU helpdesk on: Designated pharmacy staff will be trained to use the web randomisation system during the initiation process. After pharmacy staff are trained they will be issued with personal login and password details. 9.3 Delivery and storage of IMP at trial sites Clinical trial supplies will only be delivered to an investigator site once the site has been initiated by MCRN CTU, acting on behalf of sponsor to ensure full ethical and regulatory approvals have been granted. The size of the shipments to each site will be pre-determined based on the participant recruitment target for that individual site. Recruitment will be monitored centrally and drug shipment dates will be tailored accordingly to ensure that pharmacies hold adequate supplies of trial treatment. Pharmacies must document all shipment receipts and will provide copies of this documentation to the MCRN CTU. IMP stock must be received by a designated member of the pharmacy department and must be stored at 2-8 C with temperature monitoring and in accordance with IMP regulations. Records of all shipments must be kept in the drug accountability log. If IMP stock received from the distributor is unexpected, wrong, damaged or out of temperature range, the stock should be quarantined and MCRN CTU contacted for further actions. 27

106 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Dispensing, Dosage and Administration of Study Treatments 9.4.1Dispensing IMPs will be supplied as bulk stock from the distributor to pharmacy in kits containing 2 vials. Authorised, trial trained pharmacy staff should select adalimumab or placebo vials (identified by corresponding kit numbers) according to the randomisation instruction, prescription and participant s body weight (20mg for participants weighing <30kg or 40mg for participants weighing 30kg). The number of vials to be supplied at each dispensing will be determined by the date of the next clinic visit, up to a maximum of three months supply (i.e. 6 vials). Pharmacy must enter the site and trial participant identifiers onto the vial and carton labels of each kit at dispensing, (refer to section 9.6) and must complete, sign and date their accountability log. A second member of the pharmacy team must counter-sign and date the log to document the dispensing. Pharmacy must ensure that the participant and the researcher remain blinded to the treatment allocation. At each subsequent dispensing, the patient s randomised treatment allocation should be ascertained by pharmacy (adalimumab or placebo) and a corresponding kit dispensed on production of a valid trial prescription. Drug accountability logs must be maintained throughout Dose Modifications (Adalimumab and placebo) The dose of Adalimumab or placebo should remain the same as at trial entry, regardless of minor fluctuations in weight which may cause a participant to cross the 30kg threshold for the upper and lower doses. Adalimumab or placebo treatment may be suspended for clinical reasons, however this can only be for up to a maximum cumulative period of 4 weeks throughout the duration of the protocol treatment phase. Patients requiring intermittent or continuous suspension of treatment for a cumulative period longer than 4 weeks will be considered a treatment failure and should be withdrawn from trial treatment Dosage and Administration With regards to treatment timelines, 1 month treatment is defined as four weeks. The allocated treatment (adalimumab or placebo) must be administered by subcutaneous injection as per local policy every 2 weeks based on the participant s body weight (20mg/0.8mL for participants <30kg or 40mg/0.8mL for participants weighing 30kg). Participants will be allowed a -3days/+3days window for the fortnightly injections. The first dose will be administered by the research / clinical team looking after the patient. All participants or a family member will be invited to self-administer the study treatment after the first dose and taught as such to do this under procedures in place within each participating centre for teaching this. The first dose they administer will also be under supervision of the clinical team, who will ensure they are confident and able to carry out all parts of the procedure appropriately and accurately. If they do not want to do this, then arrangements will be put in place on an individual basis for ensuring trial medication is administered as prescribed. 28

107 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: The exact date and time (24-hour clock) of all doses administered must be recorded on the administration record of the CRF. For participants who are self-administering this must be recorded in their trial medication diary. 9.5 Formulation and Packaging: Two strengths of adalimumab will be manufactured by AbbVie Laboratories Ltd and supplied in bulk to the distributor for distribution to trial centres. Shipment requests will be authorised by the MCRN CTU 9.5.1Adalimumab solution for subcutaneous injection: Adalimumab 20 milligrams/0.8ml is a clear, colourless solution presented in a singleuse glass vial for subcutaneous injection. Adalimumab 40 milligrams/0.8ml is a clear, colourless solution presented in a singleuse glass vial for subcutaneous injection. Excipients: Mannitol, Citric acid monohydrate, Sodium citrate, Disodium phosphate dehydrate, Sodium dihydrogen phosphate dehydrate, Sodium Chloride, Polysorbate 80, Water for injections, Sodium hydroxide added as necessary to adjust ph. Each vial is intended for a single dose to a single patient. Discard any remaining solution in vials Placebo solution for subcutaneous injection: The matching placebo solution is a clear, colourless solutions presented in a singleuse vial for subcutaneous injection in volumes of 0.8mL. The composition and ph of the placebo is identical to that of the active vials but without adalimumab. Each vial is intended for a single dose to a single patient. Discard any remaining solution in vials 9.5.3Packaging: Contents: Each kit will consist of 2 vials of adalimumab or placebo in an outer carton. Both vials and outer carton will be labelled. 9.6 Labelling, Storage and Stability Labelling: IMPs will be labelled in accordance with regulation 46 SI2004/1031 and the detailed guidance provided in annex 13 of the EU Good Manufacturing Practice (GMP) guide. Each kit will be identified by a kit number on the labelling. Blank sections will be provided on the vial label and outer label for site and patient specific details to be filled in by pharmacy during dispensing. 29

108 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Storage and shelf life: The IMPs should be stored in a refrigerator at 2-8 C. Do not freeze. Keep the vials in the outer carton. The product has a shelf life of 24 months, cool bags with cool blocks will be provided to transport vials home by patients. Temperature excursions: In the event of storage temperatures falling outside the range permitted, stock should be quarantined and the trial coordinator at the MCRN CTU notified. 9.7 Expired and unused IMP stock Any stock that has expired at the trial site during the trial and any stock remaining at trial closedown must be notified to the MCRN CTU who will authorise destruction. Stock will be destroyed locally according to site policy and records made in the drug accountability log. Any unused vials remaining at the patient s home at the end of the trial or on early withdrawal should be returned to the dispensing pharmacy at the participating trial site. 9.8 Concomitant Medications/Treatments Any medication (including over the counter medicines such as paracetamol, antacids, mineral supplements, NSAIDs, anti-inflammatory eye drops and herbal preparations) that the participant is receiving at the time of enrolment, or receives during the study, must be recorded on the appropriate case report form (CRF) along with the reason for use, dates of administration, dosage form, dose and dose frequency Medications Permitted Methotrexate participants must be receiving at least 10-20mgs/m 2 with a maximum dose of 25mgs Low dose of steroids ( 0.2mg/kg/day of prednisone or prednisolone equivalent medication orally) are permitted prior to randomisation and during the active phase of the trial. Prednisone or prednisone equivalent dose must be unchanged for at least 30 days prior to enrolment. Weaning of systemic steroids whilst enrolled in the trial is at the discretion of the treating clinician. Topical steroid eye drops with maximum of 6 drops/ day at randomisation (this dose must have been stable for at least 4 weeks prior to screening visit). o Either within the first 3 months of being in the trial, or at the 3 month assessment visit, the drops should be reduced to a maximum of 2 drops/day (the rate at which the drops are reduced within the 3 month period will be o determined by the treating clinician). Failure to reduce eye drops to 2 drops/ day by or at the 3 month visit will be considered a treatment failure and the participant should be withdrawn from trial treatment. o After 3-6 months topical treatment must be kept at twice per day. At 6 months topical treatment can be reduced as the clinician determines, but not increased to >x2 for the length of the trial. Maxidex, Predforte or equivalent preparation to be stipulated at screening and to remain unchanged for individual throughout treatment-phase of trial Intra-articular joint injections- the participant must not receive more than two intraarticular joint injections in a single session and no more than a total of eight injections per year; no joint injections within 4 weeks of randomisation. Depot peri-ocular steroid injection but not within 30 days prior to screening. 30

109 9.8.2 Medications Not Permitted SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Intra-ocular or peri-ocular corticosteroids The introduction of oral steroids, or increase in oral steroids, is not permitted at any time during the trial. Intravenous methylprednisolone at any time Other biologic therapies, including: etanercept, infliximab, gonilumimab; rituximab, abatacept, anakinra, tocilizumab Ciclosporine, Mycophenolate Mofetil, Azathioprine, Lefunamide, Sulfazalazine, hydroxychloroquine, any other disease modifying, anti-rheumatic drug Systemic Acetazolamide 9.9 Assessment of Compliance with Study Treatments Participant diaries and dosing records will determine tolerability and compliance throughout the trial period (see section 9). The parent/guardian of a participant will maintain a diary for all trial and other medications that are administered outside of the trial visit (i.e. at home). In the diary, the date and time the drug is administered will be recorded. The dosing records will be reviewed and verified for compliance at each visit by the research personnel at the trial centre, and all relevant dosing information will be transcribed onto the CRF at each visit. Additionally, any discernible departure from the protocol regarding trial drug administration will also be recorded onto the CRF Early withdrawal of treatment Patients meeting the criteria for treatment failure (section 6.1) or failing to comply with criteria of permitted and non-permitted medicines will be withdrawn from the trial. The decision to discontinue trial therapy is at the discretion of the treating physician. Doses may be discontinued at any point during the trial period for reasons such as unacceptable adverse effects, serious adverse events, intercurrent illness, development of serious disease or any change in the participant s condition that the physician believes warrants a change in medication. Any changes must be documented in the CRF along with the justification for those changes. The PI should make contact with the Chief Investigators when a patient meets the failure critiera. As the trials uses a comprehensive failure criteria the CI s will perform a second check to ensure that the patient meets the relevant failure criteria. Contact with the CI s should be made through the trial co-ordinator Unblinding Treatment allocation will be concealed unless knowledge is essential for ongoing care. Should knowledge of treatment allocation be required by the responsible investigator this shall be obtained via their pharmacy department who will complete an unblinding CRF and submit this to the MCRN CTU. All children participating in this study during the active treatment phase of the study are immunosuppressed, in view of their concomitant MTX therapy and / or potentially corticosteroid therapy, irrespective of them being on IMP or placebo. Additionally, for the purpose of out-of-hours management of the patient, all patients should be presumed to be on anti-tnf therapy, and managed as such. In this way, in the event of an AE or SAE, such as an inter-current infection, the treating clinician should manage as patients presumed to be 31

110 32 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: on anti-tnf therapy. For this reason, should unblinding be deemed necessary, this would be carried out via the local pharmacy department following the procedure described below. If out of hours unblinding is required, this will be accessed via the local pharmacy department on-call service Unblinding of Individual Participants During Trial Conduct Upon completion of 18 months treatment Although discouraged, it is acceptable to unblind participants upon completion of their trial treatment (18 months) if this is necessary to enable appropriate ongoing treatment Early withdrawal from treatment Upon early withdrawal from trial therapy, breaking the statistical blind should generally be considered only when knowledge of the treatment assignment is deemed essential for the subject s care by the subject s physician or a regulatory body as it is considered that it may not always be necessary to know the allocation of these patients. N.B. If simply ceasing study treatment is a viable option for the patient s care, it should not be necessary for unblinding to occur Procedure a. The decision to unblind a single case should be made when knowledge of an individuals allocated treatment is essential to: i. Enable treatment of severe adverse event/s, or ii. Enable administration of another therapy that is contraindicated by the trial treatment iii. Enable appropriate ongoing care upon cessation of allocated trial therapy b. Where possible (during office hours), consent for individual unblinding should be made via the trial coordinator at MCRN CTU who will seek agreement of one of the lead investigators (Ramanan and Beresford) c. Pharmacy departments will be unblinded to the treatment allocations of patients within their centre. The PI should ensure that all research personnel are aware of contact details for obtaining details of treatment allocation should this be necessary. d. The request for the allocated treatment should be made to the local pharmacy department e. Only the individual patient is to be unblinded and the following is to be documented by pharmacy on the unblinding CRF: i. Date information needed ii. Detailed reason for unblinding iii. Identity of recipients of the unblinding information f. The local investigator will ensure all necessary CRFs to time of unblinding are completed and submitted to MCRN CTU (if possible, completed before unblinding is performed) g. All instances of unblinding should be recorded and reported in writing to the MCRN CTU by the local investigator, including the identity of all recipients of the unblinding information. h. Allocation should not routinely be revealed to MCRN CTU personnel Accidental Unblinding All instances of inadvertent unblinding should be recorded and reported in writing to the MCRN CTU by the local investigator. Reports to include: a. Date of unblinding

111 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: b. Detailed explanation of circumstances c. Recipients of the unblinding information d. Action to prevent further occurrence e. Allocation should not be routinely revealed to MCRN CTU personnel Unblinding at Trial Closure The end of the trial will be considered as the date of the final database lock. In the event that the trial is closed prematurely by the Trial Steering Committee, on the recommendation of the Independent Data and Safety Monitoring Committee, for reasons such as clear differences between safety of trial treatments, the end of the trial will still be considered as the date of the final database lock. Upon trial closure the criteria for unblinding will remain in effect. Pharmacy departments will not disclose treatment allocations on an individual basis. MCRN CTU will notify local investigators in writing of unblinding information for patients under their care. A copy of this notification should be placed in the medical records and a copy retained in the site file. It is the responsibility of the local investigator to notify trial participants of their allocated treatment Non-Investigational medicinal Product (NIMP) - Methotrexate All participants will be prescribed methotrexate in conjunction with their allocated trial treatment Dose range All participants should, at trial entry, be on a stable dose of methotrexate, which should be in the dose range of 10-20mg/m 2, with a maximum dose of 25mg/patient. The participant must have been on a stable dose for at least 4 weeks prior to the screening visit. Treatment with MTX will continue for the duration of participants continuing with randomised treatment Dose modifications - Methotrexate Upon randomisation, all participants are to remain on a stable dose of MTX in combination with their allocated trial treatment. The MTX dose/route should remain within the parameters 10-20mg/m 2 (maximum dose of 25mg/patient) No dose reduction or change in route of administration is allowed after randomisation. A dose increase is acceptable for growth (at same dose/m 2 as at trial entry) but must not be increased on clinical grounds. Methotrexate treatment may be suspended for clinical reasons, however this can only be for up to a maximum cumulative period of 4 weeks throughout the duration of the protocol treatment phase. Patients requiring intermittent or continuous suspension of methotrexate treatment for a cumulative period longer than 4 weeks should cease trial treatment and should be withdrawn from trial treatment. Participants will be allowed a -2days/+2days window for the weekly MTX administration. 33

112 10 ASSESSMENTS AND PROCEDURES SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: After obtaining written consent (and assent where appropriate) from the parent or legal guardian, or from the trial participant, a medical/ophthalmic history will be taken and recorded on the appropriate CRF with particular emphasis on other disorders of relevance and allergies. Separate sections on the CRF will be provided to record the JIA and uveitisspecific medical/ophthalmic history and the participant s other medical/surgical history. Medication (prescription, over-the-counter, and herbal supplements) use over the four weeks prior to the screening visit will also be recorded. Physical examination, measures of disease activity and complications, medication history, surgical history and laboratory tests (haematological and biochemical analysis and urinalysis) will be performed at the screening visit and will be repeated at each subsequent trial visit. Visits will be conducted as highlighted in the study visits and assessments table. The visits are calculated from the date of the 1 st dose of IMP. With regards to treatment timelines, 1 month treatment is defined as four weeks; after commencing treatment the dates of each subsequent visit should be made for four weeks after or 3 months (12 weeks) after depending on the visit. An allowance of -7days/+7 days will be allowed for monthly visits and -15days/+15days for the 3 monthly visits. Should unscheduled visits be required for any reason these will be recorded on the unscheduled visit CRF. For determining treatment failure there should be an interval of at least four weeks between assessments Schedule for Follow-up Table 1 summarises study visits and assessments: 34

113 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Table 1: Study visits and assessments: Time (months) 0^ Screening* Randomisation & commence treatment Written informed consent X Confirm consent (verbal) X X X X X X X X X X Assessment of Eligibility Criteria X X Review of Medical/ Opthalmic/ X Surgical History Review of Concomitant Medications X X X X X X X X X X X X X Pregnancy test (serum) (X) X X X X X X X Purified protein derivative (PPD) X Tuberculin Skin Test 1,2 / Test for latent TB as locally performed Urinalysis 3 X X X X X X X X X X X X Randomisation X Study Intervention X X X X X X X X X Compliance with study intervention X X X X X X X X X Physical Exam - Complete X X X X X X X X X X X X Vital Signs (heart & Respiratory rate, X X X X X X X X X X X X temperature and blood pressure) Height X X X X X X X X X X X X Weight X X X X X X X X X X X X Childhood Health Questionnaire (CHQ) X X X X X X X X X Childhood Health Assessment Questionnaire (CHAQ) X X X X X X X X X Health Utilities Index 2 Questionnaire X X X X X X X X Client Service Receipt Inventory (CSRI) X Sample for DNA collection (X) (X) (X) RNA and Serum/plasma (X) (X) (X) Haematological analysis X X X X X X X X X X X X Biochemical analysis X X X X X X X X X X X X Samples for HAHA analyses ** ANA, dsdna and ENA X X Standard ACR Pedi Core Set outcome X X X X X X X X X X X X variables Tanner Score X X X X X X Review of Participant Diaries X X X X X X X X X X X (X) Assessment of Adverse Events X X X X X X X X X X X X Opthalmic assessments: Vision assessment X X X X X X X X X X X X Optical coherence tomography (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (optional) Assessment of vitritis X X X X X X X X X X X X Slit lamp bio-microscopy X X X X X X X X X X X X Cataract scoring X X X X X X X X X X X X Goldmann tonometry or tonopen X X X X X X X X X X X X End of treatment End of trial Premature withdrawal ^ Visit 0 must be completed and treatment commenced within 14 days of the screening visit (10 days for pregnancy test) * all procedures should be done before study intervention. ** to be done if anaphylaxis occurs during trial. (X) - As applicable/indicated/appropriate 1 Participants who are PPD positive at screening will require a chest x-ray. Treatment of participants who have a positive PPD skin test and/or abnormal chest x-ray should be in accordance with regional/national guidelines, and initiated at least 4 weeks prior to receiving the first dose of trial medication 2 Participants with recent (within 6 months of trial entry screen) positive PPD ( 5 mm) who are being treated with appropriate prophylaxis may request a waiver for a screening PPD from the MCRN CTU. Documentation of the positive PPD should be available as well as chest x-ray report from the date of the positive PPD and treatment/prophylaxis history from near the time of the participant s conversion. 35

114 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Microscopic urinalysis will be obtained at baseline and for other visits only if relevant abnormalities greater than trace are noted on the dipstick analysis Procedures for Assessing Efficacy Ophthalmic Assessments Ophthalmic assessment of disease activity and ocular complications will take place by slit lamp bio-microscopy for uveitis activity (at maximum illumination), including cells and flare in anterior and posterior chambers, using SUN criteria SUN Criteria SUN Criteria is a quantitative assessment of cell number in the anterior chamber which is graded 0-4 (see table below adapted from Jabs et al 10 ). With no fully validated measures in paediatric uveitis, SUN criteria are the most robust currently available; the investigators are currently engaged in international collaborative efforts to reach consensus on their use and complete their validation in paediatric uveitis. The SUN Working Group Grading Scheme for Anterior Chamber Cells Grade Cells in Field 0 < > 50 SUN = Standardisation of Uveitis Nomenclature Field size is a 1mm by 1mm slit beam Sun Working Group Grading Scheme for criteria for grading presence of AC flare: Grade Description 0 None 1+ Faint 2+ Moderate (iris and lens details clear) 3+ Marked (iris and lens details hazy) 4+ Intense (fibrin or plastic aqueous) Vision Using age-appropriate LogMar visual acuity (Kays pictures and standard LogMar) Fundoscopy Fundoscopy to assess: Disc swelling, or macular oedema and other structural changes in macular (epiretinal membrane) and optic nerve (neovascularisation, glaucomatous neuropathy) and retina (neovascularisation, retinal detachment) Fundoscopy is to be assessed at trial entry and then at trial exit. Additional dilated fundoscopy can be done in between if clinically indicated, if the participant is in anterior remission, then it is not mandatory to undertake this assessment for the purposes of the trial. 36

115 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Optical coherence tomography (OCT) Optical coherence tomography (OCT; at least stratus II) for macular oedema; where units available to do so (non invasive). Within units - same OCT to be used throughout study. Vitritis Assessment of vitritis and vitreous haze. Grading can be assessed through the binocular indirect ophthalmoscope (BIO SCORE) Cataract Score Cataract score (LOCS III grading) Adapted from Chylack et al 45 (see Appendix A) Intraocular pressure Intraocular pressure by Goldmann tonometry, tonopen, Icare or instrument as used in local practice, as clinically deemed appropriate at the clinical trial setting Other structural Changes Presence or absence of other structural changes including extent of band keratopathy, synechiae, iris bombe, membrane formation and neovascularisation Physical Examination A full musculoskeletal and systems physical examination will be performed at each trial visit including detailed joint count. If the full examination is completed at baseline then it does not need to be completed again at first treatment visit as little time will have elapsed between visits. Vital Signs will also be measured including resting blood pressure and heart rate, with the participant in the sitting position, respiratory rate and oral body temperature. Body weight and height: will be measured at screening and at each trial visit Rheumatology Assessments: American College of Rheumatology Pedi Core Set Criteria and related outcomes Standard ACR Paediatric Core Set outcome variables 46 will be assessed at each study visit. The table below (adapted from Giannini et al 46 ) summarises the 6 core set variables.. Paediatric Core Set Criteria Physician global assessment of disease activity (10 cm visual analogue scale) Parent/patient assessment of overall well-being (10 cm visual analogue scale) Functional ability (Childhood Health Assessment Questionnaire, CHAQ) [34] Number of joints with active arthritis Number of joints with limited range of movement Erythrocyte sedimentation rate, normalised to a 0-10 scale From these core outcome variables, the following rheumatology outcome variables will be determined during data analysis, according to published methodology, namely: The ACR Paediatric 30, 50, 70, 90 and 100 levels. These are defined as 30%, 50%, 70%, 90% and 100% improvement respectively in a minimum of three variables in 37

116 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: the core set with worsening of one variable by no more than 30% as defined in the ACR criteria (see reference 46 ). Episode(s) of disease flare, defined as a minimum of 40% worsening in at least 2 out of 6 components, with no more than one component improving by >30% 76 Ability to achieve clinical remission as defined by standardised definitions of inactive disease, remission on medication and remission off medication 54 and with minimum disease activity 55 (see references) The Juvenile Arthritis Disease Activity Score, or JADAS 77. The JADAS comprises four components: (1) physician global assessment of disease activity (2) parent/patient global assessment of well-being (3) active joint count, in 27, 71 or 10 joints; and (4) erythrocyte sedimentation rate (ESR). The JADAS is calculated as a sum of scores from its four components, giving global scores of 0-57, and 0-40 for the JADAS-27, JADAS-71 and JADAS-10 respectively Procedures for Assessing Safety Adverse Events An assessment of adverse events will be undertaken at each study visit from baseline to study completion. These reviews will be carried out by the PI or other delegated staff member conducting the visit. Requirements for adverse event reporting is detailed fully in Section 11.1 (Pharmacovigilance) Screening for Tuberculosis A test for latent tuberculosis infection (LTBI) must be performed within twelve weeks prior to the baseline visit according to local practice guidelines, including those with a prior history of BCG administration. Multiple puncture tests such as the Tine and Heaf tests are not acceptable. The purified protein derivative (PPD) tuberculin skin test and the QuantiFERON -TB Gold (QFT-G) (or local equivalent) are acceptable screening assays for latent TB in this study. The TB test results should be interpreted according to local guidelines for immunocompromised patients, even though the patients entering this study may or may not be immunocompromised at baseline. The purpose of using this definition is to maximize the likelihood of detecting latent TB. Participants who are PPD / QFT-G (or local equivalent) positive according to local guidelines at screening will require a chest x-ray. Participants with recent (within 6 months of screening visit) positive PPD ( 5 mm) who are being treated with prophylaxis may be eligible for trial entry. In these circumstances, documentation of: o The positive PPD o A chest x-ray report from the date of the positive PPD o Documentation of treatment detail and duration Treatment of participants who have a positive PPD skin test / QFT-G (or local equivalent) and/or abnormal chest x-ray should be managed in accordance with regional/national guidelines, and initiated at least 4 weeks prior to receiving the first dose of trial medication Treatment for latent tuberculosis must be started with anti-tuberculosis therapy in accordance with local/national recommendations. Those with positive PPD at screen must have been treated with anti-tuberculosis therapy for at least 4 weeks prior to receiving study medication and chest radiograph is negative for active tuberculosis. 38

117 Urinalysis SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Urinalysis will also be carried out at each study visit, a fresh aliquot of urine will be tested for protein, glucose, blood, leukocyte esterase, specific gravity, and ph by dipstick. A microscopic urinalysis will be obtained at screening and the results recorded on the CRF. Subsequently, microscopic urinalysis will be obtained only if relevant abnormalities greater than trace are noted on the dipstick analysis Serum pregnancy test Designated trial personnel will perform a serum pregnancy test for all post-pubertal female participants at the screening visit. There must be evidence of a negative serum pregnancy test for all post pubertal females within 10 days before their first dose of trial drug. Subsequently, serum pregnancy tests will be undertaken three monthly for the duration of treatment and a final test three months after their final dose of trial drug Tanner Score Secondary sexual development will be measured at baseline and at weeks 12 and 48 during receipt of treatment. This will be done either by self- assessment or by clinical examination. The Tanner score 78 will also be assessed at early withdrawal from trial treatment and three monthly at post treatment follow visits. This will be done on participants of ALL ages, if the participant has reached full sexual maturity then this assessment will only take place at screening Haematological Laboratory Assessments Routine haematological assessments of full blood count will be required for the study (to include haematocrit, haemoglobin, red blood cell count, white blood cell count, neutrophils, lymphocytes, monocytes, basophils, eosinophils, platelet count and ESR), which will be analysed in local laboratories. If ESR is unable to be tested then plasma viscosity may be accepted. Results from Haematological assessments taken during the screening period can be used for the results at the baseline/randomisation visit only if the assessments have been completed within 15 days of the baseline/randomisation visit. For safety purposes, an auto- antibody screen (ANA, dsdna and ENA) should also be carried out at the baseline and 12 month visits Biochemical laboratory Assessments Routine biochemical assessments of renal and liver function tests) are required for the study (to include C- Reactive protein (CRP), urea, creatinine, sodium, potassium, calcium, inorganic phosphate, glucose, chloride, bicarbonate, total bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST]), which will be assessed in local laboratories. Results from Biochemical assessments taken during the screening period can be used for the results at the baseline/randomisation visit only if the assessments have been completed within 15 days of the baseline/randomisation visit. 39

118 Compliance with Study Treatment Participant Diaries: SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: The participant or the parent/guardian of a participant will maintain a diary for all trial and other medications that are administered outside of the trial visit (i.e. at home). For trial allocated treatment the diary will collect information on: (i) Vial number (ii) Time/ date of administration (iii) Volume/dose (iv) Any problems with administration/ protocol adherence For other prescribed medications the diary will record: (i) Medicine name (ii) Dose prescribed (iii) Number of times per day medicine was taken (iv) Number of days/ weeks supplied For over the counter medicines, the diary will record: (i) Name of medicine (ii) Cost Pharmacy/ Clinical accountability Any discernible departure from the protocol regarding trial drug administration will be recorded onto the CRF (see section 8 for IMP accountability) 10.4 Quality of Life Quality of, Life will be measured by the use of Childhood Health Questionnaire (CHQ) 79 and Childhood Health Assessment Questionnaire (CHAQ) 47. Data collection will take place on a monthly basis for the first 3 months, then 3 monthly until withdrawal from the active phase of trial treatment Child Health Assessment Questionnaire Childhood Health Assessment Questionnaire (CHAQ) is the most widely used functional measure of disability in JIA both in routine clinical practice throughout the UK and clinical trials. Translated into many languages and validated in respective cultures and countries, it is easily completed and scored. It consists of eight domains, enquiring about the child / young person s ability to manage a range of activities of daily living on a 5 point scale. Completion of the questionnaire will be checked by staff Childhood Health Questionnaire The Child Health Questionnaire (CHQ) is a generic measure of quality of life used in JIA. It explores a number of important domains including self esteem, emotional and behavioural difficulties, and family impact. Completion of the questionnaire will be checked by staff 10.5 Health Economics The primary health outcome measure for the economic evaluation will be quality-adjusted life-years (QALY). 40

119 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Health Utilities Index 2 Health Utilities Index 2 (HUI2) questionnaire will be administered to participants or their parents (guardians) where appropriate 59 for self completion. Health utilities will be assessed at baseline and at 3, 6, 9, 12, 18, and 24 months post randomisation (or at early trial withdrawal). The HUI2 is the only validated utility measure for children with UK preferences, and is specified as NICE s preferred method for this purpose 60. The 6 attributes of the HUI2 (sensation, mobility, emotion, cognition, self-care, and pain) will be summarized into a single UK-derived preference-based utility score 61. HUI2 is more likely to be sensitive to the quality of life decrement attributable to sensory (vision) loss than alternative generic measures of utility Hospital Episode Statistics Patients use of secondary care resources in English sites will be measured from routine hospital information systems via the Health & Social Care Information Centre (HSCIC) (bespoke NHS Hospital Episode Statistics (HES) Extract Service). Requests for anonymised extracts will be made according to standardised procedures at three time points during the trial. Data will be requested for the 18 months plus 6 months after the last visit Client Service Receipt Inventory Patients use of primary care services, personal social services, non-scheduled clinic attendance and out-of-pocket expenditures will be collected at baseline and at 3, 6, 9, 12, 18 and 24months post randomisation by administering a specifically designed questionnaire (based on a modified Client Service Receipt Inventory) 56 to parents (guardians) at baseline and by collecting data in the patient treatment diary at all other visits. Data on patients use of medicines will be collected within patients diaries Establishment of JIA-associated Tissue Bank Sample Collection A sample collection will be developed, integral to the trial, in accordance with Arthritis Research UK's guidelines on detailed clinical and related material banks ( Written information will be provided to families for this part of the study and written informed consent (with assent where appropriate) obtained. Patients who do not give consent to provide samples to the Tissue Bank will still be eligible to take part in the main part in the trial. All samples will be gifted to the University of Bristol Immunity and Infection Research Tissue Bank (IIRTB) under the care of Professor Adam Finn and kept for a minimum of ten years. Samples from all children enrolled in this trial who give consent for their samples to be retained (or whose parents give consent) will be included, and will be processed and stored under strict governance control according to Good Clinical Practice, and adherence to HTA licences where applicable. Samples will be identifiable by identifying number only and stored in a locked freezer. The laboratory has alarm systems and backups for all freezers containing samples and there is a high level of security for access to the building. The samples will be a resource open to all, through application and approval for use through the IIRTB Management Committee. 41

120 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: The sample collection could be used as a resource to investigate the pharmacogenetics, aetiopathogenesis and identification of biomarkers of JIA-associated uveitis, for example. Understanding the genetic basis of age-specific disease processes allows consideration of the unique and rapid period of human development through to adulthood. Pharmacologic modulation of developing gene networks may have unintended and unanticipated consequences that do not become apparent or relevant until later in life. Early predictors of response allow future personalised treatment prescription in children. Research utilising the collection of DNA samples alongside the clinical data collection could make this a very real possibility in the near future. In addition, understanding the aetiopathogenesis of JIAassociated uveitis would offer insight and opportunity into novel therapeutic targets, especially in the new era of biologic therapies. Blood samples will be collected pre treatment and at two time points post treatment (at 0 months, 3 months and 18 months). The 0 month sample must be taken before trial treatment is started. The next sample should be collected at 3 months after starting treatment. If for a very specific reason a sample cannot be taken at 3 months, then it should be taken at the very next visit / opportunity. The 3 rd (and final) sample should be taken at 18 months or at the end of treatment visit (e.g. if patient finishes trial treatment at 9 months then the sample should be taken then). Samples will be collected for DNA and RNA extraction, acdna synthesis, serum and PBLs frozen for future analysis. Separate funding and ethical approval will be sought to support future pharmacogenetic and molecular biological investigations. A range of state-of-the-art technologies will be adopted to interrogate the mechanisms and biomarker search and assessment. These will employ the ability to elaborate both epigenetic, genetic, transcriptomic and proteomic analyses as well as functional assays where appropriate or indicated. For example, 560gene-array analysis looking for candidate cytokine polymorphisms (e.g. IL-17, IL-10 and steroid resistance ) and epigenetic control of cytokine responses ; investigation using qpcr and Western Blotting of RNA control of TNF translation via FxR1P to assess activation in population of responders or nonresponders in the trial and thus validate possibilities of responsiveness to therapy Loss to Follow-up If any of the trial participants are lost to follow up contact will initially be attempted through the PI or designated research staff at each centre. If the lead investigator at the trial centre is not the participants usual clinician responsible for their specialist care then follow up will also be attempted through this latter clinician. Where these attempts are unsuccessful, the participants GP will be asked to contact the patient or the participants family to provide follow up information to the recruiting centre. This information will be included on the Patient Information Sheet. Wherever possible, information on the reason for loss to follow up will be recorded Trial Closure The end of the trial is the date of database lock as defined in the trial related Data Management Plan. At the time of database lock, data entry privileges are withdrawn from the trial database. The trial may be closed prematurely by the Trial Steering Committee (TSC), on the recommendation of the Independent Data and Safety Monitoring Committee (ISDMC).Should the trial be closed prematurely, all active participants (receiving treatment or in follow-up) will be called in for a final follow-up visit and assessments will be undertaken as per schedule (section 9). Ongoing care will be at the discretion of the treating clinician. 42

121 11 STATISTICAL CONSIDERATIONS SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: The statistical Analysis Plan will be amended to reflect early stopping of recruitment, unblinding of patients and open lable follow-up. The primary analysis will be of data up to the point of unblinding. A secondary analysis will include data on patients followed up after unblinding occurred Method of Randomisation Randomisation lists will be generated in STATA using simple block randomisation with random variable block length Outcome Measures Primary The primary endpoint is time to treatment failure. Treatment failure is defined by ONE or more of the following: 1) Anterior segment inflammatory score grade (SUN criteria) Following at least 3 months of therapy: i) 2-Step increase from baseline in SUN cell activity score (AC Cells) over 2 consecutive readings ii) Sustained non-improvement with entry grade of 3 or greater for 2 consecutive readings iii) Only partial improvement (1 grade) or no improvement, from baseline, with development of other ocular co-morbidity* which is sustained iv) Worsening of existing (on enrolment) ocular co-morbidity* after 3 months v) Sustained scores as recorded at entry grade measured over 2 consecutive readings (grades 1 to 2) still present after 6 months of therapy. 2) Use of Concomitant Medications: At any time, requirement to use concomitant medications in manner out with pre-defined acceptable criteria (see section 9.8.1), or any of the concomitant medications not allowed (see section 9.8.2) 3) Intermittent or continuous suspension of study treatment (adalimumab/placebo) for a cumulative period longer than 4 weeks * Ocular co-morbidities are defined as: v) Disc swelling and/or Cystoid Macular Oedema (CMO) as gauged clinically and where possible by OCT evidence; and/or: vi) Raised intraocular pressure (>25mm Hg) sustained over 2 consecutive visits not responding to single ocular hypotensive agent, and/or: vii) Hypotony (<6 mm Hg) sustained over 2 consecutive visits, and/or viii) Development of unexplained reduction in vision (LogMar) over two consecutive visits of 0.3 LogMar units (in the event of cataract participants will remain in trial, also if cataract surgery is required. Failure will still remain as described in endpoints above). N.B> Intraocular pressure >= 25 mmhg or < 6 mmhg are exclusion criteria at baseline and ocular co-morbidities i-iv can be developed during follow up only, i may worsen based on the existing (on enrolment) ocular co-morbidity. 43

122 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Where a reading is required to be sustained over two consecutive visits to define treatment failure the time of treatment failure will be taken as the second of these readings Secondary Endpoint(s) 1) Number of participants failing treatment 2) Incremental cost-effectiveness and cost-utility of adalimumab added to MTX compared with MTX alone 3) Health status according to the multi-attribute health utility index, HUI2 4) Safety, tolerability and compliance a. Adverse events (AEs) and serious adverse events (SAEs) b. Laboratory parameters (haematological and biochemical analysis and urinalysis c. Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period 5) Use of Corticosteroids over duration of study period and throughout follow up, including: a. Total oral corticosteroid dose b. Reduction in and rate of systemic corticosteroid dose from entry dose c. Topical corticosteroid use (frequency) compared to entry usage d. Need for pulsed corticosteroid 6) Optic and ocular a. Number of participants having disease flares (as defined by worsening on SUN criteria) following minimum 3 months disease control b. Number of participants having disease flares within the first 3 months. c. Visual acuity measured by Age-appropriate LogMar assessment d. Number of participants with resolution of associated optic nerve or macular oedema (as assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) (where available). e. Number of participants with disease control (defined as zero cells, with topical treatment for 3 and 6 months) f. Number of participants entering disease remission (defined as zero cells, without topical treatment for 3 and 6 months) g. Duration of sustaining inactive disease (zero cells, with or without topical treatment) 7) Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ)) 8) American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels (see section ) 9) Number of participants undergoing disease flare, in remission on and off medication 54 of their JIA and with minimum disease activity 55 10) Number participants requiring change in biologic / Disease-modifying anti-rheumatic drugs (DMARDs) therapy due to failure to respond from arthritis 11) Participants score of the Juvenile Arthritis Disease Activity Score (JADAS). The JADAS comprises four components: (1) physician global assessment of disease activity (2) parent/patient global assessment of well-being (3) active joint count, in 27, 71 or 10 joints; and (4) erythrocyte sedimentation rate (ESR). 44

123 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Sample Size The sample size was based on data on failure rates from 62 patients on MTX in a comparable population provided by Dr C Edelsten, Great Ormond Street Hospital. After three months 11 patients had disease control based on Grade 0 SUN criteria (18%) and therefore based on the trial inclusion criteria would not be eligible for the trial. At 15 months following the start of treatment with MTX, 23 patients of the 51 who had failed at 3 months had achieved disease control (45%), leaving 28 (55%) who had not. To detect a relative reduction of 50% between a failure rate of 60% to 30% with 90% power (there is unlikely tobe a trial of this nature again in the near future and therefore we have increased the power to 90% from the conventional power of 80% to optimise the detection of a significant difference between treatment regimes if one truly exists)at a 5% significance level, using a 2:1 randomisation a total of 140 patients (93 adalimumab, 47 placebo) are required. A trial of adalimumab in JIA with or without MTX powered the study using a 40% absolute (57% relative) difference in the rate of flare between the placebo and the adalimumab groups 40. The advent of biological therapies in JIA has led international investigators to a paradigm shift in the treatment of JIA and its related complications, leading to significantly more ambitious outcomes in clinical trials, including elimination of inflammation and normalisation of short-term and long-term function 15,52. To this end, in JIA, instead of previously accepted clinical outcomes of 30% absolute difference in outcome between active agent and placebo 53, increasingly significant differences are being expected and regarded as significant, with new definitions of response being established for use in clinical trials such as clinical remission and minimal disease activity 54,55. Indeed, 40% of patients in the adalimumab-jia trial were reported as showing an ACR Pedi 100% response (100% response rate) at 2 years 40. The clinically relevant outcomes of JIA-uveitis may take years to develop and the relationship between isolated measures of clinical activity and long term outcomes remains ill defined. Recent studies do suggest that the length of continuously controlled activity is likely to be of more clinical relevance than short term improvements in levels of activity. In view of these factors, as well as the expectation expressed unanimously through consumer consultation in the development of this trial protocol, we have set a minimum 50% relative difference in failure rate between interventions. Based on the nature of the disease resulting potentially in loss of vision and a meeting of investigators representing participating centres, as well as consumer representatives, and their experience of compliance from current usage of biologic therapies in JIA-uveitis, it is estimated that loss to follow up will be approximately 10%. Therefore we have increased the sample size by approximately 10% to allow for this, giving a total number of patients 154 (102 adalimumab, 52 placebo). The null hypothesis underlying this trial is that there is no significant difference between adalimumab and placebo in controlling disease activity of JIA-associated uveitis unresponsive to MTX therapy. 45

124 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Interim Monitoring Reports Interim monitoring reports of the accumulating data will be performed at regular intervals (at least annually) for review by the Independent Data Monitoring and Safety Committee (IDSMC). In addition to the interim monitoring reports, the IDSMC may request an interim analysis of the primary outcome to be undertaken. The Peto-Heybittle stopping rule will be applied at the interim analysis of the primary outcome. This requires an extreme p-value of p<0.001 as evidence to stop for benefit. This approach will be used to allow the ISDMC flexibility with the number and timings of further analyses based on current safety and efficacy data as it has the added benefit of preserving an overall two sided type I error of 0.05 for the final analysis (63). Any unblinded analyses requested by the IDSMC will be agreed in advance and documented in the statistical analysis plan prior to unblinding at the interim point. The IDSMC will be asked consider patient safety as well as treatment efficacy (in the event of an interim analysis of primary outcome) in their decision to stop or continue the trial based on the accumulated data from the trial, together with results from other relevant trials, justifies continuing recruitment of further patients or further follow-up. The statistical stopping guidelines presented are in relation to the primary outcome measure but the trial may be terminated early due to serious concerns with patient safety or adverse events without crossing the boundaries set for the primary outcome measure of treatment failure, as recommended by the ISDMC. As such, the primary outcome measure is only one factor for consideration in the decision process. Importantly, statistical considerations alone are not adequate for data monitoring due to the over-emphasis placed on the p-value. Clinical judgment is essential to the process to account for unexpected adverse events and balance issues of safety and efficacy in light of any new external information. The decision to stop recruitment will depend on whether the results will be convincing to the medical community. If a decision is made to continue, the IDSMC will advise on the frequency of future reviews of the data on the basis of accrual and event rates. The IDSMC will make recommendations to the Trial Steering Committee (TSC, see section 18.2) as to the continuation of the trial Analysis Plan A comprehensive statistical analysis plan will be developed before any formal statistical analyses will be carried out. The primary analysis will use the principle of intention to treat based on all the randomised participants, as far as is practically possible. If consent for treatment is withdrawn but the participant is happy to remain in the study for follow-up, they will be followed up until completion. However if they decide to withdraw consent completely then the reasons for withdrawal of consent will be collected (if possible) and reported for both groups. The primary outcome is time to failure with detailed criteria as to what constitutes a treatment failure described in section 6. A participant is eligible for the trial based upon at least one eye fulfilling the eligibility criteria (see section 5). At baseline and all subsequent assessment visits both eyes (or at least just the eligible eye(s) if eligible with just the one eye) will be assessed and decisions with regards to treatment failure will be based on the eligible eye alone. Analysis of time to treatment failure will be summarised by Kaplan-Meier curves for each treatment group and compared overall using the log rank test and survival 46

125 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: regression methods. For secondary outcomes continuous data will be reported as a difference in means and binary data will be reported in terms of the relative risk each with 95% confidence intervals. Missing data will be monitored and strategies developed to minimise its occurrence. Missing data will be handled by considering the robustness of the complete case analysis to sensitivity analyses using various imputation assumptions; however these will be informed by data collected on the reasons for missing data Economic Analysis Plan The analysis will adopt the perspectives of the NHS and personal social service providers and patients, which approximates a societal perspective. Each item of resource use (see section 7) will be multiplied by the unit cost specific to that item. Unit cost data will be obtained from appropriate sources, including routine hospital data (NHS reference costs, published annually by the Department of Health) 57, the British National Formulary and nationally published data, e.g. Unit costs of health and social care published annually by the PSSRU, University of Kent 58. Total costs per patient will be calculated. Two analytic approaches will be used: a within trial analysis and an economic model. Trialbased estimates of cost-effectiveness will be calculated based on standard methods 64. Uncertainty in parameter estimates being addressed through the application of nonparametric bootstrapping and the estimation of cost-effectiveness acceptability curves 64. We will also apply regression (GLM) models of cost and outcomes, with age, baseline active anterior uveitis grade score and other covariates as deemed appropriate, to minimise bias in the ICER estimates. A model-based extrapolation of the trial results will be performed to explore the impact of a longer analytic time horizon, and consideration of health outcomes on the treatment costeffectiveness 65. The impact of adalimumab on the development of cataract, glaucoma and blindness will be estimated by constructing risk equations based on epidemiological data 66,67. A Markov model of treatment effect on JIA will be developed, with costs and health state utilities, derived from published sources, attached to health states to assess the longterm costs and benefits of the two treatment arms. Incremental cost-utility ratios will be estimated based on QALY estimates. Costs and benefits exceeding 1-year will be discounted at 3.5% per annum, according to NICE s current rate 60. Estimates of ICERs will be compared with the 20,000 to 30,000 per QALY threshold for cost-effectiveness 60, and a range of uni- and multi-variate, as well as probabilistic sensitivity analyses will be conducted to assess the robustness of the analysis. 47

126 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: PHARMACOVIGILANCE 12.1 Terms and Definitions The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) definitions: Adverse Event (AE) Any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product. Adverse Reaction (AR) Any untoward and unintended response in a subject to an investigational medicinal product which is related to any dose administered to that subject. Unexpected Adverse Reaction (UAR) An adverse reaction the nature and severity of which is not consistent with the information about the medicinal product in question set out in: In the case of a product with a marketing authorization, in the summary of product characteristics for that product In the case of any other investigational medicinal product, in the investigator's brochure relating to the trial in question. Serious Adverse Event (SAE), Serious Adverse Reaction (SAR) or Suspected Unexpected Serious Adverse Reaction (SUSAR) Any adverse event, adverse reaction or unexpected adverse reaction, respectively, that: results in death is life-threatening* (subject at immediate risk of death) requires in-patient hospitalisation or prolongation of existing hospitalisation** results in persistent or significant disability or incapacity, or consists of a congenital anomaly or birth defect Other important medical events * life-threatening in the definition of serious refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. **Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the hospitalisation is a precautionary measure for continued observation. Hospitalisations for a pre-existing condition, including elective procedures that have not worsened, do not constitute an SAE. ***Other important medical events that may not result in death, be life-threatening, or require hospitalisation may be considered a serious adverse event/experience when, based upon appropriate medical judgment, they may jeopardise the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition 48

127 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Notes on Adverse Event Inclusions and Exclusions Include An exacerbation of a pre-existing illness An increase in frequency or intensity of a pre-existing episodic event/condition A condition (even though it may have been present prior to the start of the trial) detected after trial drug administration Continuous persistent disease or symptoms present at baseline that worsens following the administration of the study/trial treatment Laboratory abnormalities that require clinical intervention or further investigation (unless they are associated with an already reported clinical event). Abnormalities in physiological testing or physical examination that require further investigation or clinical intervention Injury or accidents Do Not Include Medical or surgical procedures- the condition which leads to the procedure is the adverse event Pre-existing disease or conditions present before treatment that do not worsen Situations where an untoward medical occurrence has occurred e.g. cosmetic elective surgery Overdose of medication without signs or symptoms The disease being treated or associated symptoms/signs unless more severe than expected for the patient s condition Reporting of Pregnancy Designated trial personnel will perform a serum pregnancy test at the screening visit for all post-pubertal female participants. This will be repeated three monthly for the duration of treatment administration and a further test three months after administration of the last dose of study drug. Any pregnancy which does occur during the course of the study should be reported to the MCRN CTU immediately as an SAE. The investigator should discuss the risks of continuing with the pregnancy with the participant and the possible effects on the foetus if they continue on trial treatment. It is at the investigator s discretion to decide whether the individual should be instructed to stop taking study drugs. All pregnancies that occur during trial treatment, or within 3 months of finishing treatment, need to be followed up until delivery and neonatal outcome (defined as 4 weeks from delivery) and reported separately Notes Severity / Grading of Adverse Events The assignment of the severity/grading should be made by the investigator responsible for the care of the participant using the definitions below. Regardless of the classification of an AE as serious or not, its severity must be assessed according to medical criteria alone using the following categories: 49

128 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Mild: does not interfere with routine activities Moderate: interferes with routine activities Severe: impossible to perform routine activities A distinction is drawn between serious and severe AEs. Severity is a measure of intensity (see above) whereas seriousness is defined using the criteria in section 10.1, hence, a severe AE need not necessarily be a Serious Adverse Event Relationship to Trial Treatment The assignment of the causality should be made by the investigator responsible for the care of the participant using the definitions in table 2. If any doubt about the causality exists the local investigator should inform the study coordination centre who will notify the Chief Investigators. In the case of discrepant views on causality between the investigator and others, the MHRA will be informed of both points of view. Table 2: Definitions of Causality Relationship Description Unrelated There is no evidence of any causal relationship. N.B. An alternative cause for the AE should be given Unlikely There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within a reasonable time after administration of the trial medication). There is another reasonable explanation for the event (e.g. the participant s clinical condition, other concomitant treatment). Possibly There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable time after administration of the trial medication). However, the influence of other factors may have contributed to the event (e.g. the participant s clinical condition, other concomitant treatments). Probably There is evidence to suggest a causal relationship and the influence of other factors is unlikely. Almost certainly There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out Expectedness An AE whose causal relationship to the study drug is assessed by the chief investigator as possible, probable, or definite is an Adverse Drug Reaction. All events judged by the chief investigator to be possibly, probably, or almost certainly related to the IMP, graded as serious and unexpected (see section 10.2 and SPC for list of Expected Adverse Events) should be reported as a SUSAR. 50

129 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Follow-up After Adverse Events All adverse events should be followed until satisfactory resolution or until the investigator responsible for the care of the participant deems the event to be chronic or the patient to be stable. When reporting SAEs and SUSARs the investigator responsible for the care of the participant should apply the following criteria to provide information relating to event outcomes: resolved; resolved with sequelae (specifying with additional narrative); not resolved/ongoing; ongoing at final follow-up; fatal or unknown Reporting Procedures All adverse events fulfilling reporting criteria should be recorded on the CRF and submitted to the MCRN CTU within the defined timelines, beginning from the time that written informed consent is obtained (i.e. prior to to undergoing any study-related procedure and/or receiving investigational medicinal product) and continuing for 30 calendar days after cessation of the investigational medicinal product. Depending on the nature of the event the reporting procedures below should be followed. Any questions concerning adverse event reporting should be directed to the CTU in the first instance. A flowchart is given overpage to aid in determining reporting requirements Non serious ARs/AEs All such events, should be recorded on an Adverse Event Form, which should be transmitted to the CTU within seven days of the form being due Serious ARs/AEs/SUSARs Serious Adverse Events and Reactions should be reported within 24 hours of the local site becoming aware of the event. The SAE form asks for the nature of event, date of onset, severity, corrective therapies given, outcome and causality. The responsible investigator should sign the causality of the event. Additional information should be sent within 5 days if the reaction has not resolved at the time of reporting. The CTU will notify the MHRA and main REC of all SUSARs occurring during the study according to the following timelines; fatal and life-threatening within 7 days of notification and non-life threatening within 15 days. All investigators will be informed of all SUSARs occurring throughout the study. Local investigators should report any SUSARs and /or SAEs as required locally. All SAE s reported should also be recorded on the Adverse Event log. Adverse Event Unrelated 51 Possibly/Probably/Almost Certainly related Serious Not Serious Serious Not Serious

130 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Responsibilities Investigator The Investigator is responsible for reporting all AEs that are observed or reported during the study, regardless of their relationship to study product. All SAEs must be reported immediately by the investigator to the CTU on an SAE form unless the SAE is specified in the protocol as not requiring immediate reporting. All other adverse events should be reported on the regular progress/follow-up reports. Study identifier Study centre Patient number A description of the event Date of onset Current status Minimum information required for reporting: Whether study treatment was discontinued The reason why the event is classified as serious Investigator assessment of the association between the event and study treatment i. The SAE form should be completed by a designated investigator, a physician named on the signature list and delegation of responsibilities log as responsible for reporting SAEs and making trial related medical decisions. The investigator should assess the SAE for the likelihood that it is a response to the investigational medicinal product. In the absence of the designated investigator the form should be completed and signed by an alternative member of the research site trial team and submitted to the CTRC. As soon as possible thereafter the responsible investigator should check the SAE form, make amendments as appropriate, sign and re-send to the CTRC. The initial report shall be followed by detailed reports as appropriate. 52

131 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: ii. iii. When submitting an SAE to the CTRC research sites should also telephone the appropriate trial co-ordinator/data manager on telephone number to advise that an SAE report has been submitted. Send the SAE form by fax (within 24 hours or next working day) to the CTU: Fax Number: iv. The responsible investigator must notify their R&D department of the event (as per standard local governance procedures). v. In the case of an SAE the subject must be followed-up until clinical recovery is complete and laboratory results have returned to normal, or until the event has stabilised. Follow-up may continue after completion of protocol treatment if necessary. vi. Follow-up information is noted on another SAE form by ticking the box marked follow-up and faxing to the CTU as information becomes available. Extra, annotated information and/or copies of test results may be provided separately. vii. The patient must be identified by trial number, date of birth and initials only. The patient s name should not be used on any correspondence Maintenance of Blinding Systems for SUSAR and SAR reporting should, as far as possible, maintain blinding of individual clinicians and of trials staff involved in the day-to-day running of the trial. Unblinding clinicians may be unavoidable if the information is necessary for the medical management of particular patients. The safety of patients in the trial always takes priority. In each report, seriousness, causality and expectedness will be evaluated for active and excipents in placebo. Cases that are considered serious, unexpected and possibly, probably or almost certainly related to one of the trial therapies (i.e. possible SUSARs) would have to be unblinded at the clinical trials unit prior to reporting to the regulator Responsibilities CTU The CTU is undertaking duties delegated by the trial sponsor, University Hospitals Bristol NHS Foundation Trust, and is responsible for the reporting of SUSARs and other SARs to the regulatory authorities (MHRA, competent authorities of other European member states in which the trial is taking place and, if required, the research ethics committees) as follows: SUSARs which are fatal or life-threatening must be reported not later than 7 days after the CTU is first aware of the reaction. Any additional relevant information must be reported within a further 8 days. SUSARs that are not fatal or life-threatening must be reported within 15 days of the CTU first becoming aware of the reaction. A list of all SARs (expected and unexpected) must be reported annually. It is recommended that the following safety issues should also be reported in an expedited fashion 53

132 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: An increase in the rate of occurrence or a qualitative change of an expected serious adverse reaction, which is judged to be clinically important; Post-study SUSARs that occur after the patient has completed a clinical trial and are notified by the investigator to the sponsor; New events related to the conduct of the trial or the development of the IMPs and likely to affect the safety of the subjects, such as: a. A serious adverse event which could be associated with the trial procedures and which could modify the conduct of the trial; b. A significant hazard to the subject population, such as lack of efficacy of an IMP used for the treatment of a life-threatening disease; c. A major safety finding from a newly completed animal study (such as carcinogenicity). d. Any anticipated end or temporary halt of a trial for safety reasons and conducted with the same IMP in another country by the same sponsor; Recommendations of the Data Monitoring Committee, if any, where relevant for the safety of the subjects. Staff at the CTU will liaise with the Chief Investigator (or designated other specified in the protocol) who will evaluate all SAEs received for seriousness, expectedness and causality. Investigator reports of suspected SARs will be reviewed immediately and those that are SUSARs identified and reported to regulatory authorities and MREC. The causality assessment given by the Local Investigator at the hospital cannot be overruled and in the case of disagreement, both opinions will be provided with the report. The CTU will also send an annual safety report containing a list of all SARs to regulatory authorities and MREC. Copies of the report will be sent to the Principal Investigator at all institutions participating in the trial Patient safety incidents that take place in the course of research should be reported to the National Patient Safety Agency (NPSA) by each participating NHS Trust in accordance with local reporting procedures SAE reporting AbbVie In line with AbbVie policies for the reporting of adverse events in connection with investigator-initiated studies supported by AbbVie Laboratories, UK, the CTU will notify AbbVie of all SAEs that occur during the trial. These reports will remain blinded Safety reports Safety reports will be generated during the course of the trial which allows for monitoring of SAE and ADR reporting rates across sites. The CTU will send annual safety reports containing a list of all SARS to regulatory authorities an MREC. Any concerns raised by the IDSMC or inconsistencies noted at a given site may prompt additional training at sites, with the potential for the CTU to carry out site visits if there is suspicion of unreported AEs in patient case notes. Additional training will also be provided if unacceptable delay in safety reporting timelines. 54

133 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: ETHICAL CONSIDERATIONS 13.1 Ethical Considerations The study will abide by the principles of the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989) and South Africa (1996) Ethical Approval The trial protocol will not be initiated until it has received the favourable opinion of the a Main Research Ethics Committee (MREC). Subsequent to this it must also undergo review at the R&D offices at participating sites. The local R&D office should be sent the appropriate SSI form complete with the necessary authorisation signatures, plus any other documentation requested for review. A copy of local Research & Development (R&D) approval should be forwarded to CTU before the site is initiated and patients recruited Informed Consent Process General Informed consent is a process initiated prior to an individual agreeing to participate in a trial and continues throughout the individual s participation. Written informed consent is required for all trial participants. In obtaining and documenting informed consent, the investigator should comply with applicable regulatory requirements and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. This trial will be recruiting minors and young people over the age of 16 years and informed consent processes will reflect the legal and ethical requirements to obtain valid informed consent for trial participants. Information will be provided to potential participants and their families verbally and in writing. All will have the opportunity to discuss the project with the responsible investigator at site and/or a designated member of the research team. Discussions will be supported with detailed written and ethically approved Patient Information Sheets and Consent forms (PISC) provided directly to young people able to consent for themselves (defined in statutory instrument 2004 No.1031 as aged 16 years) and parents / legal guardian of minors (aged <16 years). Age and stage of development appropriate information leaflets will be provided to minors and their assent obtained, where appropriate. Careful presentation will be made of the known risks of the disease and trial medications, and possible benefits, as well as a detailed explanation of the trial procedures and protocol. All participants will be given opportunity to ask any questions that may arise, should have the opportunity to discuss the study with their surrogates and time to consider the information prior to agreeing to participate. A contact point where further information about the trial may be obtained will be provided. 55

134 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Minors and young people eligible for this trial will have JIA-associated uveitis refractory to treatment with MTX. They may therefore be anxious about available treatments and the ultimate outcome for their sight if inflammation persists. All of the recruiting investigators are experienced rheumatologists and ophthalmologists familiar with imparting information to families and young people. When potentially eligible minors and young people are identified, they/ their parent/ the person with parental responsibility will be approached by the investigator, or a designated member of the investigating team, during which an opportunity will be given to understand the objectives of the trial. The treatment schedule and trial visits are in line with standard clinical care, although they will be made aware that additional travel may be needed if the trial assessments require they be reviewed at their tertiary centre rather than their local hospital. The potential risks and benefits of the anti-tnf agent will be discussed, as will treatment failure criteria and what will happen if they choose not to enter the trial or have to withdraw from the trial for any reason. In addition, the rationale for the use of a placebo and the applied randomisation ratio will be explained. Consent from the patient, or proxy consent in the case of minors, should be obtained by a designated member of the research team prior to their participation in the trial, after a full explanation has been given of the treatment options, including the conventional and generally accepted methods of treatment. Verbal information should be reinforced with the implementation of the Patient Information and Consent Forms (PISC). The right of the patient (non-minors) or parent/ legal guardian (for minors) to refuse consent to participate in the trial without giving reasons must be respected. After the patient has entered the trial, the clinician remains free to give alternative treatment to that specified in the protocol, at any stage, if he/she feels it to be in the best interest of the patient. However, the reason for doing so should be recorded and the patient will remain within the trial for the purpose of follow-up and data analysis according to the treatment option to which they have been allocated. Similarly, the patient remains free to withdraw at any time from the protocol treatment and trial follow-up without giving reasons and without prejudicing their further treatment. Adequate time to consider trial entry (at least 24 hours) will be allowed before written consent of the participant/ parent/ lrgal representative will be obtained by the responsible clinician or other designated team member (recorded on the signature and delegation log). The right of the individual to refuse participation without giving reasons will be respected Competent Adults (aged years at time of consent) Upon completion of the above, the patient will then sign and date the informed consent document. Both the person obtaining consent and the participant must personally sign and date the form. A copy of the informed consent document will be given to the patient for their records. The original copy will be filed in the participant s medical notes and a further copy of the signed consent form will be filed in the Investigators Site File. One final copy of the consent form should be sent to the CTU. 56

135 Minors (aged <16 years at time of consent) SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: The Medicines for Human use (Clinical Trials) Regulations 2004 define a person under the age of 16 years to be a minor. The regulatons require that informed consent for minors be provided by a person with parental responsibility* or a legal representative. Upon completion of the above, proxy consent from the parent or legally acceptable representative should be obtained prior to each patient participating in the trial. Both the person obtaining consent and the parent/legal representative must personally sign and date the form. A copy of the informed consent document will be given to the parent/legal representative for their records. The original copy will be filed in the participant s medical notes and a further copy of the signed consent form will be filed in the Investigators Site File. One final copy of the consent form should be sent to the CTU. * A mother automatically has parental responsibility for her child from birth. However, this is not the case for fathers. Conditions for fathers gaining parental responsibility varies throughout the UK and is summarised below. Practitioners should verify that the consenting parent has parental responsibility to do so. For births registered in England and Wales In England and Wales, if the parents of a child are married to each other at the time of the birth, or if they have jointly adopted a child, then they both have parental responsibility. Parents do not lose parental responsibility if they divorce, and this applies to both the resident and the non-resident parent. This is not automatically the case for unmarried parents. According to current law, a mother always has parental responsibility for her child. A father, however, has this responsibility only if he is married to the mother when the child is born or has acquired legal responsibility for his child through one of these three routes: (from 1 December 2003) by jointly registering the birth of the child with the mother by a parental responsibility agreement with the mother by a parental responsibility order, made by a court For births registered in Scotland A father has parental responsibility if he is married to the mother when the child is conceived, or any time after that date. An unmarried father has parental responsibility if he is na med on the child's birth certificate (from 4 May 2006). Alternatively, unmarried fathers can also be named following a re-registration of the birth. For births registered in Northern Ireland A father has parental responsibility if he is married to the mother at the time of the child's birth. However he does not have parental responsibility if he marries the mother after the birth. An unmarried father has parental responsibility if he is named on the child's birth certificate (from 15 April 2002). Alternatively, unmarried fathers can also be named following a re-registration of the birth. For births registered outside the UK If a child is born overseas and then comes to live in the UK, the parental responsibility rules apply for the UK country in which they live Assent in minors If capable, and under appropriate circumstances, minors should approached to provide assent by a member of the research team experienced with minors. Age-and-state-of- 57

136 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: development Patient information Sheet and Assent forms, approved by the independent ethical committee, describing (in simplified terms) the details of the trial intervention/product, trial procedures and risks should be used. The information leaflets will be developed in close collaboration with the consumer representatives on the trial team and with guidance from the MCRN young persons group. The minor should personally write their name and date the assent form, which is then signed by the parent/legal representative and the researcher and copies retained/disseminated as for consent forms. Assent should be obtained, where appropriate, and documented in the patient notes, however assent forms do not substitute for the consent form signed by the patient s legally acceptable representative. Whilst the absence of assent does not exclude the patient provided consent has been obtained from the parent/legal representative, the explicit wish of a minor who is capable of forming an opinion and assessing information in relation to the trial and who wishes to refuse participation in, or to be withdrawn from, the clinical trial at any time should be considered by the investigator. Reasons for absence of assent should therefore be recorded in the participant s medical notes Minors reaching 16 years during trial participation A participant involved in the study who reaches the age of 16 (and is therefore deemed competent to provide consent) should be re-consented at their next scheduled visit after their 16 th Birthday. The same process will be followed as for competent adults aged at the time of consent (refer to section ) 58

137 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: REGULATORY APPROVAL This trial has been granted a Clinical Trial Authorisation (CTA) by the MHRA. The EUdraCT reference is

138 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: TRIAL MONITORING Trial monitoring is carried out to ensure that the rights and well-being of human participants are protected during the course of a clinical trial. A risk assessment is performed for each trial coordinated by the CTU to determine the level and type of monitoring required for specific hazards. The nature and extent of monitoring will be specific to the individual trial Risk Assessment In accordance with the CTRC Standard Operating Procedures this trial will undergo a risk assessment, completed in partnership between: Representative/s of the Trial Sponsor Chief Investigator Trial Coordinator and supervising Trial Manager Trial Statistician and supervising Statistician MCRN CTU Director In conducting this risk assessment, the contributors considered potential patient, organisational and study hazards, the likelihood of their occurrence and resulting impact should they occur. The outcome of the risk assessment is expressed as a percentage, assigned according to the following categories: Score 33% = Low risk Score 34 to 67% = Moderate risk Score 68 to 100% = High risk The outcome of the SYCAMORE trial risk assessment has defined this to be a low risk trial and the level and nature of monitoring has been determined accordingly Source Documents Source data: All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies). (ICH E6, 1.51). Source documents: Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial). (ICH E6, 1.52). In order to resolve possible discrepancies between information appearing in the CRF and any other patient related documents, it is important to know what constitutes the source document and therefore the source data for all information in the CRF. The data that is to be recorded in the CRF and should be consistent and verifiable with source data in source documents other than the CRF (e.g. medical record, laboratory reports 60

139 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: and nurses notes) and the data where no prior record exists and which is recorded directly in the CRF (i.e. where the CRF is considered the source document, unless otherwise indicated by the investigator). In addition to the above, date(s) of conducting informed consent (plus assent, where appropriate) process including date of provision of patient information, screening number, randomisation number and the fact that the patient is participating in a clinical trial of adalimumab versus placebo should be added to the patient s medical record chronologically, i.e. when treatment is allocated to the patient. Further, study treatment allocation should also be noted in the patient s medical record after unblinding of the study Data Capture Methods The study case report form (CRF) is the primary data collection instrument for the study. All data requested on the CRF must be recorded. MCRN CTU will supply No Carbon Required Case Report Forms (NCR CRFs).and guidance on how the CRF should be completed. Data stored at CTU will be checked for missing or unusual values (range checks) and checked for consistency within participants over time. Any suspect data will be returned to the site in the form of data queries. Data query forms will be produced at the CTU from the trial database and sent either electronically or through the post to a named individual (as listed on the site delegation log). Sites will respond the queries providing an explanation/resolution to the discrepancies and return the data query forms to CTU. The forms will then be filed along with the appropriate CRFs and the appropriate corrections made on the database. There are a number of monitoring features in place at the CTU to ensure reliability and validity of the trial data, to be detailed in the trial monitoring plan Confidentiality Individual participant medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited with the exceptions noted below. Case report forms will be labelled with the participant s initials and unique trial screening and/or randomisation number. Medical information may be given to the participant s medical team and all appropriate medical personnel responsible for the participant s welfare. The CTU will be undertaking activities requiring the transfer of identifiable data: Verification that appropriate informed consent is obtained will be enabled by the provision of copies of participant s signed informed consent/assent forms being supplied to the CTU by recruiting centres, which requires that name data will be transferred to the CTU. This transfer of identifiable data is disclosed in the PISC. The CTU will preserve the confidentiality of participants taking part in the study and The University of Liverpool is registered as a Data Controller with the Information Commissioners Office Direct access to data In order to perform their role effectively, monitors and persons involved in Quality Assurance and Inspection will need direct access to primary subject data, e.g. patient records, laboratory reports, appointment books, etc. Participants will consent to allow the research time access to their data. 61

140 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Quality Assurance and Control QA includes all the planned and systematic actions established to ensure the study is performed and data generated, documented/recorded and reported in compliance with applicable regulatory requirements. QC includes the operational techniques and activities done within the QA system to verify that the requirements for quality of the trial-related activities are fulfilled. The level and nature of monitoring will be described in the trial monitoring plan, which will be fianlised upon completion of the trial risk assessment. To ensure the integrity of the data the following policies will be observed: The Principal Investigator, and designated staff from each centre will attend an initiation meeting, coordinated by CTU in conjunction with co-lead investigators to provide training in the trial protocol and procedures The trial coordinator will verify appropriate approvals are in place prior to the trial being initiated within the CTU The trial coordinator is to verify appropriate approvals are in place prior to the initiation of a site, and that the relevant personnel have attended study specific training The trial coordinator is to monitor screening, recruitment and withdrawal rates between sites and report to the TMG Regular QC checks will be performed on data already inputted to ensure data entered is of a high standard. Independent oversight of the study will be provided by the Independent Data and safety Monitoring Committee and the Trial Steering Committee Records Retention The investigator at each investigational site must make arrangements to store the essential trial documents, (as defined in Essential Documents for the Conduct of a Clinical Trial (ICH E6, Guideline for Good Clinical Practice)) including the Investigator Site File and Pharmacy Site File, until the Clinical Trials Unit informs the investigator that the documents are no longer to be retained, or for a maximum period of 15 years (whichever is soonest). In addition, the investigator is responsible for archiving of all relevant source documents so that the trial data can be compared against source data after completion of the trial (e.g. in case of inspection from authorities). The investigator is required to ensure the continued storage of the documents, even if the investigator, for example, leaves the clinic/practice or retires before the end of required storage period. Delegation must be documented in writing. The MCRN CTU undertakes to store originally completed CRFs and separate copies of the above documents for the same period, except for source documents pertaining to the individual investigational site, which are kept by the investigator only. Data will be boxed and transferred to specially renovated, secure, premises where unique reference numbers are applied to enable confidentiality, tracking and retrieval. The MCRN CTU will archive the documents in compliance with ICH GCP utilising the Records Management Service of the University of Liverpool. All electronic CRFs and trial data will be archived onto an appropriate media for long term accessible storage. Hard copies of data will be boxed and transferred to specially renovated, secure, premises where unique reference numbers are applied to enable confidentiality, tracking and retrieval. 62

141 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: INDEMNITY The SYCAMORE trial is sponsored by University Hospitals Bristol NHS Foundation Trust and co-ordinated by the MCRN CTU in the University of Liverpool. The University Hospitals Bristol NHS Foundation Trust cover for negligent harm is in place through the Clinical Negligence Scheme for Trusts. For NHS sponsored research HSG(96)48 reference no.2 refers If there is any negligent harm during the study when the NHS body owes a duty of care to their person harmed, NHS indemnity covers NHS staff, medical academic staff with honorary contracts, and those conducting the trial. NHS indemnity does not offer no-fault compensation and is unable to agree in advance to pay compensation for non-negligent harm. Ex-gratia payments may be considered in the case of a claim. For the purposes of the study clinical negligence is defined as: A breach of duty of care by members of the health care professions employed by NHS bodies or by others consequent on decisions or judgments made by members of those professions acting in their professional capacity in the course of their employment, and which are admitted as negligent by the employer or are determined as such through the legal process. 63

142 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: FINANCIAL ARRANGEMENTS This study is funded by a joint venture between Arthritis Research UK and the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme. Contractual agreements will be in place between the sponsor and collaborating sites that will describe financial arrangements. IMP is to be supplied by AbbVie Laboratories Participant Payment Participants and their parents / guardians will not be paid to participate in the trial and the schedule for study visits is in line with routine standard care where possible. There is provision for reimbursement of travel expenses in the event that participants are required to travel to a tertiary centre for assessment at a visit that would otherwise take place at a centre closer to their home Collaborating Centre Payments Research Team Some tasks are to be undertaken during routinely scheduled clinic appointments that are directly related to the research and will impose a time demand on clinic staff, which is in addition to their usual clinical work. Financial support for these activities are split between NHS Service Support Costs and Research Costs NHS Service Support This cost is estimated to be 2,195 per participant randomised and followed up as per protocol. This amount is calculated as a cost to the NHS, but is not necessarily reimbursed to the centre as such; resource to for NHS Service Support Costs can be accessed via the Local Comprehensive Research Network Research Support Additionally, a per patient payment of 871 pounds per participant randomised and followed up as per protocol is available. This has been calculated to cover research-associated costs for the time of personnel at collaborating centres. Payment schedule details are specified in the Research Site Agreement (paid quarterly in arrears upon receipt of valid invoice) Pharmacy Department The pharmacy costs are to support the additional workload associated with the clinical trial and have been included as NHS Service Support Costs. 64

143 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: TRIAL COMMITTEES 18.1 Trial Management Group (TMG) The TMG is be responsible for the day-to-day running and management of the trial and will convene at least monthly in the first year and at least quarterly thereafter Trial Steering Committee (TSC) The role of the TSC is to provide overall supervision for the trial and provide advice through its Chairperson, who will be one of the independent members of the committee. Additionally, the TSC will be composed of TMG members, a consumer representative appointed by the MCRN/ARC Paediatric Rheumatology Clinical Studies Group (CSG), a representative of the MCRN/ARC Paediatric Rheumatology CSG (as per Arthritis Research UK requirements) and a nursing representative. The TSC will convene to approve the protocol and then at least annually thereafter. The ultimate decision for the continuation of the trial lies with the TSC 18.3 Independent Data and Safety Monitoring Committee (IDSMC) The IDSMC will be responsible for reviewing and assessing recruitment, interim monitoring of safety, trial conduct and external data. They will first convene to approve the protocol, agree their charter and define frequency of subsequent meetings (at least annually). The IDSMC will provide a recommendation to the Trial Steering Committee concerning the continuation of the trial. 65

144 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: PUBLICATION The results from different centres will be analysed together and published as soon as possible. Individual Clinicians must undertake not to submit any part of their individual data for publication without the prior consent of the Trial Management Group. The Trial Management Group will form the basis of the Writing Committee and advise on the nature of publications. The Uniform Requirements for Manuscripts Submitted to Biomedical Journals ( will be respected. All publications shall include a list of participants, and if there are named authors, these should include the trial s Chief Investigator(s), Statistician(s), Trial Manager(s) and Health Economist(s) involved at least. If there are no named authors (i.e. group authorship) then a writing committee will be identified that would usually include these people, at least. The ISRCTN allocated to this trial should be attached to any publications resulting from this trial. The members of the TSC and IDSMC should be listed with their affiliations in the Acknowledgements/Appendix of the main publication. 66

145 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: PROTOCOL AMENDMENTS V6.0 17/04/2016 to V6.1 14/07/2016 Non Substantial Amendment 6 Page Number Section Change Made JADAS added as a secondary outcome JADAS added as a secondary outcome Text amended to state that Chief Investigator is responsible for assessing expectedness of adverse events Flow chart amended to show that site investigators assess relationship and seriousness of adverse events only Contact details changed for reporting SAE s V5.0 22/01/2015 to v6.0 17/04/2015 Substantial Amendment 12 Protocol to be amended to reflect that: The blinded phase of the trial has been stopped and all patients are followed up in open label design. Patients who have been on Adalimumab throughout the trial will continue with Adalimumab. If patient has been on placebo throughout the trial then this will stop and patient will be managed at the discretion of the treating physician. All patients will be followed up as per original protocol (18 months treatment, 6 months follow up). V5.0 11/08/2014 to 22/01/2014 Substantial Amendment 11 Page Number Section Change Made Text amended to state that for patients will be considered withdrawals and not treatment failures if they miss more than 4 weeks of MTX treatment Text amended to state that results from Haematological assessments taken at screening can be used at randomisation/baseline if assessment had been completed within 15 days Text amended to state that results from Biochemical assessments taken at screening can be used at randomisation/baseline if assessment had been completed within 15 days Text amended to clarify that tissuebank samples are taken at baseline, 3 months (or at next visit for extenuating circumstances and 18 months (or end of treatment) Text added to clarify that assessments can be done on both eyes or just the eligible eye if only one eye was eligible at time of randomisation. 67

146 V4.0 25/09/2013 to V4.1 11/08/2014 Non Substantial Amendment 4 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Page Number Section Change Made Text added to state that the IDSMC may request an interim analysis of the primary outcome to be undertaken Reference added to support new text in section 11.4 V3.0 25/04/2013 to V4.0 25/09/2013 Substantial Amendment 10 Page Number Section Change Made 4 1 Contact details added for institution and individuals 10 3 Trial population changed from 154 to 114 patients 10 3 Study duration changed from 3 to 2 years 10 3 Assessment of HAHA analysis removed from secondary objectives 11 3 Schematic of study design amended to show updated numbers in each randomisation group Assessment of HAHA analysis removed from secondary objectives Assessment of treatment failure 3 iv changed to record failure as a reduction of 0.3 LogMar units Clarification text for ocular co-morbidities added Assessment of HAHA analysis removed from secondary 68

147 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: objectives Clarification added to the inclusion criteria 2 to state that the latest date of SUN grade score must be at date of screening Clarification added to the inclusion criteria to show that patients who are 18 are not eligible for the trial Clarification added to exclusion critiera that patient cannot have more than 6 topical steroid eye drops per eye per day Systemic Acetazolamide added as medication not permitted Instructions added to contact CI when the PI feels that the patient has met the treatment failure criteria Window of -2/+2 days added for MTX administration Study visits and assessments table updated to show follow up period reduced to 6 months Trial Assessments table amended to remove HAHA sample collection Clarification added that intraocular pressure can be recorded using instruments used as part of local practice Timelines for collecting HUI2 questionnaires changed following the reduction to follow up period Clarification added to Hospital Episode Statistics to state that Requests for anonymised extracts will be made according to standardised procedures at 18 and 6 months after last patient last visit (removed) Collection of HAHA samples section removed Text added to the protocol to state that patients who do not give consent to the tissuebank can still take part in the main part of the trial Definition of end of trial updated for clarity Assessment of treatment failure 3 iv changed to record failure as a reduction of 0.3 LogMar units Clarification text for ocular co-morbidities added Secondary endpoint development of anti-adalimumab antibody samples removed SAE reporting contact details updated V2.0 30/09/2011 amended to V3.0 25/04/2013 Substantial Amendment 7 Page Number Section Change Made N/A N/A Contact details removed for TMG, IDSMC and TSC members Throughout Throughout References to sections updated following the removal of section 1 for contact details. Throughout Throughout References to Abbott changed to AbbVie Window for treatment visits changed from -3/+3 days to -7/+7 days Table updated to remove CSRI questionnaire at visits other than baseline Timeline for TB assessment changed from 4 weeks to 12 weeks prior to baseline Clarification given that Haematological samples from screening can be used at randomisation Clarification given that Biochemical samples from screening can be used at randomisation Clarification that a Markov model of treatment of treatment effect on JIA will be developed Phone number and fax numbers updated for SAE reporting. N/A N/A Appendix A Trial management group composition removed. 69

148 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: V1.1 08/09/2011 amended to V2.0 30/09/2011 Substantial Amendment 2 Page Number Section Change made Throughout Throughout Throughout Throughout Header amended to update version and date Change BioBank references to Tissue Bank 1 Front page Addition of ISRCTN number 6 1 Pharmacist contact details changed to Amy Holloway Definition of 1 month treatment added to end of section 20 6 Point 1 i wording changed to state 2 step increase from baseline 20 6 Point 1 iii addition of no improvement from baseline 20 6 Point 1 V grade score range changed from to Addition of point 3 suspension of study treatment 20 6 Clarification of treatment failure added at the end of section Text changed to read AC cell scores >/= Changed from previously failed Adalimumab to previously received Addition of exclusion points 20 and Addition of instructions for patient to be followed up after withdrawal Point 6 reference to screening more than 3 times has been removed Addition of the use of back up randomisation envelopes at site Point 3, dose range changed to 10-20mg/m Addition of date allowances regarding injection dates Addition of information regarding treatment suspension Added information regarding allowances for visit dates Table 1 changed schedule for completion of CSRI Point 1 dose range changed to 10-20mg/m Point 3,3 text has been expanded to provide more detail Dose range changed to 10-20mg/m Dose range changed to 10-20mg/m Re wording of section to refer to tissue bank instead of Tissue Bank Point 1 i wording changed to state 2 step increase from baseline Point 1 iii addition of no improvement from baseline Point 1 V grade score range changed from to Addition of point 3 suspension of study treatment Clarification of treatment failure added at the end of section Statement added regarding unblinding analysis 70

149 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: V1.0 25/02/2011 amended to V1.1 08/09/2011 Minor Amendment 1 Page Number Section Change made Throughout Throughout Header amended to update version and date 6 1 Statistician changed from Lynne Cresswell to Andrew McKay 7 1 Trial steering committee member changed from Simon Harding to Carlos Pavesio Point 1 iii typographical error corrected to add a / in between sustatined and development Point 1 iv and v have been reversed so that points 1 i-iv refer to endpoints after 3 months and point v refers to endpoints after 6 months Point 2 ii intraocular pressure has been changed from <25mm Hg to >25mm Hg Points 2 ii, 2 iii, and 2 iv have been changed from stating intervals from over 1 month to intervals over 2 consecutive visits Points 6 d and e have been deleted so that references to visual angle have been removed from the protocol Point 4 wording has been changed to remove reference to Adalimumab and state no Disease modifying immunosuppressive drugs, other than MTX, in the 4 weeks prior to screening Points 4, 5, 7 and 14 have been changed from collecting data prior to randomisation to collecting data prior to screening Points 2 ii, 2 iii, and 2 iv have been changed from stating intervals from over 1 month to intervals over 2 consecutive visits Points 1 iii typographical error corrected to add a / in between sustatined and development Points 6 d and e have been deleted so that references to visual angle have been removed from the protocol V1.0 25/02/2011 Original Submitted Version 71

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152 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Nugent J, Ruperto N, Grainger J, Machado C, Sawhney S, Baildam E, Davidson J. The British version of the childhood health questionnaire (CHAQ) and the child health questionnaire (CHQ). Clin Exp Rheumatol 2001;19 (Suppl 23):S163-S FDA. ugsafetyinformationforheathcareprofessionals/ucm htm Caspersen S, Elkjaer M, Riis L, Pedersen N, Mortensen C, Jess T, Sarto P, Hansen TS, Wewer V, Bendtsen F, Moesgaard F, Munkholm P. Infliximab for inflammatory bowel disease in Denmark : clinical outcome and follow-up evaluation of malignancy and mortality. Clin Gastroenterol Hepatol 2008;6: de Vries HS, van Oijen MG, de Jong DJ. Serious events with infliximab in patients with inflammatory bowel disease: a 9-year cohort study in the Netherlands. Drug Saf 2008;31: Kempen JH, Daniel E, Dunn JP, Foster CS, Gangaputra S, Hanish A, Helzlsouer KJ, Jabs DA, Kacmaz RO, Levy-Clarke GA, Liesegang TL, Newcomb CW, Nussenblatt RB, Pujari SS, Rosenbaum JT, Suhler EB, Thorne JE. Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs: retrospective cohort study. BMJ 2009;339:b Ilowite NT. Update on biologics in juvenile idiopathic arthritis. Curr Opin Rheumatol 2008;20: Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, Wouters C, Silverman ED, Balogh Z, Henrickson M, Apaz MT, Baildam E, Fasth A, Gerloni V, Lahdenne P, Prieur AM, Ravelli A, Saurenmann RK, Gamir ML, Wulffraat N, Marodi L, Petty RE, Joos R, Zulian F, McCurdy D, Myones BL, Nagy K, Reuman P, Szer I, Travers S, Beutler A, Keenan G, Clark J, Visvanathan S, Fasanmade A, Raychaudhuri A, Mendelsohn A, Martini A, Giannini EH. A randomized, placebocontrolled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 2007;56: Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004;31: Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, Cugno C, Bozzola E, Martini A, Ravelli A. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Rheum 2008;59: Beecham J, Knapp M. Costing psychiatric interventions. In: Thornicroft, Graham, (ed.) Measuring mental health needs. Gaskell, London, UK, pp ISBN Department of Health. NHS reference costs _ Curtis L. Costs of Health and Social Care Personal Social Services Research Unit, University of Kent Sung L, Petrou S, Ungar W. Measuring health utilities in children and their parents. In: Ungar W, ed. Economic Evaluation in Child Health. Oxford University Press National Institute for Health and Clinical Excellence (NICE). Guide to the Methods of Technology Appraisal McCabe CJ, Stevens KJ, Brazier JE. Utility scores for the Health Utilities Index Mark 2: an empirical assessment of alternative mapping functions. Med Care 2005;43: Espallargues M, Czoski-Murray CJ, Bansback NJ, Carlton J, Lewis GM, Hughes LA, Brand CS, Brazier JE. The impact of age-related macular degeneration on health status utility values. Invest Ophthalmol Vis Sci 2005;46: Pocock SJ. Current controversies in data monitoring for clinical trials. Clinical Trials. 2006;3(6): Glick H, Doshi JA, Sonnad SS, Polsky D. Economic evaluation in clinical trials. Oxford: Oxford University Press Briggs A, Sculpher M, Claxton K. Decision Modelling for Health Economic Evaluation. pp. 256 Oxford: Oxford University Press Kotaniemi K, rkela-kautiainen M, Haapasaari J, Leirisalo-Repo M. Uveitis in young adults with juvenile idiopathic arthritis: a clinical evaluation of 123 patients. Ann Rheum Dis 2005;64: Carvounis PE, Herman DC, Cha S, Burke JP. Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefes Arch Clin Exp Ophthalmol 2006;244: ICH. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

153 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: Murphy CC, Greiner K, Plskova J, Frost NA, Forrester JV, Dick AD. Validity of using vision-related quality of life as a treatment end point in intermediate and posterior uveitis. Br J Ophthalmol 2007;91: Murphy CC, Hughes EH, Frost NA, Dick AD. Quality of life and visual function in patients with intermediate uveitis. Br J Ophthalmol 2005;89: Lee RW, Creed TJ, Schewitz LP, Newcomb PV, Nicholson LB, Dick AD, Dayan CM. CD4+CD25(int) T cells in inflammatory diseases refractory to treatment with glucocorticoids. J Immunol 2007;179: Lee RW, Schewitz LP, Nicholson LB, Dayan CM, Dick AD. Steroid refractory CD4+ T cells in patients with sight-threatening uveitis. Invest Ophthalmol Vis Sci 2009;50: Schewitz LP, Lee RW, Dayan CM, Dick AD. Glucocorticoids and the emerging importance of T cell subsets in steroid refractory diseases. Immunopharmacol Immunotoxicol 2009;31: Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 1999;10: V. Kalinina Ayuso, Evelyne Leonce van de Winkel, Aniki Rothova, Joke Helena de Boer. Relapse Rate of Uveitis Post-Methotrexate Treatment in Juvenile Idiopathic Arthritis. American Journal of Opthamology; DOI: /j.ajo Brunner HI, Lovell DJ, Finck BK, Giannini EH. Preliminary definition of disease flare in juvenile rheumatoid arthritis. J Rheumatol 2002; 29(5): Consolaro A, Ruperto N, Bazso A et al. Development and validation of a composite disease activity score for juvenile idiopathic arthritis. Arthritis Rheum 2009; 61(5): Tanner Score: Blondell, Roster and dave, Disorders of Puberty. Am Fam Physician; 60(1): , Oliveira S, Ravelli A, Pistorio A, Castell E, Malattia C, Prieur AM et al. Proxy-reported health related quality of life of patients with juvenile idiopathic arthritis: the Paediatric Rheumatology International Trials Organisation multinational quality of life cohort study. Arthritis Rheum 2007; (1):

154 SYCAMORE Protocol V6.1, 14/07/2016 EudraCT number: APPENDICES Appendix A: LOCS III grading adapted from Chylack et al 45 76

155 SYCAMORE Summary of protocol changes V6.0 17/04/2016 to V6.1 14/07/2016 Non Substantial Amendment 6 Page Number Section Change Made JADAS added as a secondary outcome JADAS added as a secondary outcome Text amended to state that Chief Investigator is responsible for assessing expectedness of adverse events Flow chart amended to show that site investigators assess relationship and seriousness of adverse events only Contact details changed for reporting SAE s V5.0 22/01/2015 to v6.0 17/04/2015 Substantial Amendment 12 Protocol to be amended to reflect that: The blinded phase of the trial has been stopped and all patients are followed up in open label design. Patients who have been on Adalimumab throughout the trial will continue with Adalimumab. If patient has been on placebo throughout the trial then this will stop and patient will be managed at the discretion of the treating physician. All patients will be followed up as per original protocol (18 months treatment, 6 months follow up). V5.0 11/08/2014 to 22/01/2014 Substantial Amendment 11 Page Number Section Change Made Text amended to state that for patients will be considered withdrawals and not treatment failures if they miss more than 4 weeks of MTX treatment Text amended to state that results from Haematological assessments taken at screening can be used at randomisation/baseline if assessment had been completed within 15 days Text amended to state that results from Biochemical assessments taken at screening can be used at randomisation/baseline if assessment had been completed within 15 days Text amended to clarify that tissuebank samples are taken at baseline, 3 months (or at next visit for extenuating circumstances and 18 months (or end of treatment)

156 Text added to clarify that assessments can be done on both eyes or just the eligible eye if only one eye was eligible at time of randomisation. V4.0 25/09/2013 to V4.1 11/08/2014 Non Substantial Amendment 4 Page Number Section Change Made Text added to state that the IDSMC may request an interim analysis of the primary outcome to be undertaken Reference added to support new text in section 11.4 V3.0 25/04/2013 to V4.0 25/09/2013 Substantial Amendment 10 Page Number Section Change Made 4 1 Contact details added for institution and individuals 10 3 Trial population changed from 154 to 114 patients 10 3 Study duration changed from 3 to 2 years 10 3 Assessment of HAHA analysis removed from secondary objectives 11 3 Schematic of study design amended to show updated numbers in each randomisation group Assessment of HAHA analysis removed from secondary objectives Assessment of treatment failure 3 iv changed to record failure as a reduction of 0.3 LogMar units Clarification text for ocular co-morbidities added Assessment of HAHA analysis removed from secondary objectives Clarification added to the inclusion criteria 2 to state that the latest date Clarification of SUN added grade score to the must inclusion be at criteria date of to screening. show that patients who are Clarification 18 are not added eligible to exclusion for the trial. critiera that patient cannot have more than Systemic 6 topical Acetazolamide steroid eye added drops per as medication eye per day. not permitted Instructions added to contact CI when the PI feels that the patient has met Window the treatment of -2/+2 days failure added criteria. for MTX administration Study visits and assessments table updated to show follow up period reduced Trial Assessments to 6 months. table amended to remove HAHA sample collection Clarification added that intraocular pressure can be recorded using instruments Timelines for used collecting as part HUI2 of local questionnaires practice changed following the reduction Clarification to follow added up to period. Hospital Episode Statistics to state that (removed) Requests Collection for of HAHA anonymised samples extracts section will removed be made according to Text added to the protocol to state that patients who do not give consent Definition to of the end tissuebank of trial updated can still for take clarity part in the main part of the trial Assessment of treatment failure 3 iv changed to record failure as a reduction Clarification of 0.3 text LogMar for ocular units co-morbidities added Secondary endpoint development of anti-adalimumab antibody samples SAE reporting removed contact details updated

157 V2.0 30/09/2011 amended to V3.0 25/04/2013 Substantial Amendment 7 Page Number Section Change Made N/A N/A Contact details removed for TMG, IDSMC and TSC members Throughout Throughout References to sections updated following the removal of section 1 for contact details. Throughout Throughout References to Abbott changed to AbbVie Window for treatment visits changed from -3/+3 days to -7/+7 days Table updated to remove CSRI questionnaire at visits other than baseline Timeline for TB assessment changed from 4 weeks to 12 weeks prior to baseline Clarification given that Haematological samples from screening can be used at randomisation Clarification given that Biochemical samples from screening can be used at randomisation Clarification that a Markov model of treatment of treatment effect on JIA will be developed Phone number and fax numbers updated for SAE reporting. N/A N/A Appendix A Trial management group composition removed. V1.1 08/09/2011 amended to V2.0 30/09/2011 Substantial Amendment 2 Page Number Section Change made Throughout Throughout Throughout Throughout Front page Header amended to update version and date Change BioBank references to Tissue Bank Addition of ISRCTN number Pharmacist contact details changed to Amy Holloway Definition of 1 month treatment added to end of section Point 1 i wording changed to state 2 step increase from baseline Point 1 iii addition of no improvement from baseline Point 1 V grade score range changed from to 1-2 Addition of point 3 suspension of study treatment Clarification of treatment failure added at the end of section Text changed to read AC cell scores >/= Changed from previously failed Adalimumab to previously received Addition of exclusion points 20 and 21 Addition of instructions for patient to be followed up after withdrawal Point 6 reference to screening more than 3 times has been removed Addition of the use of back up randomisation envelopes at site Point 3, dose range changed to 10-20mg/m 2 Addition of date allowances regarding injection dates Addition of information regarding treatment suspension

158 Added information regarding allowances for visit dates Table 1 changed schedule for completion of CSRI Point 1 dose range changed to 10-20mg/m 2 Point 3,3 text has been expanded to provide more detail Dose range changed to 10-20mg/m 2 Dose range changed to 10-20mg/m 2 Re wording of section to refer to tissue bank instead of Tissue Bank Point 1 i wording changed to state 2 step increase from baseline Point 1 iii addition of no improvement from baseline Point 1 V grade score range changed from to 1-2 Addition of point 3 suspension of study treatment Clarification of treatment failure added at the end of section Statement added regarding unblinding analysis V1.0 25/02/2011 amended to V1.1 08/09/2011 Minor Amendment 1 Page Number Section Change made Throughout Throughout Header amended to update version and date 6 1 Statistician changed from Lynne Cresswell to Andrew McKay 7 1 Trial steering committee member changed from Simon Harding to Carlos Pavesio Point 1 iii typographical error corrected to add a / in between sustatined and development Point 1 iv and v have been reversed so that points 1 i-iv refer to endpoints after 3 months and point v refers to endpoints after 6 months Point 2 ii intraocular pressure has been changed from <25mm Hg to >25mm Hg Points 2 ii, 2 iii, and 2 iv have been changed from stating intervals from over 1 month to intervals over 2 consecutive visits Points 6 d and e have been deleted so that references to visual angle have been removed from the protocol Point 4 wording has been changed to remove reference to Adalimumab and state no Disease modifying immunosuppressive drugs, other than MTX, in the 4 weeks prior to screening Points 4, 5, 7 and 14 have been changed from collecting data prior to randomisation to collecting data prior to screening Points 2 ii, 2 iii, and 2 iv have been changed from stating intervals from over 1 month to intervals over 2 consecutive visits Points 1 iii typographical error corrected to add a / in between sustatined and development Points 6 d and e have been deleted so that references to visual angle have been removed from the protocol

159 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 A Randomised Controlled Trial of the Clinical Effectiveness, SafetY and Cost Effectiveness of Adalimumab in Combination with MethOtRExate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis (SYCAMORE) Eudract Number Funding reference Numbers: HTA 09/51/01 / ARUK Sponsor Reference: CH/2008/3061 Trial registration: ISRCTN Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data Name Title ORIGINATED BY QC PERFORMED BY APPROVED BY Andrew McKay Anna Rosala-Hallas (primary) Ashley Jones Michaela Blundell (safety) Trial Statistician QC Statisticians Supervising Statistician Date Version /09/2015 Protocol Version This document has been written based on information contained in the study protocol version 6.0, dated 17/04/2015. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 1 of 46

160 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Authors roles and responsibility Name Affiliation Role Mr Andrew McKay Clinical Trials Research Centre (CTRC), Trial Statistician (AM) University of Liverpool Dr Ashley Jones (AJ) Clinical Trials Research Centre (CTRC), Senior Trial Statistician University of Liverpool Ms Anna Rosala- Hallas (ARH) Clinical Trials Research Centre (CTRC), University of Liverpool Quality Control Statistician (primary outcome analysis) Ms Michaela Blundell Clinical Trials Research Centre (CTRC), Quality Control Statistician (MB) Prof Athimalaipet Vaidyanathan Ramanan (AVR) Prof Michael Beresford (MWB) Prof Andrew Dick (AD) Prof Paula Williamson (PW) Prof Caroline Doré (CD) University of Liverpool Consultant Paediatric Rheumatologist, Department of Paediatric Rheumatology, Bristol Royal Hospital for Children Brough Chair, Professor of Child Health, Honorary Consultant Paediatric Rheumatologist, University of Liverpool Professor of Ophthalmology, Academic Department of Ophthalmology, University of Bristol Clinical Trials Research Centre (CTRC), University of Liverpool Head of Statistics, Comprehensive Clinical Trials Unit, University College London (safety analysis) Co-Chief Investigator Co-Chief Investigator Ophthalmology expert on Trial Management Group Director of CTRC, University of Liverpool Independent statistical review of this statistical analysis plan AM and AJ proposed the statistical analysis plan. AM drafted the manuscript. AM, AJ, ARH, MB, AVR, MWB, AD, PW and CD read and provided comment on the statistical analysis plan. AM, AJ, MB approved the statistical analysis plan. Change Control Updated SAP version no. IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* Section number changed 8.1 Primary Outcome 12 Patient groups for analysis 14.1 Adverse reactions / events 15.2 Analysis of primary outcome Description of change Updated to match latest version of the SYCAMORE trial protocol (v4.1 created 11/08/2014). Clarification that analysis will be conducted on all patients randomised to the treatment groups that have had their randomisation CRF input into the database. Added detail to describe the tasks the quality control statistician will perform for the safety analyses. Definition added for the upper limit for the 18-month window to assess the patients that withdrew for treatment failure during follow-up. In the summary table of the missing primary outcome data table, splitting the missing data numbers into data Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 2 of 46 Date changed 26/02/15 AM 26/02/15 AM 26/02/15 AM Initials 26/02/15 AM

161 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary 15.3 Quality control of Primary outcome analysis 17 Analyses of missing data / withdrawals missing waiting for a response from site and data unobtainable site confirmed missing. Added detail as to how the patients that withdrew will be assessed for treatment failure. Addition of three sensitivity analyses ( best-case, worst case, and methotrexate including withdrawals due to methotrexate intolerance as treatment failures). The hazard ratio with 95% and 99.9% confidence intervals will now be along with the p-value obtained from the logrank test Added detail to describe the tasks the quality control statistician will perform for the primary outcome analyses. Split the text in this section into 3 subsections: 17.1 Missing primary outcome data, 17.2 Analysis of withdrawals and 17.3 Sensitivity analyses for primary outcome. 1. Introduction Updated text to be for final analysis for blinded data comparison of primary outcome and safety data rather than interim analysis. 3.2 Interim analysis 6.1 Representativeness of study sample and patient throughput 6.2 Baseline comparability of randomised groups 7. Follow up assessments 8.1 Primary Outcome 26/02/15 AM 26/02/15 AM 07/09/15 AM Further detail added on stopping rule used 07/09/15 AM Addition of screening data summary, recruitment summary and recruitment graph. Key baseline characteristics to be summarised this time. These have been listed, defined as categorical/continuous and specified how to be summarised. Maximum and minimum values will be presented instead of range for continuous baseline variables. Further crosses added to the Client Service Receipt Inventory (CRSI) row in the study assessment visits table for months 3, 6, 9, 12, 15, 18, 24. This was an oversight in the protocol and will be updated next time a protocol amendment is submitted. Updated to match latest version of the SYCAMORE trial protocol (v6.0 created 17/04/2015). 07/09/15 AM 07/09/15 AM 07/09/15 AM 07/09/15 AM Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 3 of 46

162 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ 9 Description of compliance with treatment 11. Unblinding of randomised treatments 12. Patient groups for analysis 13. Protocol deviations 14.1 Adverse reactions/events 15.1 Stopping guidelines 15.2 Analysis of primary outcome Added text to state will describe withdrawals from treatment as line listings and that they will still contribute data to the primary outcome analysis. Details of the patients that were unblinded during the trial will not be provided in this report except for those that failed treatment/had an SAE and were unblinded as these will be detailed in the treatment failure/sae line listings described in sections 15.2 and Removal of the text This analysis will be conducted on all patients randomised to the treatment groups that have had their randomisation CRF input into the database as all data on database for final analysis. Further clarity as to how cross-overs will be handles in the analysis of safety data. Monitoring plan version number added (v1.0 06/11/2013). Minor/Major/Any protocol deviation summary sentence separated for clarity. Clarifying that just the SAE data from the final report will be used for the analysis rather than copying any missing data from earlier reports. Replacement of text to say: The stopping guidelines that were pre-planned to use for the interim analysis presented to the IDSMC at the 25 th March 2015 meeting are detailed within section 15.1 Stopping guidelines of the IDSMC 25Mar2015 v1.0 statistical analysis plan. For those patients that enter the trial eligible with both eyes, time to first eye to fail will be used. The follow-up for the primary analysis will stop after this blinded assessment for all patients affected due to this to ensure that the two randomised groups remain comparable. Those patients that reached 18 months follow-up prior to this IDSMC and TSC decision will be unaffected so will have all follow-up data up to 18 months included. Rewording of Patients who are still in Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 4 of 46 07/09/15 AM 07/09/15 AM 07/09/15 AM 07/09/15 AM 07/09/15 AM 07/09/15 AM 07/09/15 AM

163 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 follow up at the time of the interim analysis: censored at last follow up visit to say Patients who are still on trial treatment at the time of unblinding: censored at the unblinding visit. Addition of text Assessment of treatment failure during the follow-up phase for patients that withdrew from treatment prior to the 18-month followup visit is described in section 17.2 for clarity. Time points of primary outcome data collection listed. Time interval between consecutive visits for assessment of treatment failure described. Addition of text to describe how to identify study eye(s) and which AC cells scores to use as the baseline score. Treatment failure is only assessed in study eye(s). This was done for previous interim analyses but text added here for clarity. Reasons for treatment failure will also be presented as a bar chart. Removal of 99.9% confidence intervals for the hazard ratio as no Haybittel- Peto stopping rule required. Just the 95% confidence interval will be presented. Additional text to describe how the proportional hazards assumption will be checked and if violated then a timedependent covariate will be added to a Cox model. Hypotheses to be tested and significance level added. Text added around regression models to further investigate the outcome between the two groups. Heterogeneity of treatment effects by centre will be considered in a graphical display by means of a Forest plot split by site. A summary table will be presented to show whether or not uveitis subsequently developed in the nonstudy eye. A secondary analysis will be carried out that includes information on whether both eyes failed treatment or not at any time during the 18-month treatment failure assessment period regardless of how many eyes they were eligible for Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 5 of 46

164 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ 17.3 Sensitivity analyses for primary outcome Appendix C Appendix E the trial with. Six further sensitivity analyses to undertake added and described. List of protocol deviations updated to include all inclusion/exclusion criteria. Addition of a list of rules to be applied for missing data in sensitivity analysis (7) 07/09/15 AM 07/09/15 AM 07/09/15 AM * Previous IDSMC SAP was IDSMC 29Sep2014 v1.0 $ Previous SAP was IDSMC 25Mar2015 v1.0 Table of Contents Authors roles and responsibility... 2 Change Control... 2 Table of Contents... 6 Table of Figures Introduction Definitions Study design and objectives Sample size calculations Interim analysis Study Outcomes Primary Outcome Secondary Outcomes Inclusion / Exclusion Criteria Inclusion Criteria Exclusion Criteria Description of study population Representativeness of study sample and patient throughput Baseline comparability of randomised groups Completeness of follow-up Follow up assessments Study Outcomes Primary Outcome Secondary Outcomes Description of compliance with treatment Trial monitoring Unblinding of randomised treatments Patient groups for analysis Protocol deviations Description of safety outcomes Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 6 of 46

165 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Adverse reactions/events Other safety signs Analysis of primary efficacy outcome Stopping guidelines Analysis of primary outcome Quality control of Primary outcome analysis Analysis of secondary efficacy outcomes Analyses of missing data / withdrawals Missing primary outcome data Analysis of withdrawals Sensitivity analyses for primary outcome Setting results in context of previous research References Approval and agreement Appendix A: Recommendations from TSC following 25Mar2015 interim analysis results report Appendix B: CONSORT 2010 flow diagram Appendix C: Protocol deviations Appendix D: Primary outcome component checks Appendix E: List of rules to be applied for missing data in sensitivity analysis (7) Table of Figures Table 1: Study visits and assessments Table 2: Protocol deviations table Table 3: Primary outcome component checks i Table 4: Primary outcome component checks ii Table 5: List of rules to be applied for missing data in sensitivity analysis (7) Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 7 of 46

166 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Introduction This Statistical Analysis Plan (SAP) provides a detailed and comprehensive description of the pre-planned final analysis for blinded data comparison of primary outcome and safety data for the study SYCAMORE: A Randomised Controlled Trial of the Clinical Effectiveness, Safety and Cost Effectiveness of Adalimumab in Combination with Methotrexate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis. This study is carried out in accordance with the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989) and South Africa (1996) amendments and will be conducted in compliance with the protocol, Clinical Trials Research Centre (CTRC) Clinical Trials Unit (CTU) Standard Operating Procedures (SOPs) and EU Directive 2001/20/EC, transposed into UK law as the UK Statutory Instrument 2004 No 1031: Medicines for Human Use (Clinical Trials) Regulations This planned analysis will be performed by the trial statistician and the results will be described in a confidential statistical analysis report. All analyses are performed with standard statistical software (SAS version 9.3 or later). The finalised analysis datasets, programs and outputs will be archived following Good Clinical Practice guidelines and SOP TM021 Archiving procedure in CTRC. The testing and validation of the statistical analysis programs will be performed following SOP ST Definitions AC AE CI CMO CONSORT CRF CTRC IDSMC IOP IQR ITT kg MTX OCT PDF PI PP QC RF SAE SAP SD SUSAR Anterior-chamber Adverse event Confidence interval Cystoid macular oedema Consolidated Standards of Reporting Trials Case report form Clinical Trials Research Centre Independent Data and Safety Monitoring Committee Intraocular pressure Inter-quartile range Intention-to-treat Kilogram Methotrexate Optical Coherence Tomography Portable document format Principal Investigator Per-protocol Quality control Rheumatoid factor Serious adverse event Statistical Analysis Plan Standard deviation Suspected Unexpected Serious Adverse Reactions Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 8 of 46

167 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 SYCAMORE TMG TSC A Randomised Controlled Trial of the Clinical Effectiveness, Safety and Cost Effectiveness of Adalimumab in Combination with Methotrexate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis Trial Management Group Trial Steering Committee 3. Study design and objectives This study is a prospective, multi-centre, randomised, double-blind, placebo-controlled, superiority study of adalimumab in combination with methotrexate (MTX) in patients with active uveitis in association with JIA refractory to MTX monotherapy. The study is conducted in sixteen centres throughout the United Kingdom. The primary objective of this study is to compare the clinical effectiveness of adalimumab in combination with methotrexate (MTX) versus MTX alone, with regard to controlling disease activity in refractory uveitis associated with juvenile idiopathic arthritis (JIA). The secondary objectives of this study are: To evaluate short term safety and tolerability of adalimumab in combination with MTX versus MTX alone, with regards ocular complications of treatment, adverse events and laboratory assessments To determine quality of life and cost effectiveness of adalimumab in combination with MTX versus MTX alone in severe uveitis associated with JIA To determine the clinical effectiveness of adalimumab in combination with MTX versus MTX alone, with regard underlying JIA disease activity To determine the durability and magnitude of adalimumab efficacy response in sustaining inactive disease and achieving complete clinical remission To determine the long term safety of adalimumab in combination with MTX versus MTX alone To assess the efficacy of treatment with adalimumab to permit concomitant medication reduction, in particular regional and parenteral steroids To develop a fully consented, trial-related Tissue Bank for collection of serum, DNA and RNA for subsequent investigation Randomisation Participants are stratified by centre and randomised in a 2:1 ratio in favour of the active therapy between the two groups: 1) 2 weekly s/c injections adalimumab, plus MTX 2) 2 weekly s/c injections placebo plus MTX. Separate randomisation lists have been generated for each centre in STATA using block randomisation with random variable block length. Randomisation and treatment commencement should occur within 2 weeks of the screening visit. Randomisation is undertaken during normal working hours (Monday Friday ) by the pharmacy departments of participating centres upon receipt of a randomisation Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 9 of 46

168 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 request form and prescription from authorised clinicians. Pharmacy personnel verify that these documents are appropriately completed before proceeding. Randomisation is completed using a secure (24-hour) web based randomisation programme. The lists incorporated random elements and are controlled centrally by the MCRN CTU; both measures are to ensure allocation concealment. Designated pharmacy staff have been issued with personal login and password details to conduct randomisation. Blinding IMPs are supplied as bulk stock from the distributor to pharmacy in kits. Pharmacy must ensure that the participant and the researcher remain blinded to the treatment allocation. The statistician needs to define the analysis population as per section 12 before obtaining the treatment allocations. 3.1 Sample size calculations Sample size calculations were undertaken using NQuery Advisor software version 4.0. Original and revised sample size calculations are included. Sample size revisions were necessary due to lower patient availability than expected. a. Original trial sample size calculation The original sample size was based on data on failure rates from 62 patients on MTX in a comparable population provided by Dr C Edelsten, Great Ormond Street Hospital. After three months 11 patients had disease control based on Grade 0 SUN criteria (18%) and therefore based on the trial inclusion criteria would not be eligible for the trial. At 15 months following the start of treatment with MTX, 23 patients of the 51 who had failed at 3 months had achieved disease control (45%), leaving 28 (55%) who had not. To detect a relative reduction of 50% between a failure rate of 60% to 30% with 90% power (there is unlikely to be a trial of this nature again in the near future and therefore we have increased the power to 90% from the conventional power of 80% to optimise the detection of a significant difference between treatment regimes if one truly exists) at a 5% significance level, using a 2:1 randomisation a total of 140 patients (93 adalimumab, 47 placebo) are required. A trial of adalimumab in JIA with or without MTX powered the study using a 40% absolute (57% relative) difference in the rate of flare between the placebo and the adalimumab groups 1. The advent of biological therapies in JIA has led international investigators to a paradigm shift in the treatment of JIA and its related complications, leading to significantly more ambitious outcomes in clinical trials, including elimination of inflammation and normalisation of short-term and long-term function 2, 3. To this end, in JIA, instead of previously accepted clinical outcomes of 30% absolute difference in outcome between active agent and placebo 4, increasingly significant differences are being expected and regarded as significant, with new definitions of response being established for use in clinical trials such as clinical remission and minimal disease activity 5, 6. Indeed, 40% of patients in the adalimumab-jia trial were reported as showing an ACR Pedi 100% response (100% response rate) at 2 years 40. The clinically relevant outcomes of JIA-uveitis may take years to develop and the relationship between isolated measures of clinical activity and long term outcomes remains ill defined. Recent studies do suggest that the length of continuously controlled activity is likely to be of more clinical relevance than short term improvements in levels of activity. In view of these factors, as well as the expectation expressed unanimously through consumer consultation in the development of this trial protocol, we have set a minimum 50% relative difference in failure rate between interventions. Based on the nature of the disease Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 10 of 46

169 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 resulting potentially in loss of vision and a meeting of investigators representing participating centres, as well as consumer representatives, and their experience of compliance from current usage of biologic therapies in JIA-uveitis, it is estimated that loss to follow up will be approximately 10%. Therefore we have increased the sample size by approximately 10% to allow for this, giving a total number of patients 154 (102 adalimumab, 52 placebo). The null hypothesis underlying this trial is that there is no significant difference between adalimumab and placebo in controlling disease activity of JIA-associated uveitis unresponsive to MTX therapy. b. Revised sample size calculation for the primary outcome The original sample size calculation had a power of 90% but given the issues that have been faced during recruitment, reducing power to what is a universally accepted convention of 80% power would maintain the status of this trial as an internationally relevant and robust contribution to the evidence base for the safety of this intervention. This we know will be both acceptable to patients/families and clinicians, and would enable the sample size to be markedly reduced, and therefore more feasible within a reasonable period. Furthermore, by September 2013 there had only been one patient who had withdrawn and refused to provide primary outcome data and therefore it would be reasonable to assume that the original assumption of adding 10% to the sample size calculation to account for missing data can be reduced to 5%. The total sample size (including 5% drop out) that is required to detect the difference between a placebo proportion of 0.6 and treatment group proportion of 0.3 (with 0.05 twosided significance level) is Interim analysis Interim monitoring reports of the accumulating data were performed at regular intervals (at least annually) for review by the Independent Data Monitoring and Safety Committee (IDSMC). For the interim analysis of the primary outcome, the Peto-Heybittle stopping rule was applied. This required an extreme p-value of p<0.001 as evidence to stop for benefit. This approach allowed the ISDMC flexibility with the number and timings of further analyses based on current safety and efficacy data as it has the added benefit of preserving an overall two sided type I error of 0.05 for the final analysis 7 The recommendations from TSC following 25Mar2015 interim analysis results report are provided in Appendix A of this SAP. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 11 of 46

170 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Study Outcomes 4.1 Primary Outcome The primary endpoint is time to treatment failure. See section 8.1 for definition. 4.2 Secondary Outcomes 1) Number of participants failing treatment 2) Incremental cost-effectiveness and cost-utility of adalimumab added to MTX compared with MTX alone 3) Health status according to the multi-attribute health utility index, HUI2 4) Safety, tolerability and compliance a. Adverse events (AEs) and serious adverse events (SAEs) b. Laboratory parameters (haematological and biochemical analysis and urinalysis c. Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period 5) Use of Corticosteroids over duration of study period and throughout follow up, including: a. Total oral corticosteroid dose b. Reduction in and rate of systemic corticosteroid dose from entry dose c. Topical corticosteroid use (frequency) compared to entry usage d. Need for pulsed corticosteroid 6) Optic and ocular a. Number of participants having disease flares (as defined by worsening on SUN criteria) following minimum 3 months disease control b. Number of participants having disease flares within the first 3 months. c. Visual acuity measured by Age-appropriate LogMAR assessment d. Number of participants with resolution of associated optic nerve or macular oedema (as assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) (where available). e. Number of participants with disease control (defined as zero cells, with topical treatment for 3 and 6 months) f. Number of participants entering disease remission (defined as zero cells, without topical treatment for 3 and 6 months) g. Duration of sustaining inactive disease (zero cells, with or without topical treatment) 7) Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ)) 8) American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels (see section of the SYCAMORE trial protocol) 9) Number of participants undergoing disease flare, in remission on and off medication (Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004; 31: ) of their JIA and with minimum disease activity (Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, Cugno C, Bozzola E, Martini A, Ravelli A. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Rheum 2008; 59: ) 10) Number participants requiring change in biologic / Disease-modifying anti-rheumatic drugs (DMARDs) therapy due to failure to respond from arthritis Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 12 of 46

171 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Inclusion / Exclusion Criteria 5.1 Inclusion Criteria A participant is eligible for the trial based upon at least one eye fulfilling the eligibility criteria 1) Children and young people aged 2 and <18 years fulfilling ILAR diagnostic criteria for JIA (all subgroups that have uveitis). 2) At the time of trial screening the participant must have active anterior uveitis, defined as a sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade >1+ or more during the preceding 12 weeks therapy despite MTX and corticosteroid (both systemic and topical) therapy. The latest date of SUN grade score must be the date of the screening visit. 3) They must have failed MTX (minimum dose of 10-20mg/m2, with a maximum dose of 25mg/participant). The participant must have been on MTX for at least 12 weeks* and have been on a stable dose for 4 weeks prior to screening visit. 4) No Disease modifying immunosuppressive drugs, other than MTX, in the 4 weeks prior to screening 5) Written informed consent of participant or parent/legal guardian, and assent where appropriate. 6) Participant and parent/legal guardian willing and able to comply with protocol requirements. 7) For participants of reproductive potential (males and females), use of a reliable means of contraception throughout their trial participation. Post pubertal females must have a negative serum pregnancy test within 10 days before the first dose of trial drug. 8) Able to be randomised and commence trial treatment within 2 weeks of the screening visit. * Omission of a maximum of 2 weeks methotrexate treatment within the 12 weeks is acceptable and will not render the patient ineligible unless they have been missed in the 4 weeks prior to the screening visit. 5.2 Exclusion Criteria 1) Uveitis without a diagnosis of JIA 2) Currently on adalimumab or has previously received adalimumab. 3) Have been on other biologic agent within previous 5 half-lives of agent (For other biologic agents and their wash out periods, (refer to protocol supplementary document #10) 4) More than 6 topical steroid eye drops per eye, per day prior to screening (this dose must have been stable for at least 4 weeks prior to screening visit) 5) For patients on Prednisone or Prednisone equivalent, change of dose within 30 days prior to screening 6) For patients on Prednisone or Prednisone equivalent with a dose >0.2mg/kg per day 7) Intra-articular joint injections within four weeks prior to screening 8) Any ongoing chronic or active infection (including infective uveitis) or any major episode of infection requiring hospitalisation or treatment with intravenous antibiotics within 30 days or oral antibiotics within 14 days prior to the screening evaluation 9) History of active tuberculosis of less than 6 months treatment or untreated latent TB 10) Participant has history of central nervous system (CNS) neoplasm, active CNS infection, demyelinating disease, or any progressive or degenerative neurological disease 11) Poorly controlled diabetes or persistently poorly controlled severe hypertension (>95th percentile for height / age) as deemed by the treating physician Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 13 of 46

172 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ ) Previous history of malignancy 13) Intraocular surgery within the 3 months prior to screening (cataract/ glaucoma/ vitrectomy) 14) Intra-ocular or peri-ocular corticosteroids within 30 days prior to screening. 15) History of ocular herpetic disease 16) Pregnant or nursing female 17) Demonstrations of clinically significant deviations in any of the following laboratory parameters: a. Platelet count < 100,000/mm3 b. Total white cell count < 4000 cells/mm3 c. Neutrophils < 1000 cells/mm3 d. AST or ALT > 2 x upper limit of normal (ULN) or serum bilirubin > 2x the ULN e. Glomerular filtration rate (GFR) of < 90 ml/min/1.73m2 [GFR (ml.min/1.73 m2 BSA) = 0.55 x height (cm)/plasma creatinine (mg/dl)] f. Hematocrit <24% 18) Having been administered a live or attenuated vaccine within three months prior to screening 19) Previous randomisation into the SYCAMORE trial to either arm of the trial. 20) Intra-ocular pressure <6mm Hg or Intra-ocular pressure > 25mm Hg 21) Intra-ocular pressure control requiring more than one topical pressure lowering therapy or requiring systemic acetazolamide 6. Description of study population 6.1 Representativeness of study sample and patient throughput A CONSORT [1] flow diagram (Appendix B) will be used to summarise the number of patients who were: assessed for eligibility at screening o eligible at screening o ineligible at screening* eligible and randomised eligible but not randomised* received the randomised allocation did not receive the randomised allocation* lost to follow-up* discontinued the intervention* randomised and included in the primary analysis randomised and excluded from the primary analysis* *reasons will be provided. Screening logs will be summarised by site with numbers of patients not eligible, eligible and not randomised and randomised presented with reasons given (including reasons for nonconsent) where available. Other free-text reasons will be summarised appropriately. A recruitment summary table will be presented showing the following for each centre: centre code, hospital name, dates site opened/closed to recruitment, dates of first/last randomisation and total number randomised. A recruitment graph will also be presented displaying the cumulative recruitment, cumulative target recruitment and number of sites open to recruitment for each month from the trial opening to closing recruitment. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 14 of 46

173 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Baseline comparability of randomised groups Patients in each treatment group (adalimumab and placebo) will be described with respect to the following: Vital signs: weight (<30kg, 30kg) # Physician global assessment of disease activity # Auto anti-body screen: Anti-nuclear antibody (ANA) $1, Double-stranded deoxyribonucleic acid (DsDNA) $1, Rheumatoid factor $1 Type of JIA: ILAR classification $2 Vision assessment: LogMAR score # Slit lamp examination [in study eye(s)]: o Test: AC cells (SUN) $3, flare score (SUN) $3, o LOCS III Grading: pseudophakic $4, nuclear $5, cortical $6, posterior $7 o Other Structural Changes: central band-keratopathy covering visual axis $4, synchiae $4, iris bombe $4, membrane formation $4, neovascularisation $4 Intraocular pressure # [in study eye(s)] Fundoscopy examination [in study eye(s)]: o Test: Vitreous Haze Grading $3 # Continuous $1 Categorical: Positive/Negative/Not Done $2 Categorical: Systemic arthritis, Persistent oligoarthritis, Extended oligoarthritis, Polyarthritis RF positive, Polyarthritis RF negative, Psoriatic arthritis, Enthesitis-related arthritis, Undifferentiated arthritis $3 Categorical: 0/0.5+/1+/2+/3+/4+ $4 Categorical: Yes/No $5 Categorical: N0/NI/NII/NIII $6 Categorical: Ctr/CI/CII/CIII/CIV/Aphakic or Pseudophakic/No Cortical Cataract $7 Categorical: O/PI/PII/PIII Note: Reasons for any tests not being done will be summarised if provided. Categorical data will be summarised by numbers and percentages. Continuous data will be summarised by mean, SD and range (maximum and minimum values) if data are normal and median, IQR and range if data are skewed. Minimum and maximum values will also be presented for continuous data. Tests of statistical significance will not be undertaken for baseline characteristics; rather the clinical importance of any imbalance will be noted. 6.3 Completeness of follow-up Completeness of follow-up will be presented in the form of a CONSORT flow diagram. See section 6.1 for details. The number lost to follow up within each treatment group will be reported and the reasons where known will be documented. Any deaths and their causes will be reported separately. 7. Follow up assessments The schedule of study procedures is given in the Table 1 below. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 15 of 46

174 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 TABLE 1: STUDY VISITS AND ASSESSMENTS Time (months) 0^ Screening* Randomisation & commence treatment Written informed consent X Confirm consent (verbal) X X X X X X X X X X X X X X Assessment of Eligibility Criteria X X Review of Medical/ Opthalmic/ X Surgical History Review of Concomitant Medications X X X X X X X X X X X X X X X X X Pregnancy test (serum) (X) X X X X X X X Purified protein derivative (PPD) X Tuberculin Skin Test 1,2 / Test for latent TB as locally performed Microscopic urinalysis will be obtained at baseline and for other visits only if relevant abnormalities greater than trace are noted on the dipst Urinalysis 3 X X X X X X X X X X X X X X X X Randomisation X Study Intervention X X X X X X X X X Compliance with study intervention X X X X X X X X X Physical Exam - Complete X X X X X X X X X X X X X X X X Vital Signs (heart & Respiratory rate, X X X X X X X X X X X X X X X X temperature and blood pressure) Height X X X X X X X X X X X X X X X X Weight X X X X X X X X X X X X X X X X Childhood Health Questionnaire (CHQ) X X X X X X X X X Childhood Health Assessment Questionnaire (CHAQ) X X X X X X X X X Health Utilities Index 2 Questionnaire X X X X X X X X X Client Service Receipt Inventory (CSRI) X X X X X X X X Sample for DNA collection (X) (X) (X) RNA and Serum/plasma (X) (X) (X) Haematological analysis X X X X X X X X X X X X X X X X Biochemical analysis X X X X X X X X X X X X X X X X Samples for HAHA analyses ** X X ANA, dsdna and ENA X X Opthalmic assessments: Vision assessment X X X X X X X X X X X X X X X X Optical coherence tomography (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (optional) Assessment of vitritis X X X X X X X X X X X X X X X X Slit lamp bio-microscopy X X X X X X X X X X X X X X X X Cataract scoring X X X X X X X X X X X X X X X X Goldmann tonometry or tonopen X X X X X X X X X X X X X X X X Standard ACR Pedi Core Set outcome X X X X X X X X X X X X X X X X variables Tanner Score X X X X X X X X X X Review of Participant Diaries X X X X X X X X X X X X X X X (X) Assessment of Adverse Events X X X X X X X X X X X X X X X X ^ Visit 0 must be completed and treatment commenced within 14 days of the screening visit (10 days for pregnancy test) * All procedures should be done before study intervention. ** To be done also as required if anaphylaxis occurs during trial. (X) - As applicable/indicated/appropriate 1 Participants who are PPD positive at screening will require a chest x-ray. Treatment of participants who have a positive PPD skin test and/or abnormal chest x-ray should be in accordance with regional/national guidelines, and initiated at least 4 weeks prior to receiving the first dose of trial medication 2 Participants with recent (within 6 months of trial entry screen) positive PPD ( 5 mm) who are being treated with appropriate prophylaxis may request a waiver for a screening PPD from the MCRN CTU. Documentation of the positive PPD should be available as well as chest x-ray report from the date of the positive PPD and treatment/prophylaxis history from near the time of the participant s conversion. analysis. End of treatment End of trial Premature withdrawal Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 16 of 46

175 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Study Outcomes 8.1 Primary Outcome The primary outcome is time to treatment failure. At each treatment visit (1, 2, 3, 6, 9, 12, 15 and 18 months following randomisation) the participants are assessed for treatment failure. If there are any participants that come in for an unscheduled visit they are also assessed for treatment failure providing they have an eye assessment carried out. For participants that withdraw from treatment but remain in the trial, they are assessed for treatment failure at their follow-up visits (3, 6, 9, 12, 15, 18 months) so their data posttreatment withdrawal is able to be included in the ITT analysis. Treatment failure being defined by one or more of the following: 1) Anterior segment inflammatory score grade (SUN criteria) Following at least 3 months of therapy: i) 2-Step increase from baseline in SUN cell activity score (AC Cells) over 2 consecutive readings ii) Sustained non-improvement with entry grade of 3 or greater for 2 consecutive readings iii) Only partial improvement (1 grade) or no improvement, from baseline, with development of other ocular co-morbidity* which is sustained iv) Worsening of existing (on enrolment) ocular co-morbidity* after 3 months v) Sustained scores as recorded at entry grade measured over 2 consecutive readings (grades 1 to 2) still present after 6 months of therapy. 2) Use of Concomitant Medications: At any time, requirement to use concomitant medications in manner out with pre-defined acceptable criteria (see section of the SYCAMORE trial protocol), or any of the concomitant medications not allowed (see section of the SYCAMORE trial protocol) 3) Intermittent or continuous suspension of study treatment (adalimumab/placebo) for a cumulative period longer than 4 weeks * Ocular co-morbidities are defined as: i) Disc swelling and/or Cystoid Macular Oedema (CMO) as gauged clinically and where possible by OCT evidence; and/or: ii) Raised intraocular pressure (>25mm Hg) sustained over 2 consecutive visits not responding to single ocular hypotensive agent, and/or: iii) Hypotony (<6 mm Hg) sustained over 2 consecutive visits, and/or iv) Development of unexplained reduction in vision (LogMAR) over two consecutive visits of 0.3 LogMAR units (in the event of cataract participants will remain in trial, also if cataract surgery is required. Failure will still remain as described in endpoints above). N.B> Intraocular pressure >= 25 mmhg or < 6 mmhg are exclusion criteria at baseline and ocular co-morbidities i)-iv) can be developed during follow up only, i) may worsen based on the existing (on enrolment) ocular co-morbidity. Where a reading is required to be sustained over two consecutive visits to define treatment failure the time of treatment failure will be taken as the second of these readings. For determining treatment failure there should be in interval of at least four weeks between assessments. Form prepared: 07/09/2015 v1.0 SYCAMORE Study Page 17 of 46

176 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Secondary Outcomes There are no analyses of secondary outcomes in this report. A complete list of secondary outcomes is provided in section 4.2 for reference purposes. 9. Description of compliance with treatment Patients that withdrew from treatment will be presented as line listings detailing: randomisation number, site, date of randomisation, date of discontinuation, reason for discontinuation, further details and whether unblinded. They will still contribute data to the analysis of primary outcome. No further information will be included in this analysis report. 10. Trial monitoring SYCAMORE is monitored by an Independent Data and Safety Monitoring Committee (IDSMC). Please see section 3.2 for details. The SYCAMORE data monitoring plan includes details of ongoing central monitoring performed by TMG, TSC and ISDMC. 11. Unblinding of randomised treatments Details of the patients that were unblinded during the trial will not be provided in this report except for those that failed treatment/had an SAE and were unblinded as these will be detailed in the treatment failure/sae line listings described in sections 15.2 and Patient groups for analysis The principle of intention-to-treat, as far as is practically possible, will be the main strategy of the analysis adopted for the primary outcome. Patients that withdrew consent for trial continuation will contribute outcome data up until the point of withdrawal unless the patients parents/guardians specifically request that the data are not to be used. The membership of the analysis set for each outcome will be determined and documented and reasons for participant exclusion will be given prior to the blind being broken and the randomisation lists being requested. Reasons may include missing data, loss to follow up and treatment withdrawal. The safety analysis data set will contain all participants that are randomised and received at least one dose of trial medication. Participants AEs/SAEs will be included in the treatment group they were actually receiving at the time of AE/SAE onset to take into account any patients that crossed over from the placebo group to the adalimumab group for some reason and vice versa Patients to be excluded from the primary analysis population and the safety analysis population will be defined in template ST001TEM03 Protocol deviations and population exclusions template and this will be agreed and approved prior to any release of randomisation codes. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 18 of 46

177 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Protocol deviations Protocol deviations that will be reported are defined in the monitoring plan v1.0 06/11/2013 for the trial and also included in Appendix C of this analysis plan. All protocol deviations of the listed protocol specifications have been included in the trial monitoring reports presented overall and by site when numbers recruited per site are sufficient. Protocol deviations are classified prior to unblinding of treatment. All protocol deviations will be defined and signedoff using ST001TEM03 Protocol deviations and population exclusions template prior to unblinding. The number (and percentage) of patients with each separate protocol deviation will be presented in this analysis report along with the number (and percentage) of patients with (i) at least one major protocol deviation; (ii) at least one minor protocol deviation; and (iii) at least one protocol deviation of any classification (minor or major). These will also be summarised across site and in total by treatment group. No formal statistical treating will be undertaken. 14. Description of safety outcomes 14.1 Adverse reactions/events AEs are captured on the CRFs as free-text. These events are categorised by the trial statistician with Chief Investigator input and subsequently signed off by Chief Investigator once complete, prior to unblinding the patients included in the analysis. All adverse events (AEs) and serious adverse events (SAEs) will be presented, by treatment group and overall. No formal statistical testing will be undertaken. The safety population will be used for these summaries listed below. The number of events and number (and percentage) of patients experiencing each AE and a cross-tabulation of AE severity (mild, moderate, severe, missing) by relationship to study drug (unrelated, unlikely, possibly, probably, almost certainly, missing) will be presented. Further details of the AEs classed as possibly, probably or almost certainly related to study drug will be presented as line listings detailing AE type, severity, whether an SAE, whether withdrew from drug as a result of AE, action taken and outcome. Additionally, of the AEs that are classified as not resolved / ongoing their severities will be listed. Each SAE will be presented in the form of line listings detailing SAE number, AE description, seriousness, severity, expectedness, relationship, cause, whether withdrew from drug as a result of AE, outcome, patient status and whether unblinded. SAEs which are SUSARs will be identified as such. Further information about any SUSARs that are reported can be provided to the IDSMC at their request. Each SAE has an initial report done. If the SAE has not yet been resolved the resolved date is left blank. Later, a follow-up report or a final report captures the resolved date and final outcome. Therefore, the latest report will be taken and presented as the line listings. To ensure quality control, an independent statistician will follow this SAP to independently program the safety analysis from the raw data. Any discrepancies found will be discussed with the trial statistician to resolve. No programming will be shared or shown between the statisticians. The independent statistician will also check the report against their output. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 19 of 46

178 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Other safety signs There are no other safety signs to be reported. 15. Analysis of primary efficacy outcome 15.1 Stopping guidelines The stopping guidelines that were pre-planned to use for the interim analysis presented to the IDSMC at the 25 th March 2015 meeting are detailed within section 15.1 Stopping guidelines of the IDSMC 25Mar2015 v1.0 statistical analysis plan Analysis of primary outcome The primary endpoint is time to treatment failure. For those patients that enter the trial eligible with both eyes, time to first eye to fail will be used. Following the recommendations of the IDSMC and TSC (see Appendix A), randomisation was stopped in April 2015 and all patients who were randomised to placebo stopped their randomised treatment. All patients still within the treatment phase of the study at this time were invited to attend a blinded assessment before being unblinded. Therefore, the follow-up for the primary analysis will stop after this blinded assessment for all patients affected due to this to ensure that the two randomised groups remain comparable. Those patients that reached 18 months follow-up prior to this IDSMC and TSC decision will be unaffected so will have all follow-up data up to 18 months included. The primary analysis will use the principle of intention to treat based on all the randomised participants, as far as is practically possible (see section 12). If consent for treatment is withdrawn but the participant is happy to remain in the study for follow-up, they will be followed up until completion. However, if they decide to withdraw consent completely then the reasons for withdrawal of consent will be collected (if possible) and reported for both groups. Before analysing the data a series of primary outcome checks are to be performed (see Appendix D for details). The primary outcome of treatment failure is a time-to-event outcome. This will not be observed in all patients; those patients that do not observe an event will be classed as censored. The event time or censoring will be calculated by subtracting the randomisation date from one of the following scenarios: Participants that failed treatment: date of the visit in which they failed treatment. Participants that completed the trial treatment phase without failing treatment: censored at date of 18-month treatment visit. Participants that withdrew* and agreed to follow-up: o If they are assessed to be a treatment failure during a follow-up visit within 18-months* following randomisation: date of follow-up visit. o If they are not assessed to be a treatment failure during their follow-up visits: censored at date of last follow-up visit within 18-months # following randomisation. Participants that are lost to follow-up: censored date of last treatment visit. Patients who are still on trial treatment at the time of unblinding: censored at the unblinding visit. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 20 of 46

179 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 * Assessment of treatment failure during the follow-up phase for patients that withdrew from treatment prior to the 18-month follow-up visit is described in section # The upper limit for the 18-month window will be 612 days. As per trial protocol, doses of trial treatment (adalimumab/placebo) are to be taken every 14 days (±3 days see Treatment regime in Table 2) so therefore the upper limit for 18-month visit is 17 days * 2 (per month) * 18 months = 612 days. The visit to be taken will be the last follow-up visit prior to 612 days. A censoring indicator will be created for each trial participant as below: 1 if failed treatment censor = { 0 if censored Treatment failure is assessed at all scheduled treatment visits (1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months and 18 months). Patients that come in for unscheduled treatment visits will also be assessed for treatment failure. Treatment failure is not formally assessed during follow-up as the patients are no longer on trial treatment. The raw data for component 1 of the primary outcome is collected during follow-up (visits at 3 months, 6 months and pre SYCAMORE protocol V4.0 25/09/2013 also at 9 months, 12 months, 15 months and 18 months). Patients that withdrew from trial treatment prior to their 18 month visit and agree to be followed up are still assessed for treatment failure during the analysis (see section 17.2 for details). When assessing for treatment failure (section 8.1), where a reading is required to be sustained over two consecutive visits to define treatment failure the time of treatment failure will be taken as the second of these readings. For determining treatment failure there should be an interval of at least four weeks between assessments. According to section 10 of the SYCAMORE protocol v6.0 17/04/2015 there is an allowance of -7days/+7 days will be allowed for monthly visits and -15days/+15days for the 3 monthly visits. Therefore, for assessing treatment failure at the 3-month scheduled treatment visit (the first visit where the assessment for treatment failure requires consecutive visits) an interval of 5 weeks will be used to account for the allowance of 7 days. All scheduled treatment visits following the 3-month treatment visit are 3 monthly so the 4-week interval is sufficient. Unscheduled visits need to be taken into account when assessing treatment failure, if this was carried out at the unscheduled visit. If the interval is less than 4 weeks then the next previous visit that is at least 4 weeks prior will be used to assess treatment failure against the current visit. Patients will be assessed for treatment failure only on the study eye(s) that they entered the trial with. They can be eligible for the trial with either one or two eyes. To determine the study eye(s), according to the inclusion/exclusion CRF patients must have active anterior uveitis (at least one eye with sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade >1+ or more during the preceding 12 weeks therapy. The latest date must be at date of screening. However, prior to protocol V4.0 17/01/2014 the protocol did not state that patients must have a score of 1+ or more at the time of screening, it rather suggested that patients have two visits of 1+ or more during the last 12 weeks before screening. Protocol V4.0 17/01/2014 was updated to state that latest date of SUN grade score must be at date of screening. Therefore: (i) Patients that have eye(s) with sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade >1+ or more during the preceding 12 weeks therapy with the latest date being at date of screening, are eligible with these eye(s) and will have treatment failure assessed accordingly for these eye(s). Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 21 of 46

180 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 (ii) Patients that do not satisfy (i) because their two assessments were within the 12 weeks without the latest date being at date of screening, are still eligible with these eye(s) according to protocols prior to protocol V4.0 17/01/2014 and will have treatment failure assessed accordingly for these eye(s). For the study eye(s), the anterior chamber of SUN criteria grade obtained at the baseline visit will be used to assess for treatment failure. As the baseline visit can be carried out within 14 days following screening the scores may be different. If the score for the study eye(s) are then <1+ i.e. interring not eligible then the latest score used for the assessment for eligibility at screening will be used as the baseline value(s) to assess for treatment failure. The data for the ocular co-morbidity defined as Cystoid Macular Oedema (CMO) as gauged clinically and where possible by OCT evidence is collected through a fundoscopy assessment and/or OCT assessment. As OCT is more sensitive it can detect macular oedema that is not obvious on fundoscopy. Therefore, if there are conflicting results between fundoscopy and OCT then the OCT result will be used. Partway through the trial (22/052013), for patients that failed at a treatment visit had their treatment visit CRF completed along with a premature withdrawal visit CRF. This meant that there was a lot of duplication of data collected. Therefore, a check will be performed to identify which of the duplicated visits has AC cells data collected and this visit will be used but if both/neither have AC cells data the premature withdrawal visit will be used. Line listings for each participant that failed treatment will be presented detailing: randomisation number, site, date of randomisation, date of discontinuation, reason for treatment failure, further details and whether unblinded. Reasons for treatment failure will also be presented as a bar chart. A Kaplan-Meier plot will be constructed with separate curves for each treatment group and will be presented in the trial report. From inspection of the Kaplan-Meier plot the separation between the curves should remain proportional across analysis time. If the curves cross again this shows that the proportional hazards assumption has been violated. To put this formally, the proportional hazards assumption is that the ratio of hazards is a constant that does not depend on time: h A (t) h B (t) = r When this assumption fails, it is because the hazard ratio changes over time. To test this, we will add predictor for group*time interaction i.e. a time-dependent covariate. Evidence that group*time interaction is not zero is evidence against proportional hazards. In SAS, PROC PHREG provides the p-value of this test. p<0.05 will indicate non-proportional hazards and thus a time-dependent covariate will be included in the Cox model. If p 0.05 survival estimates will be calculated using the method of Kaplan-Meier. In both situations, survival estimates will be calculated using the method of Kaplan and Meier with curves for each treatment group presented graphically with numbers at risk. Survival times will be measured from the date of randomisation to the date of treatment failure as identified above. The p-value obtained from the log-rank test and also the hazard ratio with 95% confidence interval will be used to assess differences in failure estimates across treatment groups. The null hypothesis is that there is no difference in outcome between the adalimumab and placebo treatment groups. The alternative hypothesis is that there is a difference between the two treatment groups. The 2-sided significance level of 0.05 will be used to indicate statistical significance for the comparison between the two treatment groups. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 22 of 46

181 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 The development of co-morbidity influence on treatment failure will be further explored split by treatment group: Co-morbidity* Cataracts IOP Macular oedema Visual acuity (LogMAR scores) Definition Identified through an adverse event report Raised IOP, hypotony or either Any macular oedema (not just cystoid) Development of unexplained reduction in vision over two consecutive visits of 0.3 LogMAR units from baseline as per definition within primary outcome? Those that satisfy component 1 of the primary outcome - particularly those that had 2 step increase in AC score. Eye inflammation (AC cells scores) * Set up as binary variables Yes/No for whether they developed these at any point during the time period that primary outcome was assessed for the primary analysis. ICH E9 states that In some trials there may be no reason to expect the centres to have any influence on the primary or secondary variables because they are unlikely to represent influences of clinical importance. In other trials the limited number of subjects per centre will make it impracticable to include centre effects in the statistical model [10] (3). Heterogeneity of treatment effects by centre will be considered in a graphical display by means of a Forest plot split by site. Of those patients that entered into the trial with one eligible study eye, a summary table will be presented to show whether or not uveitis subsequently developed in the non-study eye. An AC cells score of 1+ or more indicates the presence of uveitis. A secondary analysis will be carried out that includes information on whether both eyes failed treatment or not at any time during the 18-month treatment failure assessment period regardless of how many eyes they were eligible for the trial with. As defined above, the upper limit for the 18-month window will be 612 days. A binary variable will be included in the Cox model as follows: Study eye Eye that failed within the 18-month treatment failure assessment period Right or Left or Both None 0 Right 0 Left 0 Both Quality control of Primary outcome analysis Definition for covariate in Cox model To ensure quality control, an independent statistician will follow this SAP to independently program the primary analysis from the raw data. Any discrepancies found will be discussed with the trial statistician to resolve. No programming will be shared or shown between the statisticians. The independent statistician will also check the report against their output. 16. Analysis of secondary efficacy outcomes There will be no analysis of secondary outcome data presented in this report. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 23 of 46

182 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Analyses of missing data / withdrawals 17.1 Missing primary outcome data A summary table of the missing data from the separate assessments that feed into the primary outcome (disc swelling, CMO, OCT, IOP, vision assessment, AC cells, compliance question, conmeds question, suspension of treatment question) will be presented detailing the proportion of unobtainable assessments overall and for each visit split by each site Analysis of withdrawals Participants that withdraw from trial treatment, providing they do not withdraw from the entire study or withdraw consent they move to the follow-up phase of the trial where they are still assessed for primary outcome so therefore can still contribute to the ITT analysis. The assessments will be as follows: (1) Component 1 (Anterior segment inflammatory score grade SUN criteria): SUN scores and data to determine ocular co-morbidities are still collected at follow-up visits following withdrawal from treatment so this component can be assessed. (2) Component 2 (Use of Concomitant Medications) are not collected past treatment withdrawal so this component cannot be assessed (3) Component 3 (Intermittent or continuous suspension of study treatment) cannot be assessed following withdrawal from treatment as they are no longer on treatment. Any participants that withdraw from follow-up will contribute primary outcome data until the point at which they withdrew Sensitivity analyses for primary outcome The following sensitivity analyses will be conducted: (1) Best-case: All participants that have withdrawn from treatment will be treated as censored at time of treatment withdrawal. (2) Worst case: All participants that have withdrawn from treatment will be treated as treatment failures i.e. events at time of treatment withdrawal. (3) Methotrexate*: Any participants that withdrew from treatment due to methotrexate intolerance will be classified as treatment failures at the time of treatment withdrawal with those that withdrew for other reasons continued to follow up and assessed for treatment failure as per the primary analysis. (4) Component 1 # : All patients that fail for component 1 at a treatment failure assessment will have their event date as the mid-point between this visit and previous visit instead of the date of this visit. (5) Component 2: All patients that fail for component 2 at a treatment failure assessment will have their event date as the date that they commenced on the concomitant medications (i) used against pre-defined acceptable criteria (see section of the SYCAMORE trial protocol), or (ii) any of the concomitant medications not allowed (see section of the SYCAMORE trial protocol). The event date will be determined by the Chief Investigator making a clinical decision following review of the patients concomitant medications taken since their previous visit. This will be documented accordingly. (6) Component 3: All patients that fail for component 3 at a treatment failure assessment will have their event date as the exact date that they qualified as Intermittent or continuous suspension of study treatment (adalimumab/placebo) for a cumulative Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 24 of 46

183 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 period longer than 4 weeks. The event date will be determined by the Chief Investigator making a clinical decision following review of the patients trial treatment dose recordings in the treatment diaries. This will be documented accordingly. (7) Any missing primary outcome data $ : Any cases of missing data for any of the primary outcome components (except for unscheduled visits) will have data imputed on a worst-case basis and will be listed in a table by whether they had a treatment failure or not. A list of rules is provided in Appendix E. All patients will be treated the same regardless of whether they have had a treatment failure or not. Therefore, it is possible that patients that were a treatment failure, if they have missing data prior to this point they could fail treatment earlier. (8) Loss to follow-up: In the primary analysis of primary outcome we have classed the patients that are lost to follow-up as withdrawals assuming that they are noninformative. The reasons for loss to follow-up, where available, will be blindly reviewed by Prof Michael Beresford (Co-Chief Investigator) and Prof Andrew Dick (Ophthalmology expert on TMG) to see to see whether they think any might be related to prognosis. If any are deemed to be related, a sensitivity analysis will be undertaken assuming these patients to be a treatment failure at the time of last recorded visit. (9) Incorrectly identified to be a treatment failure: Once a patient has been deemed to be a treatment failure, treatment is stopped and they enter the follow-up phase of the study providing they still wish to be followed up. If there are any patients that were wrongly identified to be treatment failures by the assessing physician they will be classed as a withdrawal at their time of treatment failure. * This sensitivity analysis has been chosen because the usage of methotrexate section of the original trial protocol stated that methotrexate withdrawal would be classified as a treatment failure even though this was not stated as a component of the primary outcome. # This sensitivity analysis has been chosen because patients that fail treatment for component 1 at their treatment failure assessment could have in fact failed treatment prior to their visit but have only been assessed at this point. This has since been removed and is now not stated in the current up-to-date version of the trial protocol. $ This sensitivity analysis will require intense coding and given the current timelines of the analysis being completed and reported by September 2015 this will not be ready. We will therefore aim to have this sensitivity analysis completed by December Setting results in context of previous research Once the trial has been completed the results of the trial will be set in context of the existing evidence base. 19. References 1. Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. New England Journal of Medicine. 2008;359(8): Beresford MW, Baildam EM. New advances in the management of juvenile idiopathic arthritis--1: Non-biological therapy. Archives of disease in childhood-education & practice edition. 2009;94(5): Ilowite NT. Update on biologics in juvenile idiopathic arthritis. Current Opinion in Rheumatology. 2008;20(5): Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, Wouters C, et al. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 25 of 46

184 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 polyarticular-course juvenile rheumatoid arthritis. Arthritis & Rheumatism. 2007;56(9): Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, Cugno C, et al. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Care & Research. 2008;59(8): Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. Journal of Rheumatology. 2004;31(11): Pocock SJ. Current controversies in data monitoring for clinical trials. Clinical Trials. 2006;3(6): Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Ann Int Med 2010;152. Epub 24 March. 9. ICH, E3. Chapter 12 in "Structure and content of clinical study reports". International Conference on Harmonisation ICH, E9. Chapter 3 in "Statistical Principles for Clinical Trials". International Conference on Harmonisation SAS 9.3 for Windows ed: SAS Institute Inc. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 26 of 46

185 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Approval and agreement Two versions of the SAP should be approved. 1. SAP version 1.0 should be created after it has been reviewed and signed-off to ensure all are in agreement with the planned analysis and no further changes are foreseen. 2. The final SAP version should be converted to PDF and signed following the blinded review for protocol deviations and immediately prior to database lock as evidence of the analysis planned prior to unblinding of the study. SAP Version Number being approved: Trial Statistician Name Signed Date Senior Statistician or Head of Statistics Name Signed Date Chief Investigator Name Signed OR Electronic approval attached Date Chair of Trial Steering Committee Name Signed Date OR Electronic approval attached OR TSC not reviewing SAP (ensure agreement is documented) Chair of Data Monitoring Committee Name Signed Date OR Electronic approval attached OR IDSMC not reviewing SAP (ensure agreement is documented) Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 27 of 46

186 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Appendix A: Recommendations from TSC following 25Mar2015 interim analysis results report Summary of recommendations made by TSC to TMG of Prof. Ian Bruce to Chief Investigators, 17 th April 2015: In follow-up to our TCs today and in advance of the minutes being made available, I am writing to formally record the unanimous decision and recommendation of the SYCAMORE TSC after receiving a unanimous recommendation from the IDSMC. We recommend the following: 1. That recruitment to SYCAMORE should cease at this point. This is based on a clear positive signal of efficacy of the IMP vs placebo that exceeded the pre-specified P value of P<0.001 as laid down in the Analysis Plan. We and the IDSMC are satisfied that this result is of sufficient importance to influence a real change in clinical practice. 2. That the blinded trial should be stopped and the results of the trial made public at the earliest opportunity. Of course this should be done in an organised fashion that allows final blinded close-out assessments to be undertaken to complete the blinded dataset. This should happen at the earliest opportunity, which is feasible and logistically possible for child / family and clinical team (not waiting necessarily for the next formal study visit) 3. Finally we strongly recommend that there is continuing follow-up of these children in an open-label fashion, initially in their assigned groups and that this long-term follow-up will contribute important additional data on quality of life, utilities, long-term efficacy etc. Of course subsequent changes in therapy would be at the discretion of the treating clinical team. We see this as an enormous opportunity for added value to be gained from the trial and study programme. I would once again emphasize the unanimous nature of our recommendations and I am happy for you to share this information/ with the TMG. We as a TSC will continue to be available to you and the TMG to provide any additional advice or support. Form prepared: 07/09/2015 v1.0 SYCAMORE Study Page 28 of 46

187 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Appendix B: CONSORT 2010 flow diagram Enrolment Assessed for eligibility (n= ) Excluded (n= ) Not meeting inclusion criteria (n= ) Declined to participate (n= ) Other reasons (n= ) Randomized (n= ) Allocated to intervention (n= ) Received allocated intervention (n= ) Did not receive allocated intervention (give reasons) (n= ) Allocation Allocated to intervention (n= ) Received allocated intervention (n= ) Did not receive allocated intervention (give reasons) (n= ) Lost to follow-up (give reasons) (n= ) Discontinued intervention (give reasons) (n= ) Follow-Up Lost to follow-up (give reasons) (n= ) Discontinued intervention (give reasons) (n= ) Analysed (n= ) Excluded from analysis (give reasons) (n= ) Analysis Analysed (n= ) Excluded from analysis (give reasons) (n= ) Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 29 of 46

188 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Appendix C: Protocol deviations The following table lists potential deviations of important protocol specifications, including eligibility criteria, treatment regimens and study assessments. The occurrence of these deviations will be monitored during central monitoring using the approach listed in the table. Note: 1. Impact refers to the impact of the potential protocol deviation on the risk of introducing bias in the trial results, increasing the risk of harm to the participant as a result of their condition or its treatment or a violation of patient rights. Any increased risk of harm or violation of patient rights will be graded as major. For the risk of introducing bias, impact will be graded as: major (in which case patients who experience this protocol deviation would be excluded from the per protocol analysis set) minor (in which case patients who experience this protocol deviation would be included in the per protocol analysis set) 2. Justification refers to the protocol-specific justification for the assessment of the impact of each potential protocol deviation. Justification may relate to statistical concerns of bias, generalisability, loss of power or to participant safety in reference to the inherent risks in standard medical care or patient rights and wellbeing. All protocol deviations of the listed protocol specifications will be included in the trial monitoring reports and IDSMC reports and presented overall and by site when numbers recruited per site are sufficient. TABLE 2: PROTOCOL DEVIATIONS TABLE Protocol specification Inclusion criteria Potential deviation(s) Impact Justification Age range 2 and 18 years At the time of trial screening the participant must have active anterior uveitis. Outside age range Uveitis not active but patient randomised Major Major Potential impact on safety, for patients <2 years Potential impact on efficacy results therefore possibly incorporating bias. Active anterior uveitis defined as a sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade >1+ or more during the preceding 12 weeks therapy despite MTX and corticosteroid (both systemic and topical) therapy. The latest date of SUN grade score must be the date of the screening visit. Two measurements taken more than 12 weeks apart Major Potential impact on efficacy results therefore possibly incorporating bias. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 30 of 46

189 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Failed MTX. The participant must have been on MTX for at least 12 weeks and have been on a stable dose for 4 weeks prior to screening visit. Potential deviation(s) No MTX use or not stable for 4 weeks Impact Major Justification Potential impact on safety No Disease modifying immunosuppressive drugs, other than MTX, in the 4 weeks prior to screening (as checked against Eligibility and Randomisation CRF only) Use of immunosuppressi ve drugs in previous 4 weeks of screening Major Potential impact on efficacy results therefore possibly incorporating bias. Written informed consent of participant or parent/legal guardian, and assent where appropriate No consent is provided Major Violation of patient s rights Participant and parent/legal guardian willing and able to comply with protocol requirements (as checked against Eligibility and Randomisation CRF only) Use of reliable means of contraceptive (male and females of reproductive potential) (as checked against Eligibility and Randomisation CRF only) and post pubertal females must have negative serum pregnancy text Participant and parent/legal guardian are unable to comply with the requirements as set out in the protocol. Not using reliable means of contraceptive or positive pregnancy test Pregnancy test not within 10 days prior to commencement of first dose of IMP Major Major Major Potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety if medication is used incorrectly. Statistical concerns none Potential impact on patient safety Statistical concerns none Potential impact on patient safety Able to be randomised and commence treatment within two weeks of screening Treatment is unable to be commenced within two weeks of screening Major Potential impact on patient safety Exclusion criteria Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 31 of 46

190 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Uveitis without a diagnosis of JIA (as checked against Eligibility and Randomisation CRF only) Potential deviation(s) Patients without both Uveitis and JIA are randomised Impact Major Justification Inclusion of patients without a diagnosis of JIA and therefore potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety Currently on adalimumab or previously received adalimumab (as checked against Eligibility and Randomisation CRF only) Inclusion of patients who have had previous exposure to adalimumab Major Potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety Have been on other biologic agent within previous five halflives of agent (as checked against Eligibility and Randomisation CRF only) Use of biologic outside of acceptable time window Major Potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety More than 6 topical steroid eye drops per day prior to screening (this dose must have been stable for at least 4 weeks prior to screening visit) Patients on Prednisone (or equivalent ) with a dose >0.2mg/kg per day Intra-articular joint injections within four weeks of screening (as checked against Eligibility and Randomisation CRF only) Any ongoing chronic or active infection (including infective uveitis) or any major episode of infection requiring hospitalisation or treatment with intravenous antibiotics within 30 days or oral antibiotics within 14 days prior to the screening evaluation (as checked against Eligibility and Randomisation CRF only) History of active tuberculosis of less than 6 months treatment or untreated latent TB Incorrect run in dosage for steroidal eye drops Disallowed medication dosage used Intra-articular joint injection use in previous four weeks to Major Major Major Potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety. Potential impact on patient safety. Potential impact on patient safety. screening. Recent infection Major Potential impact on patient safety. Recent infection Major Potential impact on patient safety. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 32 of 46

191 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Participant has history of central nervous system (CNS) neoplasm, active CNS infection, demyelinating disease, or any progressive or degenerative neurological disease (as checked against Eligibility and Randomisation CRF only) Poorly controlled diabetes or persistently poorly controlled severe hypertension (as checked against Eligibility and Randomisation CRF only) Previous history of malignancy (as checked against Eligibility and Randomisation CRF only) Intraocular surgery within the 3 months prior to screening (as checked against Eligibility and Randomisation CRF only) Intra-ocular or peri-ocular corticosteroids within 30 days prior to screening (as checked against Eligibility and Randomisation CRF only) Potential deviation(s) History of CNS neoplasm Poorly controlled diabetes History of malignancy Impact Major Major Major Justification Potential impact on patient safety. Potential impact on patient safety. Potential impact on patient safety. Recent surgery Major Potential impact on patient safety. Use of ocular corticosteroids outside permitted time window Major Potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety History of ocular herpetic disease (as checked against Eligibility and Randomisation CRF only) Pregnant or nursing female (as checked against Eligibility and Randomisation CRF only) Patient has history of ocular herpetic disease Positive pregnancy test Major Major Potential impact on patient safety Potential impact on patient safety Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 33 of 46

192 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Demonstrations of clinically significant deviations in any of the following laboratory parameters: a) Platelet count < 100,000/mm 3 b) Total white cell count < 4000 cells/mm 3 c) Neutrophils < 1000 cells/mm 3 d) AST or ALT > 2 x upper limit of normal (ULN) or serum bilirubin > 2x the ULN e) Glomerular filtration rate (GFR) of < 90 ml/min/1.73m 2 [GFR (ml.min/1.73 m 2 BSA) = 0.55 x height (cm)/plasma creatinine (mg/dl)] f) Hematocrit <24% Potential deviation(s) Out of range laboratory parameters Impact Major Justification Potential impact on patient safety (as checked against Eligibility and Randomisation CRF only) Administration of a live or attenuated vaccine within three months prior to screening (as checked against Eligibility and Randomisation CRF only) Previous randomisation into SYCAMORE trial. (as checked against Eligibility and Randomisation CRF only) Intra-ocular pressure <6mm Hg or >25mm Hg (as checked against Eligibility and Randomisation CRF only) Patient has received vaccine out of permitted time frame Second randomisation into trial Out of range intra-ocular pressure Major Major Major Potential impact on patient safety Statistical concern: Results from the same individual will not be independent Safety concern: Patient may receive previously ineffective treatment Potential impact on efficacy results therefore possibly incorporating bias Intra-ocular pressure control requiring more than one topical pressure lowering therapy or requiring systemic acetazolamide (as checked against Eligibility and Randomisation CRF only) Treatment regime Patient has received therapy that is not permitted Major Potential impact on patient safety Potential impact on efficacy results therefore possibly incorporating bias Potential impact on patient safety Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 34 of 46

193 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Treatment compliance (one vial [0.8mL] per fortnight +/-3 days) Potential deviation(s) Use of nonspecified protocol dosing regime Impact Major Justification Impact on generalisability of trial results as well as potentially patient safety Withdrawal from treatment due to safety Withdrawal from treatment due to other reason Use of non-permitted medications (see protocol page 31 for details) Study assessments Premature discontinuation of randomised treatment Premature discontinuation of randomised treatment Uses disallowed concomitant medications Major Major Major Risk of bias if withdrawal rates differ by trial arm - major as would impact on interpretation of primary outcome. Overall withdrawal due to safety monitored in open IDSMC and TMR and by treatment arm in closed IDSMC Missing data will impact on efficacy results and potentially on power of study Impact on generalisability of trial results as well as potentially patient safety Scheduled treatment visits at 1,2,3,6,9,12 and 18 months Missing visits Major Potential issue for primary outcome as treatment failure may have occurred and exact date will be missed, which is used to calculate the time-to endpoint. Scheduled treatment visits at 1,2 and 3 months Visits occur outside +/-3 day window of visit date Major Safety issue with respect to missed visits as patients will not have any trial treatment to administer until they next attend. No issue for primary outcome as it is a time-to endpoint therefore the visit date will be used to calculate this. Potential safety issue with respect to visits after the allowable window as patients will not have any trial treatment administered within the required timeframe from the previous administration. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 35 of 46

194 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Scheduled treatment visits at 6,9,12 and 18 months Potential deviation(s) Visits occur outside +/-15 day window of visit date Impact Major Justification No issue for primary outcome as it is a time-to endpoint therefore the visit date will be used to calculate this. Scheduled follow up visits at 21, 24, 27, 30, 33 and 36 months (or equivalent if withdrawn from treatment early) Scheduled follow up visits at 21, 24, 27, 30, 33 and 36 months (or equivalent if withdrawn from treatment Potential safety issue with respect to visits after the allowable window as patients will not have any trial treatment administered within the required timeframe from the previous administration Missed visits Major Potential safety issue with respect to identifying adverse events in a timely manner Visits occur outside +/-15 day window of visit date Major Potential safety issue with respect to late visits for identifying adverse events in a timely manner early) Missing primary efficacy data Missing data Major Missing data will impact on efficacy results and correct/timely definition of treatment failure therefore possibly incorporating bias. Power of study may be affected. Missing secondary/other efficacy data Missing data Minor Missing data will impact on secondary efficacy results Missing safety data Missing data Major Potential impact on patient safety Protocol specified assessment tools not used Equipment/tools other than those specified in protocol used to perform assessments Major Impact on generalisability of results Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 36 of 46

195 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Appendix D: Primary outcome component checks TABLE 3: PRIMARY OUTCOME COMPONENT CHECKS I Ocular co-morbidities (All assessed for each study eye separately) Worsening of existing ocular comorbidity Cystoid Macular Oedema Disc swelling Development of new ocular comorbidity Cystoid Macular Oedema Disc swelling CRF Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Start assessing from which visit? Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 3 (3 months) Treatment visit 3 (3 months) Treatment visit 3 (3 months) Raw data location Section of CRF Optical Coherence Tomography (OCT) Fundoscopy Fundoscopy Optical Coherence Tomography (OCT) Fundoscopy Fundoscopy Question(s) 1. Macular oedema present? 2. If yes, is this Cystoid? 3. If yes, has this worsened since baseline? 1. Macular oedema present? 2. If yes, is this Cystoid? 3. If yes, has this worsened since baseline? 1. Presence of disc swelling? 2. If yes, has this worsened since baseline? 1. Macular oedema present? 2. If yes, is this Cystoid? Cross check the same variables for previous visits to make sure no earlier occurrences 1. Macular oedema present? 2. If yes, is this Cystoid? Cross check the same variables for previous visits to make sure no earlier occurrences Presence of disc swelling? and cross check the same variable for previous Form prepared: 07/09/2015 v1.0 SYCAMORE Study Page 37 of 46

196 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Intraocular pressure Previous visit intraocular pressure Current intraocular pressure Raised pressure (>25mmHg) over 2 consecutive visits Hypotony (<6mmHg) over 2 consecutive visits Vision assessment Previous visit change from baseline Current visit change from baseline Unexplained and sustained reduction of 15 letters or more over 2 consecutive readings? Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Intraocular pressure Intraocular pressure Intraocular pressure Intraocular pressure Vision assessment Vision assessment Vision assessment visits to make sure no earlier occurrences 1. Test conducted? 2. Intraocular pressure Cross-check value against previous visit 1. Test conducted? 2. Intraocular pressure Cross-check value against current visit 1. Test conducted? 2. Intraocular pressure Cross-check values against current and previous visit to see whether both are >25mmHG 1. Test conducted? 2. Intraocular pressure Cross-check values against current and previous visit to see whether both are <6mmHG 1. LogMAR score Cross-check values from previous visit and baseline and then calculate the difference and compare 1. LogMAR score Cross-check values from current visit and baseline and then calculate the difference and compare Calculate the LogMAR scores based on the number of letters recorded and also the chart type used Check that the changes in LogMAR score calculated for the two checks below reach the same conclusion as the Y/N for this question Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 38 of 46

197 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Summary Any new or worsened ocular comorbidity? (Any of above criteria ticked Yes ) N/A Treatment visit 3 (3 months) Note: remember to take into account unscheduled visits N/A Check all selected Y/N in this Ocular co-morbidities table give the correct Y/N for this question TABLE 4: PRIMARY OUTCOME COMPONENT CHECKS II Failure criteria [recorded for each study eye] SUN cell activity score [L/R] Baseline AC cells score Previous visit AC cells score Current AC cells score Increase in SUN cell activity score from baseline by 2-steps sustained over 2 consecutive readings [L/R] Baseline SUN cell activity score of 3+ or more without improvement over 2 consecutive readings [L/R] Partial improvement (1 grade) or no improvement, from baseline in SUN cell activity score plus CRF Treatment/Follow-up visit Treatment/Follow-up visit Treatment/Follow-up visit Treatment/Follow-up visit Treatment/Follow-up visit Treatment/Follow-up visit Raw data location Start assessing Section of CRF from which visit? Treatment visit 3 (3 months) Treatment visit 3 (3 months) Treatment visit 3 (3 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 3 (3 months) Slit lamp examination Slit lamp examination Slit lamp examination Slit lamp examination Slit lamp examination Slit lamp examination & ocular co- Question(s) 1. AC cells Cross-check value against baseline visit 1. AC cells Cross-check value against previous visit 1. AC cells Cross-check value against current visit 1. AC cells Cross-check current and previous visit values against baseline visit to see whether both are 2-steps up from baseline AC cells reading 1. AC cells Cross-check current and previous visit values against baseline If baseline visit AC cells score is 3+ check to see whether both reading are AC cells 2. Any new or worsened ocular comorbidity? Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 39 of 46

198 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 sustained/development of co-morbidity (see table above) [L/R] Sustained baseline score of 1+ or 2+ over 2 consecutive readings after 6 months of treatment [L/R] Worsening of existing ocular comorbidity (see table above) [L/R] Permitted concomitant medications used against acceptable criteria as defined in the protocol [standalone Q] Concomitant medication used that are not allowed as defined in the protocol [standalone Q] Intermittent or continuous suspension of study treatment (adalimumab/placebo) for a cumulative period longer than 4 weeks [standalone Q] Treatment failure (Any of above criteria ticked Yes ) [L/R] Treatment/Follow-up visit Treatment/Follow-up visit Treatment visit 5 (12 months) Treatment visit 4 (6 months) Conmeds Treatment visit 1 (1 month) Conmeds Treatment visit 1 (1 month) 1. Treatment/Followup visit 2. Treatment diary Treatment/Follow-up visit Treatment visit 1 (1 month) Treatment visit 1 (1 month) morbidities Cross-check current visit values against baseline If no improvement or improvement of 1 grade from baseline visit AC cells score then check to see whether there is sustained/development of a comorbidity Slit lamp 1. AC cells examination Cross-check current and previous visit values against baseline If baseline visit AC cells score is 1+ or 2+ check to see whether both Ocular comorbidities Conmed type Conmed type 1. Participant in compliance with trial intervention 2. Study treatment dates All questions in Failure criteria reading are the same Worsening of existing ocular comorbidity questions Cross check conmed type against list of permitted concomitant medications used against acceptable criteria as defined in the protocol to identify any cases Cross check conmed type against list of concomitant medication used that are not allowed as defined in the protocol to identify any cases 1. Cross check to see whether yes / no selected corresponds 2. Check study treatment dates to identify intermittent or continuous suspension Check if any failure criteria are ticked yes that treatment failure is ticked Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 40 of 46

199 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 table yes L/R = Separate questions to assess for each eye Standalone Q = One question (not assessed for each eye separately) Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 41 of 46

200 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Appendix E: List of rules to be applied for missing data in sensitivity analysis (7) Note: For all of the situations for missing data below, for each patient the overall treatment failure will be the earliest occurrence of one. TABLE 5: LIST OF RULES TO BE APPLIED FOR MISSING DATA IN SENSITIVITY ANALYSIS (7) Component number 1)i) 1)ii) 1)iii) Component description Following at least 3 months of therapy: 2-Step increase from baseline in SUN cell activity score (AC Cells) over 2 consecutive readings Following at least 3 months of therapy: Sustained nonimprovement with entry grade of 3 or greater for 2 consecutive readings Following at least 3 months of therapy: Only partial Rule to handle missing data post-baseline in the study eye(s) For visits at 3 months or later, if missing AC cells score follows or precedes a visit that has a 2- step increase then assume this is also a 2-step increase so this will be a treatment failure for 1)i) at the second of the consecutive visits. For visits at 3 months or later, for those that enter the trial with a baseline score of 3+ or 4+: If missing AC cells score follows or precedes a visit that is 3+ or 4+ then assume this is also 3+ or 4+ so this will be a treatment failure for 1)ii) at the second of the consecutive visits. Scenario (1): For visits at 3 months or later, if there is partial Examples Baseline Month 2 Month 3 a 1+ b. 3+ or 4+ b 1+ b 3+ or 4+ b. a: This visit can be at Month 3 or later. b: Baseline score could be any of 1+, 2+, 3+, 4+ and at least a 2-step increase is assessed for 1)i). This situation would be a treatment failure for 1)i) at month 3. Baseline Month 6 Month 9 a 3+ or or or or 4+. a: This visit can be at Month 3 or later. This situation would be a treatment failure for 1)ii) at month 9. Disc swelling/macular oedema (DS/MO): Baseline Month 9 Month 12 a Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 42 of 46

201 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Component number Component description improvement (1 grade) or no improvement, from baseline, with development of other ocular co-morbidity* which is sustained Rule to handle missing data post-baseline in the study eye(s) improvement (1 grade) or no improvement from baseline & the development of other ocular co-morbidity has missing data at this visit or the previous visit (when one of the visits satisfies the criteria for the other ocular co-morbidity) then this will be a treatment failure for 1)iii) at the second of the consecutive visits i.e. this visit. Scenario (2): For visits at 3 months or later, if there is a missing AC score at this visit & the development of other ocular co-morbidity is satisfied over consecutive visits (this visit and previous visit) then this will be a treatment failure for 1)iii) at the second of the consecutive visits i.e. this visit. Examples (1) (2) AC cells score Presence of DS or MO AC cells score Presence of DS or MO 1+ b N/A c 0.5+ or 1+ b No. Yes d No Yes d. 1+ b N/A c. No Yes d Yes a: This visit can be at Month 3 or later. b: Baseline score could be any of 1+, 2+, 3+, 4+ and partial improvement (1 grade) or no improvement from baseline is assessed at subsequent visits. c: Score not needed to assess for 1)iii). d: This must be the first occurrence of DS/MO. These situations for scenario (1) and scenario (2) would be a treatment failure for 1)iii)DS/MO at month 12. Hypotony (IOP <6mmHg) or Raised IOP (IOP >25mmHg): Baseline Month 12 Month 15 a AC cells 2+ (1) N/A c 1+ or 2+ b score IOP No d. <6 score <6 No d <6. IOP No d. >25 score No d >25. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 43 of 46

202 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Component number Component description Rule to handle missing data post-baseline in the study eye(s) Examples >25 AC cells 2+ (2) N/A c. score IOP No d <6 <6 score <6 IOP score >25 No d >25 >25 a: This visit can be at Month 3 or later. b: Baseline score could be any of 1+, 2+, 3+, 4+ and partial improvement (1 grade) or no improvement from baseline is assessed at subsequent visits. c: Score not needed to assess for 1)iii). d: All patients cannot have at baseline. These situations for scenario (1) and scenario (2) would be a treatment failure for 1)iii)Hypotony/Raised IOP at month 15. Development of unexplained reduction in vision (LogMAR): Baseline Month 15 Month 18 a AC cells 3+ (1) b N/A c 2+ or 3+ b score LogMAR Any score score. A reduced score of 0.3 LogMAR units or more from baseline score Any A reduced. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 44 of 46

203 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Component number Component description Rule to handle missing data post-baseline in the study eye(s) Examples (2) AC cells score LogMAR score score score of 0.3 LogMAR units or more from baseline score 3+ b N/A c. Any score A reduced score of 0.3 LogMAR units or more from baseline score A reduced score of 0.3 LogMAR units or more from baseline score a: This visit can be at Month 3 or later. b: Baseline score could be any of 1+, 2+, 3+, 4+ and partial improvement (1 grade) or no improvement from baseline is assessed at subsequent visits. c: Score not needed to assess for 1)iii). 1)iv) Following at least 3 months of therapy: Worsening of existing (on enrolment) ocular comorbidity* after 3 months For visits at 3 months or later, for those that enter the trial with Yes selected for presence of disc swelling/macular oedema if at a later visit they have worsening of existing disc swelling/macular oedema missing they will be a treatment failure at this visit for worsening of existing (on enrolment) ocular These situations for scenario (1) and scenario (2) would be a treatment failure for 1)iii) Development of unexplained reduction in vision at month 18. No example required. Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 45 of 46

204 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Component number 1)v) Component description Sustained scores as recorded at entry grade measured over 2 consecutive readings (grades 1 to 2) still present after 6 months of therapy Rule to handle missing data post-baseline in the study eye(s) co-morbidity* after 3 months. For visits at 6 months or later, for those that enter the trial with a baseline score of 1+ or 2+: If missing AC cells score follows or precedes a visit that is 1+ or 2+ then assume this is also 1+ or 2+ so this will be a treatment failure for 1)v) at the second of the consecutive visits. Examples Baseline Month 6 Month 9 a , 2+, 3+ or , 3+ or a: This visit can be at Month 6 or later. This situation would be a treatment failure for 1)v) at month 9. * Ocular co-morbidities are defined as: i) Disc swelling and/or Cystoid Macular Oedema (CMO) as gauged clinically and where possible by OCT evidence; and/or: ii) Raised intraocular pressure (>25mm Hg) sustained over 2 consecutive visits not responding to single ocular hypotensive agent, and/or: iii) Hypotony (<6 mm Hg) sustained over 2 consecutive visits, and/or iv) Development of unexplained reduction in vision (LogMAR) over two consecutive visits of 0.3 LogMAR units (in the event of cataract participants will remain in trial, also if cataract surgery is required. Failure will still remain as described in endpoints above). Form prepared: 07/09/2015 v1.0 for SYCAMORE Study Page 46 of 46

205 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 A Randomised Controlled Trial of the Clinical Effectiveness, SafetY and Cost Effectiveness of Adalimumab in Combination with MethOtRExate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis (SYCAMORE) Eudract Number Funding reference Numbers: HTA 09/51/01 / ARUK Sponsor Reference: CH/2008/3061 Trial registration: ISRCTN Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data Name Title ORIGINATED BY QC PERFORMED BY APPROVED BY Andrew McKay Anna Rosala-Hallas (primary) Ashley Jones Michaela Blundell (safety) Trial Statistician QC Statisticians Supervising Statistician Date Version /10/2016 Protocol Version This document has been written based on information contained in the study protocol version 6.1, dated 14/07/2016. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 1 of 52

206 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Authors roles and responsibility Name Affiliation Role Mr Andrew McKay Clinical Trials Research Centre (CTRC), Trial Statistician (AM) University of Liverpool Dr Ashley Jones (AJ) Clinical Trials Research Centre (CTRC), Senior Trial Statistician University of Liverpool Ms Anna Rosala- Hallas (ARH) Clinical Trials Research Centre (CTRC), University of Liverpool Quality Control Statistician (primary outcome analysis) Ms Michaela Blundell Clinical Trials Research Centre (CTRC), Quality Control Statistician (MB) Prof Athimalaipet Vaidyanathan Ramanan (AVR) Prof Michael Beresford (MWB) Prof Andrew Dick (AD) Prof Paula Williamson (PW) Prof Caroline Doré (CD) University of Liverpool Consultant Paediatric Rheumatologist, Department of Paediatric Rheumatology, Bristol Royal Hospital for Children Brough Chair, Professor of Child Health, Honorary Consultant Paediatric Rheumatologist, University of Liverpool Professor of Ophthalmology, Academic Department of Ophthalmology, University of Bristol Clinical Trials Research Centre (CTRC), University of Liverpool Head of Statistics, Comprehensive Clinical Trials Unit, University College London (safety analysis) Co-Chief Investigator Co-Chief Investigator Ophthalmology expert on Trial Management Group Director of CTRC, University of Liverpool Independent statistical review of this statistical analysis plan AM and AJ proposed the statistical analysis plan (Version 1.0, 2.0 & 3.0). AM drafted the manuscript (Version 1.0, 2.0 & 3.0). AM, AJ, ARH, MB, AVR, MWB, AD, PW and CD read and provided comment on the statistical analysis plan (Version 1.0). AM, AJ, MB, AVR approved the statistical analysis plan (Version 1.0, 2.0 & 3.0). Change Control Updated SAP version no. IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* Section number changed 8.1 Primary Outcome 12 Patient groups for analysis 14.1 Adverse reactions / events 15.2 Analysis of primary outcome Description of change Updated to match latest version of the SYCAMORE trial protocol (v4.1 created 11/08/2014). Clarification that analysis will be conducted on all patients randomised to the treatment groups that have had their randomisation CRF input into the database. Added detail to describe the tasks the quality control statistician will perform for the safety analyses. Definition added for the upper limit for the 18-month window to assess the patients that withdrew for treatment failure during follow-up. In the summary table of the missing primary outcome data table, splitting Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 2 of 52 Date changed 26/02/15 AM 26/02/15 AM 26/02/15 AM Initials 26/02/15 AM

207 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Updated SAP version no. IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* IDSMC 25Mar2015 v1.0* Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Section number changed 15.3 Quality control of Primary outcome analysis 17 Analyses of missing data / withdrawals Description of change the missing data numbers into data missing waiting for a response from site and data unobtainable site confirmed missing. Added detail as to how the patients that withdrew will be assessed for treatment failure. Addition of three sensitivity analyses ( best-case, worst case, and methotrexate including withdrawals due to methotrexate intolerance as treatment failures). The hazard ratio with 95% and 99.9% confidence intervals will now be along with the p-value obtained from the logrank test Added detail to describe the tasks the quality control statistician will perform for the primary outcome analyses. Split the text in this section into 3 subsections: 17.1 Missing primary outcome data, 17.2 Analysis of withdrawals and 17.3 Sensitivity analyses for primary outcome. 1. Introduction Updated text to be for final analysis for blinded data comparison of primary outcome and safety data rather than interim analysis. 3.2 Interim analysis 6.1 Representativeness of study sample and patient throughput 6.2 Baseline comparability of randomised groups 7. Follow up assessments Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 3 of 52 Date changed 26/02/15 AM 26/02/15 AM 07/09/15 AM Further detail added on stopping rule used 07/09/15 AM Addition of screening data summary, recruitment summary and recruitment graph. Key baseline characteristics to be summarised this time. These have been listed, defined as categorical/continuous and specified how to be summarised. Maximum and minimum values will be presented instead of range for continuous baseline variables. Further crosses added to the Client Service Receipt Inventory (CRSI) row in the study assessment visits table for months 3, 6, 9, 12, 15, 18, 24. This was an oversight in the protocol and will be updated next time a protocol amendment is submitted. 07/09/15 AM 07/09/15 AM Initials 07/09/15 AM

208 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Updated SAP version no. Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Section number changed 8.1 Primary Outcome 9 Description of compliance with treatment 11. Unblinding of randomised treatments 12. Patient groups for analysis 13. Protocol deviations 14.1 Adverse reactions/events 15.1 Stopping guidelines 15.2 Analysis of primary outcome Description of change Updated to match latest version of the SYCAMORE trial protocol (v6.0 created 17/04/2015). Added text to state will describe withdrawals from treatment as line listings and that they will still contribute data to the primary outcome analysis. Details of the patients that were unblinded during the trial will not be provided in this report except for those that failed treatment/had an SAE and were unblinded as these will be detailed in the treatment failure/sae line listings described in sections 15.2 and Removal of the text This analysis will be conducted on all patients randomised to the treatment groups that have had their randomisation CRF input into the database as all data on database for final analysis. Further clarity as to how cross-overs will be handles in the analysis of safety data. Monitoring plan version number added (v1.0 06/11/2013). Minor/Major/Any protocol deviation summary sentence separated for clarity. Clarifying that just the SAE data from the final report will be used for the analysis rather than copying any missing data from earlier reports. Replacement of text to say: The stopping guidelines that were pre-planned to use for the interim analysis presented to the IDSMC at the 25 th March 2015 meeting are detailed within section 15.1 Stopping guidelines of the IDSMC 25Mar2015 v1.0 statistical analysis plan. For those patients that enter the trial eligible with both eyes, time to first eye to fail will be used. The follow-up for the primary analysis will stop after this blinded assessment for all patients affected due to this to Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 4 of 52 Date changed 07/09/15 AM 07/09/15 AM 07/09/15 AM 07/09/15 AM 07/09/15 AM 07/09/15 AM 07/09/15 AM Initials 07/09/15 AM

209 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Updated SAP version no. Section number changed Description of change ensure that the two randomised groups remain comparable. Those patients that reached 18 months follow-up prior to this IDSMC and TSC decision will be unaffected so will have all follow-up data up to 18 months included. Rewording of Patients who are still in follow up at the time of the interim analysis: censored at last follow up visit to say Patients who are still on trial treatment at the time of unblinding: censored at the unblinding visit. Addition of text Assessment of treatment failure during the follow-up phase for patients that withdrew from treatment prior to the 18-month followup visit is described in section 17.2 for clarity. Time points of primary outcome data collection listed. Time interval between consecutive visits for assessment of treatment failure described. Addition of text to describe how to identify study eye(s) and which AC cells scores to use as the baseline score. Treatment failure is only assessed in study eye(s). This was done for previous interim analyses but text added here for clarity. Reasons for treatment failure will also be presented as a bar chart. Removal of 99.9% confidence intervals for the hazard ratio as no Haybittel- Peto stopping rule required. Just the 95% confidence interval will be presented. Additional text to describe how the proportional hazards assumption will be checked and if violated then a timedependent covariate will be added to a Cox model. Hypotheses to be tested and significance level added. Text added around regression models to further investigate the outcome between the two groups. Heterogeneity of treatment effects by centre will be considered in a graphical display by means of a Forest plot split by site. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 5 of 52 Date changed Initials

210 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Updated SAP version no. Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v1.0 $ Final Analysis for blinded data comparison of primary outcome and safety data v2.0 Final Analysis for blinded data comparison of primary outcome and safety data v2.0 Final Analysis for blinded data comparison of primary outcome and safety data v2.0 Section number changed 17.3 Sensitivity analyses for primary outcome Appendix C Appendix E Description of change A summary table will be presented to show whether or not uveitis subsequently developed in the nonstudy eye. A secondary analysis will be carried out that includes information on whether both eyes failed treatment or not at any time during the 18-month treatment failure assessment period regardless of how many eyes they were eligible for the trial with. Six further sensitivity analyses to undertake added and described. List of protocol deviations updated to include all inclusion/exclusion criteria. Addition of a list of rules to be applied for missing data in sensitivity analysis (7) Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 6 of 52 Date changed 07/09/15 AM 07/09/15 AM 07/09/15 AM 2. Definitions MedDRA abbreviations added. 02/06/16 AM 6.2 Baseline comparability of randomised groups 12. Patient groups for analysis Additional baseline characteristics listed following discussion with Chief Investigators. Skewness now not to be assessed to determine summary statistics. Mean, SD, median, IQR (upper and lower quartile) and range (maximum and minimum values) if data are normal and median, IQR and range if regardless of whether the data are skewed or not. Eye baseline characteristics to be presented in three ways: (i) Eye-level; (ii) Best-case; (iii) Worst-case. Description of end of blinded phase added. Any AEs recorded with an onset date after this 30-day cut off will be excluded. Protocol states that adverse 02/06/16 AM 02/06/16 AM Initials

211 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Updated SAP version no. Final Analysis for blinded data comparison of primary outcome and safety data v2.0 Final Analysis for blinded data comparison of primary outcome and safety data v2.0 Section number changed 14.1 Adverse reactions/events 15.2 Analysis of primary outcome Description of change event data should only be collected up to 30 days following cessation of treatment. MedDRA coding now used instead of manual categories. Updated severity*relationship cross-tab text to reflect how presented in ICH E3. Text removed as only used for IDSMC reports and not in CSR: Further details of the AEs classed as possibly, probably or almost certainly related to study drug will be presented as line listings detailing AE type, severity, whether an SAE, whether withdrew from drug as a result of AE, action taken and outcome. Additionally, of the AEs that are classified as not resolved / ongoing their severities will be listed. SAE line listings variables added following review of ICH E3. Addition of text to describe the lower limit for 3-months (components 1)i)- 1)iv)) and 6-months (component 1)v)). Line listings tables will be presented for treatment withdrawals as well as treatment failures (separately). Unit of time for Kaplan-Meier analyses are weeks. Development of co-morbidity influence on treatment failure secondary analysis: further detail described for how to construct the model because the SAP text is vague. Development of uveitis in non-study eye secondary analysis: o o Added description of consecutive visits of 1+ or more for development of uveitis. A sensitivity analysis will be conducted to include patients that had a single AC cells score of 1+ or more (i.e. not sustained over consecutive visits) and were a treatment failure in their study eye at this same visit. This sensitivity analysis was added after the blind was broken so should be treated as a post-hoc analysis. The time to treatment failure in the other eye analysis did not make any Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 7 of 52 Date changed 02/06/16 AM 02/06/16 AM Initials

212 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Updated SAP version no. Final Analysis for blinded data comparison of primary outcome and safety data v2.0 Final Analysis for blinded data comparison of primary outcome and safety data v3.0 Final Analysis for blinded data comparison of primary outcome and safety data v3.0 Section number changed 17.3 Sensitivity analyses for primary outcome 14.1 Adverse reactions/events Extent of exposure Description of change sense and could not be interpreted. AM, AJ and PW saw the results. The decision was made to re-do the analysis as time to treatment failure in both eyes including information on the time to failure in the first eye. Post-hoc analysis added: Time to treatment response. Further clarification of the event dates added for sensitivity analyses (4), (5) and (6). Of the AE/SAE analyses already listed in v2.0, additional detail added to each analysis for clarity to state whether the AE/SAE descriptions will be summarised using MedDRA SOC, MedDRA PT or both. The most commonly observed AEs in the adalimumab group, defined as those events with an incidence rate in the adalimumab group of 5%, will be presented (split by MedDRA SOC and PT) along with the rates for the placebo group and overall for the respective disorder. This addition to the CSR is for presentation purposes. The incidence rates for the AEs/SAEs will be presented by treatment group and overall along with 95% confidence intervals*. This addition to the CSR is to help with interpretation. * If the estimate is based on very few sample cases, the confidence interval can include a negative lower confidence limit. For these cases, the lower limits should be set to 0. The extent of trial treatment exposure will be summarised in terms of number of doses and total duration of treatment (days). This addition to the CSR is to help with interpretation. Date changed 02/06/16 AM 20/10/16 AM 20/10/16 AM Initials * Previous IDSMC SAP was IDSMC 29Sep2014 v1.0 $ Previous SAP was IDSMC 25Mar2015 v1.0 Previous SAP was Final analysis for blinded data comparison of primary outcome and safety data 07Sep2015 v1.0 Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 8 of 52

213 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Previous SAP was Final analysis for blinded data comparison of primary outcome and safety data 02Jun2016 v2.0 Table of Contents Authors roles and responsibility... 2 Change Control... 2 Table of Contents... 9 Table of Figures Introduction Definitions Study design and objectives Sample size calculations Interim analysis Study Outcomes Primary Outcome Secondary Outcomes Inclusion / Exclusion Criteria Inclusion Criteria Exclusion Criteria Description of study population Representativeness of study sample and patient throughput Baseline comparability of randomised groups Completeness of follow-up Follow up assessments Study Outcomes Primary Outcome Secondary Outcomes Description of compliance with treatment Trial monitoring Unblinding of randomised treatments Patient groups for analysis Protocol deviations Description of safety outcomes Adverse reactions/events Other safety signs Extent of exposure Analysis of primary efficacy outcome Stopping guidelines Analysis of primary outcome Quality control of Primary outcome analysis Analysis of secondary efficacy outcomes Analyses of missing data / withdrawals Missing primary outcome data Analysis of withdrawals Sensitivity analyses for primary outcome Setting results in context of previous research References Approval and agreement Appendix A: Recommendations from TSC following 25Mar2015 interim analysis results report Appendix B: CONSORT 2010 flow diagram Appendix C: Protocol deviations Appendix D: Primary outcome component checks Appendix E: List of rules to be applied for missing data in sensitivity analysis (7) Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 9 of 52

214 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Table of Figures Table 1: Study visits and assessments Table 2: Protocol deviations table Table 3: Primary outcome component checks i Table 4: Primary outcome component checks ii Table 5: List of rules to be applied for missing data in sensitivity analysis (7) Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 10 of 52

215 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Introduction This Statistical Analysis Plan (SAP) provides a detailed and comprehensive description of the pre-planned final analysis for blinded data comparison of primary outcome and safety data for the study SYCAMORE: A Randomised Controlled Trial of the Clinical Effectiveness, Safety and Cost Effectiveness of Adalimumab in Combination with Methotrexate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis. This study is carried out in accordance with the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989) and South Africa (1996) amendments and will be conducted in compliance with the protocol, Clinical Trials Research Centre (CTRC) Clinical Trials Unit (CTU) Standard Operating Procedures (SOPs) and EU Directive 2001/20/EC, transposed into UK law as the UK Statutory Instrument 2004 No 1031: Medicines for Human Use (Clinical Trials) Regulations This planned analysis will be performed by the trial statistician and the results will be described in a confidential statistical analysis report. All analyses are performed with standard statistical software (SAS version 9.3 or later). The finalised analysis datasets, programs and outputs will be archived following Good Clinical Practice guidelines and SOP TM021 Archiving procedure in CTRC. The testing and validation of the statistical analysis programs will be performed following SOP ST Definitions AC AE CI CMO CONSORT CRF CTRC IDSMC IOP IQR ITT kg LLT MedDRA MTX OCT PDF PI PP PT QC RF SAE Anterior-chamber Adverse event Confidence interval Cystoid macular oedema Consolidated Standards of Reporting Trials Case report form Clinical Trials Research Centre Independent Data and Safety Monitoring Committee Intraocular pressure Inter-quartile range Intention-to-treat Kilogram Lower Level Term Medical Dictionary for Regulatory Activities Methotrexate Optical Coherence Tomography Portable document format Principal Investigator Per-protocol Preferred Term Quality control Rheumatoid factor Serious adverse event Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 11 of 52

216 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 SAP SD SOC SUSAR SYCAMORE TMG TSC Statistical Analysis Plan Standard deviation System Organ Class Suspected Unexpected Serious Adverse Reactions A Randomised Controlled Trial of the Clinical Effectiveness, Safety and Cost Effectiveness of Adalimumab in Combination with Methotrexate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis Trial Management Group Trial Steering Committee 3. Study design and objectives This study is a prospective, multi-centre, randomised, double-blind, placebo-controlled, superiority study of adalimumab in combination with methotrexate (MTX) in patients with active uveitis in association with JIA refractory to MTX monotherapy. The study is conducted in sixteen centres throughout the United Kingdom. The primary objective of this study is to compare the clinical effectiveness of adalimumab in combination with methotrexate (MTX) versus MTX alone, with regard to controlling disease activity in refractory uveitis associated with juvenile idiopathic arthritis (JIA). The secondary objectives of this study are: To evaluate short term safety and tolerability of adalimumab in combination with MTX versus MTX alone, with regards ocular complications of treatment, adverse events and laboratory assessments To determine quality of life and cost effectiveness of adalimumab in combination with MTX versus MTX alone in severe uveitis associated with JIA To determine the clinical effectiveness of adalimumab in combination with MTX versus MTX alone, with regard underlying JIA disease activity To determine the durability and magnitude of adalimumab efficacy response in sustaining inactive disease and achieving complete clinical remission To determine the long term safety of adalimumab in combination with MTX versus MTX alone To assess the efficacy of treatment with adalimumab to permit concomitant medication reduction, in particular regional and parenteral steroids To develop a fully consented, trial-related Tissue Bank for collection of serum, DNA and RNA for subsequent investigation Randomisation Participants are stratified by centre and randomised in a 2:1 ratio in favour of the active therapy between the two groups: 1) 2 weekly s/c injections adalimumab, plus MTX 2) 2 weekly s/c injections placebo plus MTX. Separate randomisation lists have been generated for each centre in STATA using block randomisation with random variable block length. Randomisation and treatment commencement should occur within 2 weeks of the screening visit. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 12 of 52

217 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Randomisation is undertaken during normal working hours (Monday Friday ) by the pharmacy departments of participating centres upon receipt of a randomisation request form and prescription from authorised clinicians. Pharmacy personnel verify that these documents are appropriately completed before proceeding. Randomisation is completed using a secure (24-hour) web based randomisation programme. The lists incorporated random elements and are controlled centrally by the MCRN CTU; both measures are to ensure allocation concealment. Designated pharmacy staff have been issued with personal login and password details to conduct randomisation. Blinding IMPs are supplied as bulk stock from the distributor to pharmacy in kits. Pharmacy must ensure that the participant and the researcher remain blinded to the treatment allocation. The statistician needs to define the analysis population as per section 12 before obtaining the treatment allocations. 3.1 Sample size calculations Sample size calculations were undertaken using NQuery Advisor software version 4.0. Original and revised sample size calculations are included. Sample size revisions were necessary due to lower patient availability than expected. a. Original trial sample size calculation The original sample size was based on data on failure rates from 62 patients on MTX in a comparable population provided by Dr C Edelsten, Great Ormond Street Hospital. After three months 11 patients had disease control based on Grade 0 SUN criteria (18%) and therefore based on the trial inclusion criteria would not be eligible for the trial. At 15 months following the start of treatment with MTX, 23 patients of the 51 who had failed at 3 months had achieved disease control (45%), leaving 28 (55%) who had not. To detect a relative reduction of 50% between a failure rate of 60% to 30% with 90% power (there is unlikely to be a trial of this nature again in the near future and therefore we have increased the power to 90% from the conventional power of 80% to optimise the detection of a significant difference between treatment regimes if one truly exists) at a 5% significance level, using a 2:1 randomisation a total of 140 patients (93 adalimumab, 47 placebo) are required. A trial of adalimumab in JIA with or without MTX powered the study using a 40% absolute (57% relative) difference in the rate of flare between the placebo and the adalimumab groups 1. The advent of biological therapies in JIA has led international investigators to a paradigm shift in the treatment of JIA and its related complications, leading to significantly more ambitious outcomes in clinical trials, including elimination of inflammation and normalisation of short-term and long-term function 2, 3. To this end, in JIA, instead of previously accepted clinical outcomes of 30% absolute difference in outcome between active agent and placebo 4, increasingly significant differences are being expected and regarded as significant, with new definitions of response being established for use in clinical trials such as clinical remission and minimal disease activity 5, 6. Indeed, 40% of patients in the adalimumab-jia trial were reported as showing an ACR Pedi 100% response (100% response rate) at 2 years 40. The clinically relevant outcomes of JIA-uveitis may take years to develop and the relationship between isolated measures of clinical activity and long term outcomes remains ill defined. Recent studies do suggest that the length of continuously controlled activity is likely to be of more clinical relevance than short term improvements in levels of activity. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 13 of 52

218 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 In view of these factors, as well as the expectation expressed unanimously through consumer consultation in the development of this trial protocol, we have set a minimum 50% relative difference in failure rate between interventions. Based on the nature of the disease resulting potentially in loss of vision and a meeting of investigators representing participating centres, as well as consumer representatives, and their experience of compliance from current usage of biologic therapies in JIA-uveitis, it is estimated that loss to follow up will be approximately 10%. Therefore we have increased the sample size by approximately 10% to allow for this, giving a total number of patients 154 (102 adalimumab, 52 placebo). The null hypothesis underlying this trial is that there is no significant difference between adalimumab and placebo in controlling disease activity of JIA-associated uveitis unresponsive to MTX therapy. b. Revised sample size calculation for the primary outcome The original sample size calculation had a power of 90% but given the issues that have been faced during recruitment, reducing power to what is a universally accepted convention of 80% power would maintain the status of this trial as an internationally relevant and robust contribution to the evidence base for the safety of this intervention. This we know will be both acceptable to patients/families and clinicians, and would enable the sample size to be markedly reduced, and therefore more feasible within a reasonable period. Furthermore, by September 2013 there had only been one patient who had withdrawn and refused to provide primary outcome data and therefore it would be reasonable to assume that the original assumption of adding 10% to the sample size calculation to account for missing data can be reduced to 5%. The total sample size (including 5% drop out) that is required to detect the difference between a placebo proportion of 0.6 and treatment group proportion of 0.3 (with 0.05 twosided significance level) is Interim analysis Interim monitoring reports of the accumulating data were performed at regular intervals (at least annually) for review by the Independent Data Monitoring and Safety Committee (IDSMC). For the interim analysis of the primary outcome, the Peto-Heybittle stopping rule was applied. This required an extreme p-value of p<0.001 as evidence to stop for benefit. This approach allowed the ISDMC flexibility with the number and timings of further analyses based on current safety and efficacy data as it has the added benefit of preserving an overall two sided type I error of 0.05 for the final analysis 7 The recommendations from TSC following 25Mar2015 interim analysis results report are provided in Appendix A of this SAP. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 14 of 52

219 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Study Outcomes 4.1 Primary Outcome The primary endpoint is time to treatment failure. See section 8.1 for definition. 4.2 Secondary Outcomes 1) Number of participants failing treatment 2) Incremental cost-effectiveness and cost-utility of adalimumab added to MTX compared with MTX alone 3) Health status according to the multi-attribute health utility index, HUI2 4) Safety, tolerability and compliance a. Adverse events (AEs) and serious adverse events (SAEs) b. Laboratory parameters (haematological and biochemical analysis and urinalysis c. Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period 5) Use of Corticosteroids over duration of study period and throughout follow up, including: a. Total oral corticosteroid dose b. Reduction in and rate of systemic corticosteroid dose from entry dose c. Topical corticosteroid use (frequency) compared to entry usage d. Need for pulsed corticosteroid 6) Optic and ocular a. Number of participants having disease flares (as defined by worsening on SUN criteria) following minimum 3 months disease control b. Number of participants having disease flares within the first 3 months. c. Visual acuity measured by Age-appropriate LogMAR assessment d. Number of participants with resolution of associated optic nerve or macular oedema (as assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) (where available). e. Number of participants with disease control (defined as zero cells, with topical treatment for 3 and 6 months) f. Number of participants entering disease remission (defined as zero cells, without topical treatment for 3 and 6 months) g. Duration of sustaining inactive disease (zero cells, with or without topical treatment) 7) Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ)) 8) American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels (see section of the SYCAMORE trial protocol) 9) Number of participants undergoing disease flare, in remission on and off medication (Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004; 31: ) of their JIA and with minimum disease activity (Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, Cugno C, Bozzola E, Martini A, Ravelli A. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Rheum 2008; 59: ) 10) Number participants requiring change in biologic / Disease-modifying anti-rheumatic drugs (DMARDs) therapy due to failure to respond from arthritis Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 15 of 52

220 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Inclusion / Exclusion Criteria 5.1 Inclusion Criteria A participant is eligible for the trial based upon at least one eye fulfilling the eligibility criteria 1) Children and young people aged 2 and <18 years fulfilling ILAR diagnostic criteria for JIA (all subgroups that have uveitis). 2) At the time of trial screening the participant must have active anterior uveitis, defined as a sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade >1+ or more during the preceding 12 weeks therapy despite MTX and corticosteroid (both systemic and topical) therapy. The latest date of SUN grade score must be the date of the screening visit. 3) They must have failed MTX (minimum dose of 10-20mg/m2, with a maximum dose of 25mg/participant). The participant must have been on MTX for at least 12 weeks* and have been on a stable dose for 4 weeks prior to screening visit. 4) No Disease modifying immunosuppressive drugs, other than MTX, in the 4 weeks prior to screening 5) Written informed consent of participant or parent/legal guardian, and assent where appropriate. 6) Participant and parent/legal guardian willing and able to comply with protocol requirements. 7) For participants of reproductive potential (males and females), use of a reliable means of contraception throughout their trial participation. Post pubertal females must have a negative serum pregnancy test within 10 days before the first dose of trial drug. 8) Able to be randomised and commence trial treatment within 2 weeks of the screening visit. * Omission of a maximum of 2 weeks methotrexate treatment within the 12 weeks is acceptable and will not render the patient ineligible unless they have been missed in the 4 weeks prior to the screening visit. 5.2 Exclusion Criteria 1) Uveitis without a diagnosis of JIA 2) Currently on adalimumab or has previously received adalimumab. 3) Have been on other biologic agent within previous 5 half-lives of agent (For other biologic agents and their wash out periods, (refer to protocol supplementary document #10) 4) More than 6 topical steroid eye drops per eye, per day prior to screening (this dose must have been stable for at least 4 weeks prior to screening visit) 5) For patients on Prednisone or Prednisone equivalent, change of dose within 30 days prior to screening 6) For patients on Prednisone or Prednisone equivalent with a dose >0.2mg/kg per day 7) Intra-articular joint injections within four weeks prior to screening 8) Any ongoing chronic or active infection (including infective uveitis) or any major episode of infection requiring hospitalisation or treatment with intravenous antibiotics within 30 days or oral antibiotics within 14 days prior to the screening evaluation 9) History of active tuberculosis of less than 6 months treatment or untreated latent TB 10) Participant has history of central nervous system (CNS) neoplasm, active CNS infection, demyelinating disease, or any progressive or degenerative neurological disease 11) Poorly controlled diabetes or persistently poorly controlled severe hypertension (>95th percentile for height / age) as deemed by the treating physician Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 16 of 52

221 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ ) Previous history of malignancy 13) Intraocular surgery within the 3 months prior to screening (cataract/ glaucoma/ vitrectomy) 14) Intra-ocular or peri-ocular corticosteroids within 30 days prior to screening. 15) History of ocular herpetic disease 16) Pregnant or nursing female 17) Demonstrations of clinically significant deviations in any of the following laboratory parameters: a. Platelet count < 100,000/mm3 b. Total white cell count < 4000 cells/mm3 c. Neutrophils < 1000 cells/mm3 d. AST or ALT > 2 x upper limit of normal (ULN) or serum bilirubin > 2x the ULN e. Glomerular filtration rate (GFR) of < 90 ml/min/1.73m2 [GFR (ml.min/1.73 m2 BSA) = 0.55 x height (cm)/plasma creatinine (mg/dl)] f. Hematocrit <24% 18) Having been administered a live or attenuated vaccine within three months prior to screening 19) Previous randomisation into the SYCAMORE trial to either arm of the trial. 20) Intra-ocular pressure <6mm Hg or Intra-ocular pressure > 25mm Hg 21) Intra-ocular pressure control requiring more than one topical pressure lowering therapy or requiring systemic acetazolamide 6. Description of study population 6.1 Representativeness of study sample and patient throughput A CONSORT [1] flow diagram (Appendix B) will be used to summarise the number of patients who were: assessed for eligibility at screening o eligible at screening o ineligible at screening* eligible and randomised eligible but not randomised* received the randomised allocation did not receive the randomised allocation* lost to follow-up* discontinued the intervention* randomised and included in the primary analysis randomised and excluded from the primary analysis* *reasons will be provided. Screening logs will be summarised by site with numbers of patients not eligible, eligible and not randomised and randomised presented with reasons given (including reasons for nonconsent) where available. Other free-text reasons will be summarised appropriately. A recruitment summary table will be presented showing the following for each centre: centre code, hospital name, dates site opened/closed to recruitment, dates of first/last randomisation and total number randomised. A recruitment graph will also be presented displaying the cumulative recruitment, cumulative target recruitment and number of sites open to recruitment for each month from the trial opening to closing recruitment. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 17 of 52

222 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Baseline comparability of randomised groups Patients in each treatment group (adalimumab and placebo) will be described with respect to the following: Demographics: Age #, gender $1,weight (<30kg, 30kg) # Number of study eyes $2 Physician global assessment of disease activity # Auto anti-body screen: Anti-nuclear antibody (ANA) $3, Double-stranded deoxyribonucleic acid (DsDNA) $3, Rheumatoid factor $3 Type of JIA: ILAR classification $4 JIA disease duration # Joint counts*: Active #, swollen # Vision assessment: LogMAR score # [in study eye(s)] Slit lamp examination [in study eye(s)]: o Test: AC cells (SUN) $5, flare score (SUN) $5, o LOCS III Grading: pseudophakic $6, nuclear $7, cortical $8, posterior $9 o Other Structural Changes: central band-keratopathy covering visual axis $6, synchiae $6, iris bombe $6, membrane formation $6, neovascularisation $6 Intraocular pressure # [in study eye(s)] Fundoscopy examination [in study eye(s)]: o Test: Vitreous Haze Grading $5 Number of topical steroid drops taken per day. * If Not done has been selected for a joint count assessment treat as no joints are active/swollen (as directed by the Chief Investigators). # Continuous $1 Categorical: Male/Female $2 Categorical: Unilateral/Bilateral $3 Categorical: Positive/Negative/Not Done $4 Categorical: Systemic arthritis, Persistent oligoarthritis, Extended oligoarthritis, Polyarthritis RF positive, Polyarthritis RF negative, Psoriatic arthritis, Enthesitis-related arthritis, Undifferentiated arthritis $5 Categorical: 0/0.5+/1+/2+/3+/4+ $6 Categorical: Yes/No $7 Categorical: N0/NI/NII/NIII $8 Categorical: Ctr/CI/CII/CIII/CIV/Aphakic or Pseudophakic/No Cortical Cataract $9 Categorical: O/PI/PII/PIII Note: Reasons for any tests not being done will be summarised if provided. Categorical data will be summarised by numbers and percentages. Continuous data will be summarised by mean, SD, median, IQR (upper and lower quartile) and range (maximum and minimum values) regardless of whether the data are skewed or not. A summary table will be presented overall and separate summary tables for each site. The characteristics highlighted above with [in study eye(s)] will be presented in three ways: (i) Eye-level; (ii) Best-case; (iii) Worst-case. Tests of statistical significance will not be undertaken for baseline characteristics; rather the clinical importance of any imbalance will be noted. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 18 of 52

223 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Completeness of follow-up Completeness of follow-up will be presented in the form of a CONSORT flow diagram. See section 6.1 for details. The number lost to follow up within each treatment group will be reported and the reasons where known will be documented. Any deaths and their causes will be reported separately. 7. Follow up assessments The schedule of study procedures is given in the Table 1 below. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 19 of 52

224 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 TABLE 1: STUDY VISITS AND ASSESSMENTS Time (months) 0^ Screening* Randomisation & commence treatment Written informed consent X Confirm consent (verbal) X X X X X X X X X X X X X X Assessment of Eligibility Criteria X X Review of Medical/ Opthalmic/ X Surgical History Review of Concomitant Medications X X X X X X X X X X X X X X X X X Pregnancy test (serum) (X) X X X X X X X Purified protein derivative (PPD) X Tuberculin Skin Test 1,2 / Test for latent TB as locally performed Urinalysis 3 X X X X X X X X X X X X X X X X Randomisation X Study Intervention X X X X X X X X X Compliance with study intervention X X X X X X X X X Physical Exam - Complete X X X X X X X X X X X X X X X X Vital Signs (heart & Respiratory rate, X X X X X X X X X X X X X X X X temperature and blood pressure) Height X X X X X X X X X X X X X X X X Weight X X X X X X X X X X X X X X X X Childhood Health Questionnaire (CHQ) X X X X X X X X X Childhood Health Assessment Questionnaire (CHAQ) X X X X X X X X X Health Utilities Index 2 Questionnaire X X X X X X X X X Client Service Receipt Inventory (CSRI) X X X X X X X X Sample for DNA collection (X) (X) (X) RNA and Serum/plasma (X) (X) (X) Haematological analysis X X X X X X X X X X X X X X X X Biochemical analysis X X X X X X X X X X X X X X X X Samples for HAHA analyses ** X X ANA, dsdna and ENA X X Opthalmic assessments: Vision assessment X X X X X X X X X X X X X X X X Optical coherence tomography (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (optional) Assessment of vitritis X X X X X X X X X X X X X X X X Slit lamp bio-microscopy X X X X X X X X X X X X X X X X Cataract scoring X X X X X X X X X X X X X X X X Goldmann tonometry or tonopen X X X X X X X X X X X X X X X X Standard ACR Pedi Core Set outcome X X X X X X X X X X X X X X X X variables Tanner Score X X X X X X X X X X Review of Participant Diaries X X X X X X X X X X X X X X X (X) Assessment of Adverse Events X X X X X X X X X X X X X X X X ^ Visit 0 must be completed and treatment commenced within 14 days of the screening visit (10 days for pregnancy test) * All procedures should be done before study intervention. ** To be done also as required if anaphylaxis occurs during trial. (X) - As applicable/indicated/appropriate 1 Participants who are PPD positive at screening will require a chest x-ray. Treatment of participants who have a positive PPD skin test and/or abnormal chest x-ray should be in accordance with regional/national guidelines, and initiated at least 4 weeks prior to receiving the first dose of trial medication 2 Participants with recent (within 6 months of trial entry screen) positive PPD ( 5 mm) who are being treated with appropriate prophylaxis may request a waiver for a screening PPD from the MCRN CTU. Documentation of the positive PPD should be available as well as chest x-ray report from the date of the positive PPD and treatment/prophylaxis history from near the time of the participant s conversion. 3 Microscopic urinalysis will be obtained at baseline and for other visits only if relevant abnormalities greater than trace are noted on the dipstick analysis. End of treatment End of trial Premature withdrawal Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 20 of 52

225 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Study Outcomes 8.1 Primary Outcome The primary outcome is time to treatment failure. At each treatment visit (1, 2, 3, 6, 9, 12, 15 and 18 months following randomisation) the participants are assessed for treatment failure. If there are any participants that come in for an unscheduled visit they are also assessed for treatment failure providing they have an eye assessment carried out. For participants that withdraw from treatment but remain in the trial, they are assessed for treatment failure at their follow-up visits (3, 6, 9, 12, 15, 18 months) so their data posttreatment withdrawal is able to be included in the ITT analysis. Treatment failure being defined by one or more of the following: 1) Anterior segment inflammatory score grade (SUN criteria) Following at least 3 months of therapy: i) 2-Step increase from baseline in SUN cell activity score (AC Cells) over 2 consecutive readings ii) Sustained non-improvement with entry grade of 3 or greater for 2 consecutive readings iii) Only partial improvement (1 grade) or no improvement, from baseline, with development of other ocular co-morbidity* which is sustained iv) Worsening of existing (on enrolment) ocular co-morbidity* after 3 months v) Sustained scores as recorded at entry grade measured over 2 consecutive readings (grades 1 to 2) still present after 6 months of therapy. 2) Use of Concomitant Medications: At any time, requirement to use concomitant medications in manner out with pre-defined acceptable criteria (see section of the SYCAMORE trial protocol), or any of the concomitant medications not allowed (see section of the SYCAMORE trial protocol) 3) Intermittent or continuous suspension of study treatment (adalimumab/placebo) for a cumulative period longer than 4 weeks * Ocular co-morbidities are defined as: i) Disc swelling and/or Cystoid Macular Oedema (CMO) as gauged clinically and where possible by OCT evidence; and/or: ii) Raised intraocular pressure (>25mm Hg) sustained over 2 consecutive visits not responding to single ocular hypotensive agent, and/or: iii) Hypotony (<6 mm Hg) sustained over 2 consecutive visits, and/or iv) Development of unexplained reduction in vision (LogMAR) over two consecutive visits of 0.3 LogMAR units (in the event of cataract participants will remain in trial, also if cataract surgery is required. Failure will still remain as described in endpoints above). N.B> Intraocular pressure >= 25 mmhg or < 6 mmhg are exclusion criteria at baseline and ocular co-morbidities i)-iv) can be developed during follow up only, i) may worsen based on the existing (on enrolment) ocular co-morbidity. Where a reading is required to be sustained over two consecutive visits to define treatment failure the time of treatment failure will be taken as the second of these readings. For determining treatment failure there should be in interval of at least four weeks between assessments. Form prepared: 20/10/2016 v3.0 SYCAMORE Study Page 21 of 52

226 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Secondary Outcomes There are no analyses of secondary outcomes in this report. A complete list of secondary outcomes is provided in section 4.2 for reference purposes. 9. Description of compliance with treatment Patients that withdrew from treatment will be presented as line listings detailing: randomisation number, site, date of randomisation, date of discontinuation, reason for discontinuation, further details and whether unblinded. They will still contribute data to the analysis of primary outcome. No further information will be included in this analysis report. 10. Trial monitoring SYCAMORE is monitored by an Independent Data and Safety Monitoring Committee (IDSMC). Please see section 3.2 for details. The SYCAMORE data monitoring plan includes details of ongoing central monitoring performed by TMG, TSC and ISDMC. 11. Unblinding of randomised treatments Details of the patients that were unblinded during the trial will not be provided in this report except for those that failed treatment/had an SAE and were unblinded as these will be detailed in the treatment failure/sae line listings described in sections 15.2 and Patient groups for analysis The principle of intention-to-treat, as far as is practically possible, will be the main strategy of the analysis adopted for the primary outcome. Patients that withdrew consent for trial continuation will contribute outcome data up until the point of withdrawal unless the patients parents/guardians specifically request that the data are not to be used. The membership of the analysis set for each outcome will be determined and documented and reasons for participant exclusion will be given prior to the blind being broken and the randomisation lists being requested. Reasons may include missing data, loss to follow up and treatment withdrawal. Following the recommendations of the IDSMC and TSC (see Appendix A), randomisation was stopped in April 2015 and all patients who were randomised to placebo stopped their randomised treatment. All patients still within the treatment phase of the study at this time were invited to attend a blinded assessment before being unblinded. Therefore, the follow-up for the primary analysis will stop after this blinded assessment for all patients affected due to this to ensure that the two randomised groups remain comparable. Any treatment visits that occurred after these final blinded assessments will not be included in the efficacy analyses unless stated otherwise. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 22 of 52

227 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 The safety analysis data set will contain all participants that are randomised and received at least one dose of trial medication. Participants AEs/SAEs will be included in the treatment group they were actually receiving at the time of AE/SAE onset to take into account any patients that crossed over from the placebo group to the adalimumab group for some reason and vice versa. As per the SYCAMORE trial protocol (all versions), adverse event data should only be collected up to 30 days following cessation of treatment or final blinded assessment as described above. Any AEs recorded with an onset date after this 30-day cut off will be excluded. Any AEs with a missing onset date will be included. Patients to be excluded from the primary analysis population and the safety analysis population will be defined in template ST001TEM03 Protocol deviations and population exclusions template and this will be agreed and approved prior to any release of randomisation codes. 13. Protocol deviations Protocol deviations that will be reported are defined in the monitoring plan v1.0 06/11/2013 for the trial and also included in Appendix C of this analysis plan. All protocol deviations of the listed protocol specifications have been included in the trial monitoring reports presented overall and by site when numbers recruited per site are sufficient. Protocol deviations are classified prior to unblinding of treatment. All protocol deviations will be defined and signedoff using ST001TEM03 Protocol deviations and population exclusions template prior to unblinding. The number (and percentage) of patients with each separate protocol deviation will be presented in this analysis report along with the number (and percentage) of patients with (i) at least one major protocol deviation; (ii) at least one minor protocol deviation; and (iii) at least one protocol deviation of any classification (minor or major). These will also be summarised across site and in total by treatment group. No formal statistical treating will be undertaken. 14. Description of safety outcomes 14.1 Adverse reactions/events AEs are captured on the CRFs as free-text. These events are categorised by the Data Manager using MedDRA coding with Chief Investigator input and subsequently signed off by Chief Investigator once complete, prior to unblinding the patients included in the analysis. All adverse events (AEs) and serious adverse events (SAEs) will be presented, by treatment group and overall at the MedDRA SOC level. No formal statistical testing will be undertaken. The safety population will be used for these summaries listed below. The number of events and number (and percentage) of patients experiencing each AE (split by MedDRA SOC and PT) and a cross-tabulation of AE severity (mild, moderate, severe, missing) by relationship to study drug (Unrelated (unrelated, unlikely); Related (possibly, probably, almost certainly); Missing) will be presented by treatment group and overall. Randomisation numbers with frequency of occurrence will be listed next to each AE MedDRA PT in the appropriate cells within this table. The most commonly observed AEs in the adalimumab group, defined as those events with an incidence rate in the adalimumab group of 5%, will be presented (split by MedDRA SOC and PT) alongwith the rates for the placebo group and overall for the respective disorder. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 23 of 52

228 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 The incidence rates of total numbers of AEs/SAEs will be calculated separately for each treatment group and overall in person-years. This is defined as the total number of AEs/SAEs divided by the total exposure time in years (calculated as total days / ) for all participants in that treatment group or overall. A table will be presented with a separate row for each treatment and opverall showing: Total years Total AEs AE rate per patient year 95% confidence interval* for AE rate per patient year Total SAEs SAE rate per patient year 95% confidence* interval for SAE rate per patient year. * If the estimate is based on very few sample cases, the confidence interval can include a negative lower confidence limit. For these cases, the lower limits should be set to 0. Each SAE will be presented in the form of line listings detailing: SAE number Treatment SAE report date Age Gender Weight at baseline Weight at SAE assessment date Height Location of CRF AE description (verbatim and MedDRA SOC/PT/LLT) SAE Duration (days) Severity Seriousness Action taken Outcome Expectedness to adalimumab/placebo (PI and Chief Investigator assessments) Relationship to adalimumab/placebo (PI and Chief Investigator assessments) Cause SAE onset date Onset timing since last dose of IMP Study treatment at time of even Drug concentration at baseline Dose at last administration Duration of IMP Patient status Whether unblinded Last dose of IMP Whether withdrew from drug as a result of AE. SAEs which are SUSARs will be identified as such. Each SAE has an initial report done. If the SAE has not yet been resolved the resolved date is left blank. Later, a follow-up report or a final report captures the resolved date and final outcome. Therefore, the latest report will be taken and presented as the line listings. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 24 of 52

229 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 To ensure quality control, an independent statistician will follow this SAP to independently program the safety analysis from the raw data. Any discrepancies found will be discussed with the trial statistician to resolve. No programming will be shared or shown between the statisticians. The independent statistician will also check the report against their output Other safety signs Extent of exposure Both the total number of doses of trial treatment (adalimumab/placebo) and total duration of treatment (days) will be calculated per patient and will be summarised by mean, SD, median and range (maximum and minimum values) regardless of whether the data are skewed or not for each treatment group. The duration of treatment (days) will also be categorised and summarised by frequencies and percentages for each treatment group. The categories will be displayed as separate batches of 28-day intervals: 1-28, 29-56, etc. 15. Analysis of primary efficacy outcome 15.1 Stopping guidelines The stopping guidelines that were pre-planned to use for the interim analysis presented to the IDSMC at the 25 th March 2015 meeting are detailed within section 15.1 Stopping guidelines of the IDSMC 25Mar2015 v1.0 statistical analysis plan Analysis of primary outcome The primary endpoint is time to treatment failure. For those patients that enter the trial eligible with both eyes, time to first eye to fail will be used. Following the recommendations of the IDSMC and TSC (see Appendix A), randomisation was stopped in April 2015 and all patients who were randomised to placebo stopped their randomised treatment. All patients still within the treatment phase of the study at this time were invited to attend a blinded assessment before being unblinded. Therefore, the follow-up for the primary analysis will stop after this blinded assessment for all patients affected due to this to ensure that the two randomised groups remain comparable. Those patients that reached 18 months follow-up prior to this IDSMC and TSC decision will be unaffected so will have all follow-up data up to 18 months included. The primary analysis will use the principle of intention to treat based on all the randomised participants, as far as is practically possible (see section 12). If consent for treatment is withdrawn but the participant is happy to remain in the study for follow-up, they will be followed up until completion. However, if they decide to withdraw consent completely then the reasons for withdrawal of consent will be collected (if possible) and reported for both groups. Before analysing the data a series of primary outcome checks are to be performed (see Appendix D for details). The primary outcome of treatment failure is a time-to-event outcome. This will not be observed in all patients; those patients that do not observe an event will be classed as Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 25 of 52

230 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 censored. The event time or censoring will be calculated by subtracting the randomisation date from one of the following scenarios: Participants that failed treatment: date of the visit in which they failed treatment. Participants that completed the trial treatment phase without failing treatment: censored at date of 18-month treatment visit. Participants that withdrew* and agreed to follow-up: o If they are assessed to be a treatment failure during a follow-up visit within 18-months* following randomisation: date of follow-up visit. o If they are not assessed to be a treatment failure during their follow-up visits: censored at date of last follow-up visit within 18-months # following randomisation. Participants that are lost to follow-up: censored date of last treatment visit. Patients who are still on trial treatment at the time of unblinding: censored at the unblinding visit. * Assessment of treatment failure during the follow-up phase for patients that withdrew from treatment prior to the 18-month follow-up visit is described in section # The upper limit for the 18-month window will be 612 days. As per trial protocol, doses of trial treatment (adalimumab/placebo) are to be taken every 14 days (±3 days see Treatment regime in Table 2) so therefore the upper limit for 18-month visit is 17 days * 2 (per month) * 18 months = 612 days. The visit to be taken will be the last follow-up visit prior to 612 days. A censoring indicator will be created for each trial participant as below: 1 if failed treatment censor = { 0 if censored Treatment failure is assessed at all scheduled treatment visits (1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months and 18 months). Patients that come in for unscheduled treatment visits will also be assessed for treatment failure. Treatment failure is not formally assessed during follow-up as the patients are no longer on trial treatment. The raw data for component 1 of the primary outcome is collected during follow-up (visits at 3 months, 6 months and pre SYCAMORE protocol V4.0 25/09/2013 also at 9 months, 12 months, 15 months and 18 months). Patients that withdrew from trial treatment prior to their 18 month visit and agree to be followed up are still assessed for treatment failure during the analysis (see section 17.2 for details). When assessing for treatment failure (section 8.1), where a reading is required to be sustained over two consecutive visits to define treatment failure the time of treatment failure will be taken as the second of these readings. For determining treatment failure there should be an interval of at least four weeks between assessments. According to section 10 of the SYCAMORE protocol v6.1 14/07/2016 there is an allowance of -7days/+7 days will be allowed for monthly visits and -15days/+15days for the 3 monthly visits. Therefore, for assessing treatment failure at the 3-month scheduled treatment visit (the first visit where the assessment for treatment failure requires consecutive visits) an interval of 5 weeks will be used to account for the allowance of 7 days. All scheduled treatment visits following the 3-month treatment visit are 3 monthly so the 4-week interval is sufficient. Unscheduled visits need to be taken into account when assessing treatment failure, if this was carried out at the unscheduled visit. If the interval is less than 4 weeks then the next previous visit that is at least 4 weeks prior will be used to assess treatment failure against the current visit. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 26 of 52

231 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Patients will be assessed for treatment failure only on the study eye(s) that they entered the trial with. They can be eligible for the trial with either one or two eyes. To determine the study eye(s), according to the inclusion/exclusion CRF patients must have active anterior uveitis (at least one eye with sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade >1+ or more during the preceding 12 weeks therapy. The latest date must be at date of screening. However, prior to protocol V4.0 17/01/2014 the protocol did not state that patients must have a score of 1+ or more at the time of screening, it rather suggested that patients have two visits of 1+ or more during the last 12 weeks before screening. Protocol V4.0 17/01/2014 was updated to state that latest date of SUN grade score must be at date of screening. Therefore: (i) Patients that have eye(s) with sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade >1+ or more during the preceding 12 weeks therapy with the latest date being at date of screening, are eligible with these eye(s) and will have treatment failure assessed accordingly for these eye(s). (ii) Patients that do not satisfy (i) because their two assessments were within the 12 weeks without the latest date being at date of screening, are still eligible with these eye(s) according to protocols prior to protocol V4.0 17/01/2014 and will have treatment failure assessed accordingly for these eye(s). For the study eye(s), the anterior chamber of SUN criteria grade obtained at the baseline visit will be used to assess for treatment failure. As the baseline visit can be carried out within 14 days following screening the scores may be different. If the score for the study eye(s) are then <1+ i.e. interring not eligible then the latest score used for the assessment for eligibility at screening will be used as the baseline value(s) to assess for treatment failure. Primary outcome components 1)i)-1)iv) are measured from 3 months. The lower limit for the 3-month window will be 66 days. As per trial protocol, doses of trial treatment (adalimumab/placebo) are to be taken every 14 days (±3 days see Treatment regime in Table 2) so therefore the lower limit for 3-month visit is 11 days * 2 (per month) * 3 months = 66 days. Primary outcome component 1)v) is measured from 6 months. Following the same principles outlined earlier in this paragraph, the lower limit for the 6-month window will be 132 days. The data for the ocular co-morbidity defined as Cystoid Macular Oedema (CMO) as gauged clinically and where possible by OCT evidence is collected through a fundoscopy assessment and/or OCT assessment. As OCT is more sensitive it can detect macular oedema that is not obvious on fundoscopy. Therefore, if there are conflicting results between fundoscopy and OCT then the OCT result will be used. Partway through the trial (22/05/2013), for patients that failed at a treatment visit had their treatment visit CRF completed along with a premature withdrawal visit CRF. This meant that there was a lot of duplication of data collected. Therefore, a check will be performed to identify which of the duplicated visits has AC cells data collected and this visit will be used but if both/neither have AC cells data the premature withdrawal visit will be used. Line listings for each participant that failed treatment/withdrew from treatment (separately) will be presented detailing: randomisation number, site, date of randomisation, date of discontinuation, reason for treatment failure/treatment withdrawal, further details and whether unblinded. Reasons for treatment failure will also be presented as a bar chart. A Kaplan-Meier plot will be constructed with separate curves for each treatment group and will be presented in the trial report. The units of time for the x-axis will be weeks. From inspection of the Kaplan-Meier plot the separation between the curves should remain Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 27 of 52

232 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 proportional across analysis time. If the curves cross again this shows that the proportional hazards assumption has been violated. To put this formally, the proportional hazards assumption is that the ratio of hazards is a constant that does not depend on time: h A (t) h B (t) = r When this assumption fails, it is because the hazard ratio changes over time. To test this, we will add predictor for group*time interaction i.e. a time-dependent covariate. Evidence that group*time interaction is not zero is evidence against proportional hazards. In SAS, PROC PHREG provides the p-value of this test. p<0.05 will indicate non-proportional hazards and thus a time-dependent covariate will be included in the Cox model. If p 0.05 survival estimates will be calculated using the method of Kaplan-Meier. In both situations, survival estimates will be calculated using the method of Kaplan and Meier with curves for each treatment group presented graphically with numbers at risk. Survival times (presented in weeks) will be measured from the date of randomisation to the date of treatment failure as identified above. The p-value obtained from the log-rank test and also the hazard ratio with 95% confidence interval will be used to assess differences in failure estimates across treatment groups. The null hypothesis is that there is no difference in outcome between the adalimumab and placebo treatment groups. The alternative hypothesis is that there is a difference between the two treatment groups. The 2-sided significance level of 0.05 will be used to indicate statistical significance for the comparison between the two treatment groups. The development of co-morbidity influence on treatment failure will be further explored split by treatment group: Co-morbidity Cataracts IOP Macular oedema Visual acuity (LogMAR scores) Eye inflammation (AC cells scores) Definition Identified through an adverse event report Raised IOP, hypotony or either Any macular oedema (not just cystoid) Development of unexplained reduction in vision over two consecutive visits of 0.3 LogMAR units from baseline as per definition within primary outcome? Those that satisfy component 1 of the primary outcome - particularly those that had 2 step increase in AC score. Five separate Cox-proportional hazards models will be constructed for each of these comorbidities. The outcome will be defined as time to treatment failure as per definition of the primary outcome above. The covariates in the models will be (i) a treatment*time interaction term and (ii) the co-morbidity set up as a time-dependent covariate (ind*time where ind=1 for a time at or after a Yes for the co-morbidity and a 0 otherwise). ICH E9 states that In some trials there may be no reason to expect the centres to have any influence on the primary or secondary variables because they are unlikely to represent influences of clinical importance. In other trials the limited number of subjects per centre will make it impracticable to include centre effects in the statistical model [10] (3). Heterogeneity of treatment effects by centre will be considered in a graphical display by means of a Forest plot split by site. Of those patients that entered into the trial with one eligible study eye, the number and percentage of patients that subsequently developed uveitis in the non-study eye. An AC cells score of 1+ or more over two consecutive visits at least four weeks apart indicates the Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 28 of 52

233 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 presence of uveitis. Line listings will be presented of each occurrence providing further information. A sensitivity analysis will be conducted to include patients that had a single AC cells score of 1+ or more (i.e. not sustained over consecutive visits) and were a treatment failure in their study eye at this same visit. A secondary analysis will be carried for time to treatment failure in both eyes. The analysis will not be restricted to the 18-month treatment failure assessment period so all available follow-up data post treatment cessation will be utilised. Treatment failure will be assessed in both eyes regardless of how many eyes they were eligible for the trial with. Assessment of treatment failure during the follow-up phase is described in section Patients that fail treatment for component 2 of the primary outcome, if the concomitant medication taken is not for the eyes then this treatment failure will count as for both eyes. Patients that fail treatment for component 3 of the primary outcome will count as a treatment failure for both eyes. Treatment failure may not necessarily happen in both eyes at the same time. In the event that they happen at different times the latter of the two dates will be their event date for this analysis. Those that do not fail treatment in either eye will be censored at their last trial visit. Those that fail with one eye will also be censored. A Cox proportional hazards model will be fitted with time to failure in both eyes as the outcome. The covariates in the model will be (i) a treatment*time interaction term and (ii) a time-dependent covariate for time to treatment failure in the first eye (ind*time where ind=1 for a time at or after a treatment failure in the first eye and a 0 otherwise). Line listings will be presented of each treatment failure occurrence providing further information. A post-hoc analysis of time to treatment response will be conducted. Treatment response is defined as a 2-step AC cells score improvement from baseline sustained over two consecutive visits (in study eye(s)). Three analyses will be undertaken: (1) Kaplan-Meier analysis: The same approach taken as for the time to treatment failure primary outcome analysis described above will be used. A table of reasons for being censored will be presented split by treatment: o Completed 18 months o Completed treatment phase due to early trial closure o Still on trial treatment o Treatment failure o Treatment failure (after withdrawing) o Treatment failure but responded to treatment later on prior to 18 months o WD and specified no follow-up o WD and taken last follow-up date. A table of reasons for being an event will be presented split by treatment: o Responded to treatment o Responded to treatment but were a treatment failure later on prior to 18 months. (2) Proportion of (i) responders, (ii) failures, (iii) no change, at 3 months and 6 months: (i) Responders: 2-step improvement from baseline sustained over two consecutive visits (in study eye(s)). (ii) Failures: As per primary outcome definition. (iii) No change: still in trial without responding/failing. (i)-(iii) will be summarised the number (and percentage) split by treatment. A Cochran-Armitage trend test will be performed for both the 3-month and 6- month analysis with p-values presented. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 29 of 52

234 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 (3) AUC: Reasons for exclusions to these 3-month and 6-month analyses will be described. Area under curve calculated for each patient and standardised by dividing by the total length of time (weeks) and totalled for each treatment group. Total length of time is defined as per definition of primary outcome. To take into account the patients eligible with both eyes, three analyses will be presented: (i) Eye-level (ii) Best-case (iii) Worst-case The difference in AUC between the two treatment groups for (i)-(iii) will be tested using a t-test with the differences, 95% CIs and p-values being reported Quality control of Primary outcome analysis To ensure quality control, an independent statistician will follow this SAP to independently program the primary analysis from the raw data. Any discrepancies found will be discussed with the trial statistician to resolve. No programming will be shared or shown between the statisticians. The independent statistician will also check the report against their output. 16. Analysis of secondary efficacy outcomes There will be no analysis of secondary outcome data presented in this report. 17. Analyses of missing data / withdrawals 17.1 Missing primary outcome data A summary table of the missing data from the separate assessments that feed into the primary outcome (disc swelling, CMO, OCT, IOP, vision assessment, AC cells, compliance question, conmeds question, suspension of treatment question) will be presented detailing the proportion of unobtainable assessments overall and for each visit split by each site Analysis of withdrawals Participants that withdraw from trial treatment, providing they do not withdraw from the entire study or withdraw consent they move to the follow-up phase of the trial where they are still assessed for primary outcome so therefore can still contribute to the ITT analysis. The assessments will be as follows: (1) Component 1 (Anterior segment inflammatory score grade SUN criteria): SUN scores and data to determine ocular co-morbidities are still collected at follow-up visits following withdrawal from treatment so this component can be assessed. (2) Component 2 (Use of Concomitant Medications) are not collected past treatment withdrawal so this component cannot be assessed (3) Component 3 (Intermittent or continuous suspension of study treatment) cannot be assessed following withdrawal from treatment as they are no longer on treatment. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 30 of 52

235 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Any participants that withdraw from follow-up will contribute primary outcome data until the point at which they withdrew Sensitivity analyses for primary outcome The following sensitivity analyses will be conducted: (1) Best-case: All participants that have withdrawn from treatment will be treated as censored at time of treatment withdrawal. (2) Worst case: All participants that have withdrawn from treatment will be treated as treatment failures i.e. events at time of treatment withdrawal. (3) Methotrexate*: Any participants that withdrew from treatment due to methotrexate intolerance will be classified as treatment failures at the time of treatment withdrawal with those that withdrew for other reasons continued to follow up and assessed for treatment failure as per the primary analysis. (4) Component 1 # : All patients that fail for component 1 at a treatment failure assessment will have their event date as the mid-point (rounded down to nearest date) between this visit and previous visit instead of the date of this visit. (5) Component 2: All patients that fail for component 2 at a treatment failure assessment will have their event date as the date that they commenced on the concomitant medications (i) used against pre-defined acceptable criteria (see section of the SYCAMORE trial protocol), or (ii) any of the concomitant medications not allowed (see section of the SYCAMORE trial protocol). The event date will be determined by the Chief Investigator making a clinical decision following review of the patients concomitant medications taken since their previous visit. This will be documented accordingly. If not obvious which conmed taken for the treatment failure take the treatment failure visit date. If the conmed start date is missing take the treatment failure visit date. If multiple conmeds take the earliest one. (6) Component 3: All patients that fail for component 3 at a treatment failure assessment will have their event date as the exact date that they qualified as Intermittent or continuous suspension of study treatment (adalimumab/placebo) for a cumulative period longer than 4 weeks. The event date will be determined by the Chief Investigator making a clinical decision following review of the patients trial treatment dose recordings in the treatment diaries. This will be documented accordingly. If it is not obvious when the missed final dose was due to missing treatment diaries take the treatment failure visit date. (7) Any missing primary outcome data $ : Any cases of missing data for any of the primary outcome components (except for unscheduled visits) will have data imputed on a worst-case basis and will be listed in a table by whether they had a treatment failure or not. A list of rules is provided in Appendix E. All patients will be treated the same regardless of whether they have had a treatment failure or not. Therefore, it is possible that patients that were a treatment failure, if they have missing data prior to this point they could fail treatment earlier. (8) Loss to follow-up: In the primary analysis of primary outcome we have classed the patients that are lost to follow-up as withdrawals assuming that they are noninformative. The reasons for loss to follow-up, where available, will be blindly reviewed by Prof Michael Beresford (Co-Chief Investigator) and Prof Andrew Dick (Ophthalmology expert on TMG) to see to see whether they think any might be related to prognosis. If any are deemed to be related, a sensitivity analysis will be undertaken assuming these patients to be a treatment failure at the time of last recorded visit. (9) Incorrectly identified to be a treatment failure: Once a patient has been deemed to be a treatment failure, treatment is stopped and they enter the follow-up phase of the study providing they still wish to be followed up. If there are any patients that were Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 31 of 52

236 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 wrongly identified to be treatment failures by the assessing physician they will be classed as a withdrawal at their time of treatment failure. * This sensitivity analysis has been chosen because the usage of methotrexate section of the original trial protocol stated that methotrexate withdrawal would be classified as a treatment failure even though this was not stated as a component of the primary outcome. # This sensitivity analysis has been chosen because patients that fail treatment for component 1 at their treatment failure assessment could have in fact failed treatment prior to their visit but have only been assessed at this point. This has since been removed and is now not stated in the current up-to-date version of the trial protocol. $ This sensitivity analysis will require intense coding and given the current timelines of the analysis being completed and reported by September 2015 this will not be ready. We will therefore aim to have this sensitivity analysis completed by December Setting results in context of previous research Once the trial has been completed the results of the trial will be set in context of the existing evidence base. 19. References 1. Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. New England Journal of Medicine. 2008;359(8): Beresford MW, Baildam EM. New advances in the management of juvenile idiopathic arthritis--1: Non-biological therapy. Archives of disease in childhood-education & practice edition. 2009;94(5): Ilowite NT. Update on biologics in juvenile idiopathic arthritis. Current Opinion in Rheumatology. 2008;20(5): Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, Wouters C, et al. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis & Rheumatism. 2007;56(9): Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, Cugno C, et al. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Care & Research. 2008;59(8): Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. Journal of Rheumatology. 2004;31(11): Pocock SJ. Current controversies in data monitoring for clinical trials. Clinical Trials. 2006;3(6): Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Ann Int Med 2010;152. Epub 24 March. 9. ICH, E3. Chapter 12 in "Structure and content of clinical study reports". International Conference on Harmonisation ICH, E9. Chapter 3 in "Statistical Principles for Clinical Trials". International Conference on Harmonisation SAS 9.3 for Windows ed: SAS Institute Inc. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 32 of 52

237 ST001TEM01 Statistical Analysis Plan v2.0 26/09/ Approval and agreement Two versions of the SAP should be approved. 1. SAP version 1.0 should be created after it has been reviewed and signed-off to ensure all are in agreement with the planned analysis and no further changes are foreseen. 2. The final SAP version should be converted to PDF and signed following the blinded review for protocol deviations and immediately prior to database lock as evidence of the analysis planned prior to unblinding of the study. SAP Version Number being approved: Trial Statistician Name Signed Date Senior Statistician or Head of Statistics Name Signed Date Chief Investigator Name Signed OR Electronic approval attached Date Chair of Trial Steering Committee Name Signed Date OR Electronic approval attached OR TSC not reviewing SAP (ensure agreement is documented) Chair of Data Monitoring Committee Name Signed Date OR Electronic approval attached OR IDSMC not reviewing SAP (ensure agreement is documented) Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 33 of 52

238 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Appendix A: Recommendations from TSC following 25Mar2015 interim analysis results report Summary of recommendations made by TSC to TMG of Prof. Ian Bruce to Chief Investigators, 17 th April 2015: In follow-up to our TCs today and in advance of the minutes being made available, I am writing to formally record the unanimous decision and recommendation of the SYCAMORE TSC after receiving a unanimous recommendation from the IDSMC. We recommend the following: 1. That recruitment to SYCAMORE should cease at this point. This is based on a clear positive signal of efficacy of the IMP vs placebo that exceeded the pre-specified P value of P<0.001 as laid down in the Analysis Plan. We and the IDSMC are satisfied that this result is of sufficient importance to influence a real change in clinical practice. 2. That the blinded trial should be stopped and the results of the trial made public at the earliest opportunity. Of course this should be done in an organised fashion that allows final blinded close-out assessments to be undertaken to complete the blinded dataset. This should happen at the earliest opportunity, which is feasible and logistically possible for child / family and clinical team (not waiting necessarily for the next formal study visit) 3. Finally we strongly recommend that there is continuing follow-up of these children in an open-label fashion, initially in their assigned groups and that this long-term follow-up will contribute important additional data on quality of life, utilities, long-term efficacy etc. Of course subsequent changes in therapy would be at the discretion of the treating clinical team. We see this as an enormous opportunity for added value to be gained from the trial and study programme. I would once again emphasize the unanimous nature of our recommendations and I am happy for you to share this information/ with the TMG. We as a TSC will continue to be available to you and the TMG to provide any additional advice or support. Form prepared: 20/10/2016 v3.0 SYCAMORE Study Page 34 of 52

239 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Appendix B: CONSORT 2010 flow diagram Enrolment Assessed for eligibility (n= ) Excluded (n= ) Not meeting inclusion criteria (n= ) Declined to participate (n= ) Other reasons (n= ) Randomized (n= ) Allocated to intervention (n= ) Received allocated intervention (n= ) Did not receive allocated intervention (give reasons) (n= ) Allocation Allocated to intervention (n= ) Received allocated intervention (n= ) Did not receive allocated intervention (give reasons) (n= ) Lost to follow-up (give reasons) (n= ) Discontinued intervention (give reasons) (n= ) Follow-Up Lost to follow-up (give reasons) (n= ) Discontinued intervention (give reasons) (n= ) Analysed (n= ) Excluded from analysis (give reasons) (n= ) Analysis Analysed (n= ) Excluded from analysis (give reasons) (n= ) Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 35 of 52

240 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Appendix C: Protocol deviations The following table lists potential deviations of important protocol specifications, including eligibility criteria, treatment regimens and study assessments. The occurrence of these deviations will be monitored during central monitoring using the approach listed in the table. Note: 1. Impact refers to the impact of the potential protocol deviation on the risk of introducing bias in the trial results, increasing the risk of harm to the participant as a result of their condition or its treatment or a violation of patient rights. Any increased risk of harm or violation of patient rights will be graded as major. For the risk of introducing bias, impact will be graded as: major (in which case patients who experience this protocol deviation would be excluded from the per protocol analysis set) minor (in which case patients who experience this protocol deviation would be included in the per protocol analysis set) 2. Justification refers to the protocol-specific justification for the assessment of the impact of each potential protocol deviation. Justification may relate to statistical concerns of bias, generalisability, loss of power or to participant safety in reference to the inherent risks in standard medical care or patient rights and wellbeing. All protocol deviations of the listed protocol specifications will be included in the trial monitoring reports and IDSMC reports and presented overall and by site when numbers recruited per site are sufficient. TABLE 2: PROTOCOL DEVIATIONS TABLE Protocol specification Inclusion criteria Potential deviation(s) Impact Justification Age range 2 and 18 years At the time of trial screening the participant must have active anterior uveitis. Outside age range Uveitis not active but patient randomised Major Major Potential impact on safety, for patients <2 years Potential impact on efficacy results therefore possibly incorporating bias. Active anterior uveitis defined as a sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade >1+ or more during the preceding 12 weeks therapy despite MTX and corticosteroid (both systemic and topical) therapy. The latest date of SUN grade score must be the date of the screening visit. Two measurements taken more than 12 weeks apart Major Potential impact on efficacy results therefore possibly incorporating bias. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 36 of 52

241 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Failed MTX. The participant must have been on MTX for at least 12 weeks and have been on a stable dose for 4 weeks prior to screening visit. Potential deviation(s) No MTX use or not stable for 4 weeks Impact Major Justification Potential impact on safety No Disease modifying immunosuppressive drugs, other than MTX, in the 4 weeks prior to screening (as checked against Eligibility and Randomisation CRF only) Use of immunosuppressi ve drugs in previous 4 weeks of screening Major Potential impact on efficacy results therefore possibly incorporating bias. Written informed consent of participant or parent/legal guardian, and assent where appropriate No consent is provided Major Violation of patient s rights Participant and parent/legal guardian willing and able to comply with protocol requirements (as checked against Eligibility and Randomisation CRF only) Use of reliable means of contraceptive (male and females of reproductive potential) (as checked against Eligibility and Randomisation CRF only) and post pubertal females must have negative serum pregnancy text Participant and parent/legal guardian are unable to comply with the requirements as set out in the protocol. Not using reliable means of contraceptive or positive pregnancy test Pregnancy test not within 10 days prior to commencement of first dose of IMP Major Major Major Potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety if medication is used incorrectly. Statistical concerns none Potential impact on patient safety Statistical concerns none Potential impact on patient safety Able to be randomised and commence treatment within two weeks of screening Treatment is unable to be commenced within two weeks of screening Major Potential impact on patient safety Exclusion criteria Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 37 of 52

242 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Uveitis without a diagnosis of JIA (as checked against Eligibility and Randomisation CRF only) Potential deviation(s) Patients without both Uveitis and JIA are randomised Impact Major Justification Inclusion of patients without a diagnosis of JIA and therefore potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety Currently on adalimumab or previously received adalimumab (as checked against Eligibility and Randomisation CRF only) Inclusion of patients who have had previous exposure to adalimumab Major Potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety Have been on other biologic agent within previous five halflives of agent (as checked against Eligibility and Randomisation CRF only) Use of biologic outside of acceptable time window Major Potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety More than 6 topical steroid eye drops per day prior to screening (this dose must have been stable for at least 4 weeks prior to screening visit) Patients on Prednisone (or equivalent ) with a dose >0.2mg/kg per day Intra-articular joint injections within four weeks of screening (as checked against Eligibility and Randomisation CRF only) Any ongoing chronic or active infection (including infective uveitis) or any major episode of infection requiring hospitalisation or treatment with intravenous antibiotics within 30 days or oral antibiotics within 14 days prior to the screening evaluation (as checked against Eligibility and Randomisation CRF only) History of active tuberculosis of less than 6 months treatment or untreated latent TB Incorrect run in dosage for steroidal eye drops Disallowed medication dosage used Intra-articular joint injection use in previous four weeks to Major Major Major Potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety. Potential impact on patient safety. Potential impact on patient safety. screening. Recent infection Major Potential impact on patient safety. Recent infection Major Potential impact on patient safety. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 38 of 52

243 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Participant has history of central nervous system (CNS) neoplasm, active CNS infection, demyelinating disease, or any progressive or degenerative neurological disease (as checked against Eligibility and Randomisation CRF only) Poorly controlled diabetes or persistently poorly controlled severe hypertension (as checked against Eligibility and Randomisation CRF only) Previous history of malignancy (as checked against Eligibility and Randomisation CRF only) Intraocular surgery within the 3 months prior to screening (as checked against Eligibility and Randomisation CRF only) Intra-ocular or peri-ocular corticosteroids within 30 days prior to screening (as checked against Eligibility and Randomisation CRF only) Potential deviation(s) History of CNS neoplasm Poorly controlled diabetes History of malignancy Impact Major Major Major Justification Potential impact on patient safety. Potential impact on patient safety. Potential impact on patient safety. Recent surgery Major Potential impact on patient safety. Use of ocular corticosteroids outside permitted time window Major Potential impact on efficacy results therefore possibly incorporating bias. Potential impact on patient safety History of ocular herpetic disease (as checked against Eligibility and Randomisation CRF only) Pregnant or nursing female (as checked against Eligibility and Randomisation CRF only) Patient has history of ocular herpetic disease Positive pregnancy test Major Major Potential impact on patient safety Potential impact on patient safety Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 39 of 52

244 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Demonstrations of clinically significant deviations in any of the following laboratory parameters: a) Platelet count < 100,000/mm 3 b) Total white cell count < 4000 cells/mm 3 c) Neutrophils < 1000 cells/mm 3 d) AST or ALT > 2 x upper limit of normal (ULN) or serum bilirubin > 2x the ULN e) Glomerular filtration rate (GFR) of < 90 ml/min/1.73m 2 [GFR (ml.min/1.73 m 2 BSA) = 0.55 x height (cm)/plasma creatinine (mg/dl)] f) Hematocrit <24% Potential deviation(s) Out of range laboratory parameters Impact Major Justification Potential impact on patient safety (as checked against Eligibility and Randomisation CRF only) Administration of a live or attenuated vaccine within three months prior to screening (as checked against Eligibility and Randomisation CRF only) Previous randomisation into SYCAMORE trial. (as checked against Eligibility and Randomisation CRF only) Intra-ocular pressure <6mm Hg or >25mm Hg (as checked against Eligibility and Randomisation CRF only) Patient has received vaccine out of permitted time frame Second randomisation into trial Out of range intra-ocular pressure Major Major Major Potential impact on patient safety Statistical concern: Results from the same individual will not be independent Safety concern: Patient may receive previously ineffective treatment Potential impact on efficacy results therefore possibly incorporating bias Intra-ocular pressure control requiring more than one topical pressure lowering therapy or requiring systemic acetazolamide (as checked against Eligibility and Randomisation CRF only) Treatment regime Patient has received therapy that is not permitted Major Potential impact on patient safety Potential impact on efficacy results therefore possibly incorporating bias Potential impact on patient safety Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 40 of 52

245 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Treatment compliance (one vial [0.8mL] per fortnight +/-3 days) Potential deviation(s) Use of nonspecified protocol dosing regime Impact Major Justification Impact on generalisability of trial results as well as potentially patient safety Withdrawal from treatment due to safety Withdrawal from treatment due to other reason Use of non-permitted medications (see protocol page 31 for details) Study assessments Premature discontinuation of randomised treatment Premature discontinuation of randomised treatment Uses disallowed concomitant medications Major Major Major Risk of bias if withdrawal rates differ by trial arm - major as would impact on interpretation of primary outcome. Overall withdrawal due to safety monitored in open IDSMC and TMR and by treatment arm in closed IDSMC Missing data will impact on efficacy results and potentially on power of study Impact on generalisability of trial results as well as potentially patient safety Scheduled treatment visits at 1,2,3,6,9,12 and 18 months Missing visits Major Potential issue for primary outcome as treatment failure may have occurred and exact date will be missed, which is used to calculate the time-to endpoint. Scheduled treatment visits at 1,2 and 3 months Visits occur outside +/-3 day window of visit date Major Safety issue with respect to missed visits as patients will not have any trial treatment to administer until they next attend. No issue for primary outcome as it is a time-to endpoint therefore the visit date will be used to calculate this. Potential safety issue with respect to visits after the allowable window as patients will not have any trial treatment administered within the required timeframe from the previous administration. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 41 of 52

246 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Protocol specification Scheduled treatment visits at 6,9,12 and 18 months Potential deviation(s) Visits occur outside +/-15 day window of visit date Impact Major Justification No issue for primary outcome as it is a time-to endpoint therefore the visit date will be used to calculate this. Scheduled follow up visits at 21, 24, 27, 30, 33 and 36 months (or equivalent if withdrawn from treatment early) Scheduled follow up visits at 21, 24, 27, 30, 33 and 36 months (or equivalent if withdrawn from treatment Potential safety issue with respect to visits after the allowable window as patients will not have any trial treatment administered within the required timeframe from the previous administration Missed visits Major Potential safety issue with respect to identifying adverse events in a timely manner Visits occur outside +/-15 day window of visit date Major Potential safety issue with respect to late visits for identifying adverse events in a timely manner early) Missing primary efficacy data Missing data Major Missing data will impact on efficacy results and correct/timely definition of treatment failure therefore possibly incorporating bias. Power of study may be affected. Missing secondary/other efficacy data Missing data Minor Missing data will impact on secondary efficacy results Missing safety data Missing data Major Potential impact on patient safety Protocol specified assessment tools not used Equipment/tools other than those specified in protocol used to perform assessments Major Impact on generalisability of results Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 42 of 52

247 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Appendix D: Primary outcome component checks TABLE 3: PRIMARY OUTCOME COMPONENT CHECKS I Ocular co-morbidities (All assessed for each study eye separately) Worsening of existing ocular comorbidity Cystoid Macular Oedema Disc swelling Development of new ocular comorbidity Cystoid Macular Oedema Disc swelling CRF Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Start assessing from which visit? Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 3 (3 months) Treatment visit 3 (3 months) Treatment visit 3 (3 months) Raw data location Section of CRF Optical Coherence Tomography (OCT) Fundoscopy Fundoscopy Optical Coherence Tomography (OCT) Fundoscopy Fundoscopy Question(s) 1. Macular oedema present? 2. If yes, is this Cystoid? 3. If yes, has this worsened since baseline? 1. Macular oedema present? 2. If yes, is this Cystoid? 3. If yes, has this worsened since baseline? 1. Presence of disc swelling? 2. If yes, has this worsened since baseline? 1. Macular oedema present? 2. If yes, is this Cystoid? Cross check the same variables for previous visits to make sure no earlier occurrences 1. Macular oedema present? 2. If yes, is this Cystoid? Cross check the same variables for previous visits to make sure no earlier occurrences Presence of disc swelling? and cross check the same variable for previous Form prepared: 20/10/2016 v3.0 SYCAMORE Study Page 43 of 52

248 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Intraocular pressure Previous visit intraocular pressure Current intraocular pressure Raised pressure (>25mmHg) over 2 consecutive visits Hypotony (<6mmHg) over 2 consecutive visits Vision assessment Previous visit change from baseline Current visit change from baseline Unexplained and sustained reduction of 15 letters or more over 2 consecutive readings? Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment/Followup visit Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Intraocular pressure Intraocular pressure Intraocular pressure Intraocular pressure Vision assessment Vision assessment Vision assessment visits to make sure no earlier occurrences 1. Test conducted? 2. Intraocular pressure Cross-check value against previous visit 1. Test conducted? 2. Intraocular pressure Cross-check value against current visit 1. Test conducted? 2. Intraocular pressure Cross-check values against current and previous visit to see whether both are >25mmHG 1. Test conducted? 2. Intraocular pressure Cross-check values against current and previous visit to see whether both are <6mmHG 1. LogMAR score Cross-check values from previous visit and baseline and then calculate the difference and compare 1. LogMAR score Cross-check values from current visit and baseline and then calculate the difference and compare Calculate the LogMAR scores based on the number of letters recorded and also the chart type used Check that the changes in LogMAR score calculated for the two checks below reach the same conclusion as the Y/N for this question Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 44 of 52

249 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Summary Any new or worsened ocular comorbidity? (Any of above criteria ticked Yes ) N/A Treatment visit 3 (3 months) Note: remember to take into account unscheduled visits N/A Check all selected Y/N in this Ocular co-morbidities table give the correct Y/N for this question TABLE 4: PRIMARY OUTCOME COMPONENT CHECKS II Failure criteria [recorded for each study eye] SUN cell activity score [L/R] Baseline AC cells score Previous visit AC cells score Current AC cells score Increase in SUN cell activity score from baseline by 2-steps sustained over 2 consecutive readings [L/R] Baseline SUN cell activity score of 3+ or more without improvement over 2 consecutive readings [L/R] Partial improvement (1 grade) or no improvement, from baseline in SUN cell activity score plus CRF Treatment/Follow-up visit Treatment/Follow-up visit Treatment/Follow-up visit Treatment/Follow-up visit Treatment/Follow-up visit Treatment/Follow-up visit Raw data location Start assessing Section of CRF from which visit? Treatment visit 3 (3 months) Treatment visit 3 (3 months) Treatment visit 3 (3 months) Treatment visit 4 (6 months) Treatment visit 4 (6 months) Treatment visit 3 (3 months) Slit lamp examination Slit lamp examination Slit lamp examination Slit lamp examination Slit lamp examination Slit lamp examination & ocular co- Question(s) 1. AC cells Cross-check value against baseline visit 1. AC cells Cross-check value against previous visit 1. AC cells Cross-check value against current visit 1. AC cells Cross-check current and previous visit values against baseline visit to see whether both are 2-steps up from baseline AC cells reading 1. AC cells Cross-check current and previous visit values against baseline If baseline visit AC cells score is 3+ check to see whether both reading are AC cells 2. Any new or worsened ocular comorbidity? Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 45 of 52

250 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 sustained/development of co-morbidity (see table above) [L/R] Sustained baseline score of 1+ or 2+ over 2 consecutive readings after 6 months of treatment [L/R] Worsening of existing ocular comorbidity (see table above) [L/R] Permitted concomitant medications used against acceptable criteria as defined in the protocol [standalone Q] Concomitant medication used that are not allowed as defined in the protocol [standalone Q] Intermittent or continuous suspension of study treatment (adalimumab/placebo) for a cumulative period longer than 4 weeks [standalone Q] Treatment failure (Any of above criteria ticked Yes ) [L/R] Treatment/Follow-up visit Treatment/Follow-up visit Treatment visit 5 (12 months) Treatment visit 4 (6 months) Conmeds Treatment visit 1 (1 month) Conmeds Treatment visit 1 (1 month) 1. Treatment/Followup visit 2. Treatment diary Treatment/Follow-up visit Treatment visit 1 (1 month) Treatment visit 1 (1 month) morbidities Cross-check current visit values against baseline If no improvement or improvement of 1 grade from baseline visit AC cells score then check to see whether there is sustained/development of a comorbidity Slit lamp 1. AC cells examination Cross-check current and previous visit values against baseline If baseline visit AC cells score is 1+ or 2+ check to see whether both Ocular comorbidities Conmed type Conmed type 1. Participant in compliance with trial intervention 2. Study treatment dates All questions in Failure criteria reading are the same Worsening of existing ocular comorbidity questions Cross check conmed type against list of permitted concomitant medications used against acceptable criteria as defined in the protocol to identify any cases Cross check conmed type against list of concomitant medication used that are not allowed as defined in the protocol to identify any cases 1. Cross check to see whether yes / no selected corresponds 2. Check study treatment dates to identify intermittent or continuous suspension Check if any failure criteria are ticked yes that treatment failure is ticked Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 46 of 52

251 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 table yes L/R = Separate questions to assess for each eye Standalone Q = One question (not assessed for each eye separately) Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 47 of 52

252 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Appendix E: List of rules to be applied for missing data in sensitivity analysis (7) Note: For all of the situations for missing data below, for each patient the overall treatment failure will be the earliest occurrence of one. TABLE 5: LIST OF RULES TO BE APPLIED FOR MISSING DATA IN SENSITIVITY ANALYSIS (7) Component number 1)i) 1)ii) 1)iii) Component description Following at least 3 months of therapy: 2-Step increase from baseline in SUN cell activity score (AC Cells) over 2 consecutive readings Following at least 3 months of therapy: Sustained nonimprovement with entry grade of 3 or greater for 2 consecutive readings Following at least 3 months of therapy: Only partial Rule to handle missing data post-baseline in the study eye(s) For visits at 3 months or later, if missing AC cells score follows or precedes a visit that has a 2- step increase then assume this is also a 2-step increase so this will be a treatment failure for 1)i) at the second of the consecutive visits. For visits at 3 months or later, for those that enter the trial with a baseline score of 3+ or 4+: If missing AC cells score follows or precedes a visit that is 3+ or 4+ then assume this is also 3+ or 4+ so this will be a treatment failure for 1)ii) at the second of the consecutive visits. Scenario (1): For visits at 3 months or later, if there is partial Examples Baseline Month 2 Month 3 a 1+ b. 3+ or 4+ b 1+ b 3+ or 4+ b. a: This visit can be at Month 3 or later. b: Baseline score could be any of 1+, 2+, 3+, 4+ and at least a 2-step increase is assessed for 1)i). This situation would be a treatment failure for 1)i) at month 3. Baseline Month 6 Month 9 a 3+ or or or or 4+. a: This visit can be at Month 3 or later. This situation would be a treatment failure for 1)ii) at month 9. Disc swelling/macular oedema (DS/MO): Baseline Month 9 Month 12 a Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 48 of 52

253 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Component number Component description improvement (1 grade) or no improvement, from baseline, with development of other ocular co-morbidity* which is sustained Rule to handle missing data post-baseline in the study eye(s) improvement (1 grade) or no improvement from baseline & the development of other ocular co-morbidity has missing data at this visit or the previous visit (when one of the visits satisfies the criteria for the other ocular co-morbidity) then this will be a treatment failure for 1)iii) at the second of the consecutive visits i.e. this visit. Scenario (2): For visits at 3 months or later, if there is a missing AC score at this visit & the development of other ocular co-morbidity is satisfied over consecutive visits (this visit and previous visit) then this will be a treatment failure for 1)iii) at the second of the consecutive visits i.e. this visit. Examples (1) (2) AC cells score Presence of DS or MO AC cells score Presence of DS or MO 1+ b N/A c 0.5+ or 1+ b No. Yes d No Yes d. 1+ b N/A c. No Yes d Yes a: This visit can be at Month 3 or later. b: Baseline score could be any of 1+, 2+, 3+, 4+ and partial improvement (1 grade) or no improvement from baseline is assessed at subsequent visits. c: Score not needed to assess for 1)iii). d: This must be the first occurrence of DS/MO. These situations for scenario (1) and scenario (2) would be a treatment failure for 1)iii)DS/MO at month 12. Hypotony (IOP <6mmHg) or Raised IOP (IOP >25mmHg): Baseline Month 12 Month 15 a AC cells 2+ (1) N/A c 1+ or 2+ b score IOP No d. <6 score <6 No d <6. IOP No d. >25 score No d >25. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 49 of 52

254 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Component number Component description Rule to handle missing data post-baseline in the study eye(s) Examples >25 AC cells 2+ (2) N/A c. score IOP No d <6 <6 score <6 IOP score >25 No d >25 >25 a: This visit can be at Month 3 or later. b: Baseline score could be any of 1+, 2+, 3+, 4+ and partial improvement (1 grade) or no improvement from baseline is assessed at subsequent visits. c: Score not needed to assess for 1)iii). d: All patients cannot have at baseline. These situations for scenario (1) and scenario (2) would be a treatment failure for 1)iii)Hypotony/Raised IOP at month 15. Development of unexplained reduction in vision (LogMAR): Baseline Month 15 Month 18 a AC cells 3+ (1) b N/A c 2+ or 3+ b score LogMAR Any score score. A reduced score of 0.3 LogMAR units or more from baseline score Any A reduced. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 50 of 52

255 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Component number Component description Rule to handle missing data post-baseline in the study eye(s) Examples (2) AC cells score LogMAR score score score of 0.3 LogMAR units or more from baseline score 3+ b N/A c. Any score A reduced score of 0.3 LogMAR units or more from baseline score A reduced score of 0.3 LogMAR units or more from baseline score a: This visit can be at Month 3 or later. b: Baseline score could be any of 1+, 2+, 3+, 4+ and partial improvement (1 grade) or no improvement from baseline is assessed at subsequent visits. c: Score not needed to assess for 1)iii). 1)iv) Following at least 3 months of therapy: Worsening of existing (on enrolment) ocular comorbidity* after 3 months For visits at 3 months or later, for those that enter the trial with Yes selected for presence of disc swelling/macular oedema if at a later visit they have worsening of existing disc swelling/macular oedema missing they will be a treatment failure at this visit for worsening of existing (on enrolment) ocular These situations for scenario (1) and scenario (2) would be a treatment failure for 1)iii) Development of unexplained reduction in vision at month 18. No example required. Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 51 of 52

256 ST001TEM01 Statistical Analysis Plan v2.0 26/09/2012 Component number 1)v) Component description Sustained scores as recorded at entry grade measured over 2 consecutive readings (grades 1 to 2) still present after 6 months of therapy Rule to handle missing data post-baseline in the study eye(s) co-morbidity* after 3 months. For visits at 6 months or later, for those that enter the trial with a baseline score of 1+ or 2+: If missing AC cells score follows or precedes a visit that is 1+ or 2+ then assume this is also 1+ or 2+ so this will be a treatment failure for 1)v) at the second of the consecutive visits. Examples Baseline Month 6 Month 9 a , 2+, 3+ or , 3+ or a: This visit can be at Month 6 or later. This situation would be a treatment failure for 1)v) at month 9. * Ocular co-morbidities are defined as: i) Disc swelling and/or Cystoid Macular Oedema (CMO) as gauged clinically and where possible by OCT evidence; and/or: ii) Raised intraocular pressure (>25mm Hg) sustained over 2 consecutive visits not responding to single ocular hypotensive agent, and/or: iii) Hypotony (<6 mm Hg) sustained over 2 consecutive visits, and/or iv) Development of unexplained reduction in vision (LogMAR) over two consecutive visits of 0.3 LogMAR units (in the event of cataract participants will remain in trial, also if cataract surgery is required. Failure will still remain as described in endpoints above). Form prepared: 20/10/2016 v3.0 for SYCAMORE Study Page 52 of 52

257 SAP v2.0 (02/06/2016) changes from v1.0 (07/09/2015) 2. Definitions: MedDRA abbreviations added. 6.2 Baseline comparability of randomised groups Additional baseline characteristics listed following discussion with Chief Investigators. Skewness now not to be assessed to determine summary statistics. Mean, SD, median, IQR (upper and lower quartile) and range (maximum and minimum values) if data are normal and median, IQR and range if regardless of whether the data are skewed or not. Eye baseline characteristics to be presented in three ways: (i) Eye-level; (ii) Best-case; (iii) Worst-case. 12. Patient groups for analysis Description of end of blinded phase added. Any AEs recorded with an onset date after this 30-day cut off will be excluded. Protocol states that adverse event data should only be collected up to 30 days following cessation of treatment Adverse reactions/events MedDRA coding now used instead of manual categories. Updated severity*relationship cross-tab text to reflect how presented in ICH E3. Text removed as only used for IDSMC reports and not in CSR: Further details of the AEs classed as possibly, probably or almost certainly related to study drug will be presented as line listings detailing AE type, severity, whether an SAE, whether withdrew from drug as a result of AE, action taken and outcome. Additionally, of the AEs that are classified as not resolved / ongoing their severities will be listed. SAE line listings variables added following review of ICH E Analysis of primary outcome Addition of text to describe the lower limit for 3-months (components 1)i)-1)iv)) and 6-months (component 1)v)). Line listings tables will be presented for treatment withdrawals as well as treatment failures (separately). Unit of time for Kaplan-Meier analyses are weeks. Development of co-morbidity influence on treatment failure secondary analysis: further detail described for how to construct the model because the SAP text is vague. Development of uveitis in non-study eye secondary analysis: o Added description of consecutive visits of 1+ or more for development of uveitis. o A sensitivity analysis will be conducted to include patients that had a single AC cells score of 1+ or more (i.e. not sustained over consecutive visits) and were a treatment failure in their study eye at this same visit. This sensitivity analysis was added after the blind was broken so should be treated as a post-hoc analysis. The time to treatment failure in the other eye analysis did not make any sense and could not be interpreted. AM, AJ and PW saw the results. The decision was made to re-do the analysis as time to treatment failure in both eyes including information on the time to failure in the first eye. Post-hoc analysis added: Time to treatment response Sensitivity analyses for primary outcome Further clarification of the event dates added for sensitivity analyses (4), (5) and (6).

258 SAP v3.0 (20/10/2016) changes from v2.0 (02/06/2016) 14.1 Adverse reactions/events Of the AE/SAE analyses already listed in v2.0, additional detail added to each analysis for clarity to state whether the AE/SAE descriptions will be summarised using MedDRA SOC, MedDRA PT or both. The most commonly observed AEs in the adalimumab group, defined as those events with an incidence rate in the adalimumab group of 5%, will be presented (split by MedDRA SOC and PT) along with the rates for the placebo group and overall for the respective disorder. This addition to the CSR is for presentation purposes. The incidence rates for the AEs/SAEs will be presented by treatment group and overall along with 95% confidence intervals*. This addition to the CSR is to help with interpretation. * If the estimate is based on very few sample cases, the confidence interval can include a negative lower confidence limit. For these cases, the lower limits should be set to Extent of exposure The extent of trial treatment exposure will be summarised in terms of number of doses and total duration of treatment (days). This addition to the CSR is to help with interpretation.

259 A Randomised Controlled Trial of the Clinical Effectiveness, SafetY and Cost Effectiveness of Adalimumab in Combination with MethOtRExate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis (SYCAMORE) Eudract No Statistical Analysis Plan Secondary outcomes ORIGINATED BY QC PERFORMED BY APPROVED BY Name Naomi Bacon N/A Susie Dodd Title Date Protocol Version and Date Blinded Statistician N/A 11/04/2016 Version /04/2015 Senior Blinded Statistician Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 1 of 41

260 1. Change Control Protocol version Updated SAP version no. Section number changed Description of change Date changed Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 2 of 41

261 2. Approval and agreement At a minimum two versions of the SAP should be approved and stored within the statistics trial file. 1. SAP version 1.0 should be created after it has been reviewed and signed-off to ensure all are in agreement with the planned analysis and no further changes are foreseen. 2. The final SAP version should be converted to PDF and signed following the blinded review for protocol deviations and immediately prior to database lock as evidence of the analysis planned prior to unblinding of the study. SAP Version Number being approved: Trial Statistician Name Signed Date Senior Statistician Name Signed Date Chief Investigator/clinical lead Name Signed Date OR Electronic approval attached Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 3 of 41

262 3. Roles and responsibilities N Bacon (Department of Biostatistics, University of Liverpool): Blinded Statistician, S Dodd (Department of Biostatistics, University of Liverpool): Senior Blinded Statistician, G Hickey (Department of Biostatistics, University of Liverpool): Blinded Statistician, R Kolamunnage Dona (Department of Biostatistics, University of Liverpool): Senior Blinded Statistician, A Vaidyanathan Ramanan (Department of Paediatric Rheumatology, Bristol Royal Hospital for Children): Co-Chief Investigator, M Beresford (University of Liverpool): Co-Chief Investigator Author s contributions N Bacon and S Dodd proposed the statistical analysis plan. N Bacon, G Hickey and R Kolamunnage Dona drafted the manuscript. S Dodd, A Vaidyanathan Ramanan and M Beresford read, amended and approved the statistical analysis plan. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 4 of 41

263 4. List of abbreviations and definitions of terms ACR AE CHAQ CHQ CRF CTRC CTU DMARD IDSMC IMP ITT JIA MCRN MTX OCT RCT SAE SAP S/C MTX SOP SUN SYCAMORE TNF American College of Rheumatology Adverse Event Childhood Health Assessment Questionnaire Childhood Health Questionnaire Case Report Form Clinical Trials Research Centre Clinical Trials Unit Disease Modifying Anti-Rheumatic Drugs Independent Data and Safety and Monitoring Committee Investigational Medicinal Product Intention to Treat Juvenile Idiopathic Arthritis Medicines for Children Research Network Methotrexate Optical Coherence Tomography Randomised Controlled Trial Serious Adverse Event Statistical Analysis Plan Subcutaneous Methotrexate Standard Operating Procedure Standardisation of the Uveitis Nomenclature A Randomised Controlled Trial of the Clinical Effectiveness, SafetY and Cost Effectiveness of Adalimumab in Combination with MethOtRExate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis Tumor Necrosis Factor Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 5 of 41

264 Contents 1. Change Control Approval and agreement Roles and responsibilities List of abbreviations and definitions of terms Statement of Compliance Background and Rationale SYCAMORE Study Objectives Investigational Plan and Study Design Overall study design and plan- description Treatments studied Treatment compliance Patient population studied Inclusion criteria Exclusion criteria Removal of patients from therapy or assessment Consent process Blinding Method of assignment to treatment Sequence and duration of all study periods Schedule of assessments Listing of Outcomes Primary outcome(s) Secondary outcomes Determination of Sample Size Study Framework Confidence Intervals, p-values and Multiplicity Timing and Objectives of Interim and Final Analyses Interim monitoring and analyses Final analysis Disposition of Participants Screening, eligibility and recruitment Post randomisation discontinuations Protocol Deviations Unblinding Efficacy Evaluations Data Sets Analysed Demographic and Other Baseline Characteristics Compliance with treatment Analysis of outcomes Primary Outcome Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 6 of 41

265 18.2 Number of participants failing treatment Incremental cost-effectiveness and cost-utility of adalimumab added to MTX compared with MTX alone Health status according to the multi-attribute health utility index, HUI Safety, tolerability and compliance Use of Corticosteroids over duration of study period and throughout follow up Optic and ocular Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ)) American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels Number of participants undergoing disease flare, in remission on and off medication of their JIA and with minimum disease activity Number participants requiring change in biologic / Disease-modifying antirheumatic drugs (DMARDs) therapy due to failure to respond from arthritis Missing data and withdrawals Additional analyses Vital signs Physical exam Safety Evaluations Data sets analysed Presentation of the data Quality Control References Appendix I Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 7 of 41

266 ST001TEM01 Statistical Analysis Plan v3.0 19/10/ Statement of Compliance This Statistical Analysis Plan (SAP) provides a detailed and comprehensive description of the pre-planned final analyses for the secondary outcomes and safety for the study SYCAMORE. The planned statistical analyses described within this document are compliant with those specified in brief within the SYCAMORE protocol version /04/2015. This SAP comprehensively describes in the planned final analyses for the secondary outcomes. This study is carried out in accordance with the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989) and South Africa (1996) amendments and will be conducted in compliance with the protocol, Clinical Trials Research Centre (CTRC) Clinical Trials Unit (CTU) Standard Operating Procedures (SOPs) and EU Directive 2001/20/EC, transposed into UK law as the UK Statutory Instrument 2004 No 1031: Medicines for Human Use (Clinical Trials) Regulations These planned analyses will be performed by the trial statistician. The results of the final analysis described within this statistical analysis plan will be contained within a statistical analysis report. This report will be used as the basis of the primary research publications according to the study publication plan. All analyses are performed with standard statistical software (SAS version 9.3 or later). The finalised analysis datasets, programs and outputs will be archived following Good Clinical Practice guidelines and SOP TM021 Archiving procedure in CTRC. The testing and validation of the statistical analysis programs will be performed following SOP ST001. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 8 of 41

267 6. Background and Rationale Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA also are at risk of inflammation of the uvea in the eye (uveitis). Defining the severity of inflammation and structural complications in uveitis patients can now be more consistently described following Standardised Uveitis Nomenclature (SUN) guidelines, allowing their incorporation into design of randomised controlled trials (RCT) and cohort studies. Despite current screening and therapeutic options (pre-biologics) 10-15% of children with JIA associated uveitis may eventually develop bilateral visual impairment and are certified legally blind. It is therefore critical to find more effective therapeutic interventions. Methotrexate (MTX) is well established as the first-line disease modifying agent in the management of JIA. MTX is also thought to be effective for JIA-associated uveitis in children with moderate-to-severe uveitis, but there have been no prospective randomised placebocontrolled trials of MTX or steroid regimens in JIA-associated uveitis. Adalimumab is a fully human monoclonal antibody engineered by gene technology that uses site-directed mutagenesis to enhance its binding efficiency to tumor necrosis factor (TNF). It does not contain nonhuman or artificial protein sequences. There are no prospective studies of efficacy and safety of anti-tnf agents in JIA-associated uveitis. In the randomised controlled trial of adalimumab in JIA that demonstrated safety and efficacy, the most commonly reported adverse events were infections and injection-site reactions. Serious adverse events considered possibly related to study drug by the investigator occurred in 14 patients. 7. SYCAMORE Study Objectives The primary objective of this study is to compare the clinical effectiveness of adalimumab in combination with methotrexate (MTX) versus MTX alone, with regard to controlling disease activity in refractory uveitis associated with juvenile idiopathic arthritis (JIA). The secondary objectives of this study are: To evaluate short term safety and tolerability of adalimumab in combination with MTX versus MTX alone, with regards ocular complications of treatment, adverse events and laboratory assessments To determine quality of life and cost effectiveness of adalimumab in combination with MTX versus MTX alone in severe uveitis associated with JIA To determine the clinical effectiveness of adalimumab in combination with MTX versus MTX alone, with regard underlying JIA disease activity To determine the durability and magnitude of adalimumab efficacy response in sustaining inactive disease and achieving complete clinical remission To determine the long term safety of adalimumab in combination with MTX versus MTX alone To assess the efficacy of treatment with adalimumab to permit concomitant medication reduction, in particular regional and parenteral steroids Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 9 of 41

268 To develop a fully consented, trial-related Tissue Bank for collection of serum, DNA and RNA for subsequent investigation The null hypothesis underlying this trial is that there is no significant difference between adalimumab and placebo in controlling disease activity of JIA-associated uveitis unresponsive to MTX therapy. 8. Investigational Plan and Study Design 8.1. Overall study design and plan- description This study is a prospective, multi-centre, randomised, double-blind, placebo-controlled, superiority study of adalimumab in combination with methotrexate (MTX) in patients with active uveitis in association with JIA refractory to MTX monotherapy Treatments studied The active study drug is adalimumab. All participants will receive a stable dose of MTX and in addition either adalimumab (20mg/0.8ml for patients <30kg or 40mg/0.8ml for patients weighing 30kg, s/c injection every 2 weeks based on body weight), or placebo (0.8ml as appropriate according to body weight) s/c injection every 2 weeks Treatment compliance See section 9.9 of the study protocol for details on treatment compliance Patient population studied 90 patients with persistently active JIA-associated uveitis (despite optimised methotrexate (MTX) treatment for at least 12 weeks) Inclusion criteria See section 7.1 of the study protocol for the inclusion criteria Exclusion criteria See section 7.2 of the study protocol for the exclusion criteria Removal of patients from therapy or assessment See section of the study protocol for information on withdrawal from trial intervention Consent process See section 8.2 of the protocol for details on the consent process. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 10 of 41

269 8.9. Blinding SYCAMORE is a double-blind trial, so both the patient and the researcher are blinded to the allocation. Investigational medicinal products (IMPs) are supplied as bulk stock from the distributor to pharmacy in kits. Pharmacy must ensure that the participant and the researcher remain blinded to the treatment allocation. The statistician needs to define the ITT analysis population as per section 17.1 before obtaining the treatment allocations Method of assignment to treatment See section 3 of Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for details on randomisation Sequence and duration of all study periods The study flow diagram detailing the flow of participants through the trial can be found in section 3 of the study protocol. To summarise this information, once a patient has been assessed for eligibility and provided consent they will be randomised into SYCAMORE. They will undergo one injection (either Adalimumab or placebo) every 2 weeks plus a weekly dose of MTX for both arms. This will continue for 18 months post randomisation or until treatment failure. Patients will be assessed for treatment failure each month for the first 3 months. After this they will be assessed every three months until 18 months post randomisation. If a patient experiences treatment failure or reaches 18 months without treatment failure, they will be followed up until 24 months after randomisation Schedule of assessments A schematic detailing the study visits and assessments can be found in section 10.1 of the study protocol. 9. Listing of Outcomes 9.1. Primary outcome(s) This SAP refers to the secondary outcomes only. See section of the study protocol for details on the primary outcome Secondary outcomes 1) Number of participants failing treatment Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 11 of 41

270 2) Incremental cost-effectiveness and cost-utility of adalimumab added to MTX compared with MTX alone 3) Health status according to the multi-attribute health utility index, HUI2 4) Safety, tolerability and compliance a. Adverse events (AEs) and serious adverse events (SAEs) b. Laboratory parameters (haematological and biochemical analysis and urinalysis) c. Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period 5) Use of Corticosteroids over duration of study period and throughout follow up, including: a. Total oral corticosteroid dose b. Reduction in and rate of systemic corticosteroid dose from entry dose c. Topical corticosteroid use (frequency) compared to entry usage d. Need for pulsed corticosteroid 6) Optic and ocular a. Number of participants having disease flares (as defined by worsening on SUN criteria) following minimum 3 months disease control b. Number of participants having disease flares within the first 3 months. c. Visual acuity measured by Age-appropriate LogMar assessment d. Number of participants with resolution of associated optic nerve or macular oedema (as assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) (where available). e. Number of participants with disease control (defined as zero cells, with topical treatment for 3 and 6 months) f. Number of participants entering disease remission (defined as zero cells, without topical treatment for 3 and 6 months) g. Duration of sustaining inactive disease (zero cells, with or without topical treatment) 7) Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ)) 8) American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels. 9) Number of participants undergoing disease flare, in remission on and off medication of their JIA and with minimum disease activity Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 12 of 41

271 10) Number participants requiring change in biologic / Disease-modifying anti-rheumatic rugs (DMARDs) therapy due to failure to respond from arthritis. 10. Determination of Sample Size See section 11.3 of the study protocol for details on the sample size. 11. Study Framework The overall objective for each of the secondary outcomes is to test the superiority of adalimumab in combination with methotrexate (MTX) compared with MTX with placebo. 12. Confidence Intervals, p-values and Multiplicity All applicable statistical tests will be two-sided and will be performed using a 5% significance level; confidence intervals presented will be 95%. No adjustment will be made for multiplicity for the secondary outcomes. 13. Timing and Objectives of Interim and Final Analyses Interim monitoring and analyses See section 3.2 of Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for details on interim monitoring and analyses Final analysis The end of the trial will be considered as the date of the final database lock. 14. Disposition of Participants Screening, eligibility and recruitment See section 6.1 of Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for details on how the screening, eligibility and recruitment on participants will be presented Post randomisation discontinuations See section 17 of Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for details on how missing data/withdrawals will be reported and handled. 15. Protocol Deviations Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 13 of 41

272 See section 13 of Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for details on how protocol deviations will be reported and handled. 16. Unblinding See section 11 of Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for details on unblinding. Further details regarding unblinding can be found in section 9.11 of the study protocol. 17. Efficacy Evaluations Data Sets Analysed The principle of intention-to-treat (ITT), as far as is practically possible, will be the main strategy of the analysis adopted for the secondary outcomes. Patients that withdrew consent for trial continuation will contribute outcome data up until the point of withdrawal unless the patients parents/guardians specifically request that the data are not to be used. The membership of the analysis set for each outcome will be determined and documented and reasons for participant exclusion will be given prior to the blind being broken and the randomisation lists being requested. Reasons may include missing data, loss to follow up and treatment withdrawal. Patients to be excluded from the secondary analysis population will be defined in template ST001TEM03 Protocol deviations and population exclusions template and this will be agreed and approved prior to any release of randomisation codes. For safety outcomes, any dates that have the month and year recorded but not the specific day will be imputed as being the middle of the month (the 15 th ). For efficacy outcomes, any dates that have the month (mm) and year (yyyy) recorded but not the specific day will be imputed as the start of the month (01/mm/yyyy). Any dates that have the year (yyyy) recorded but not the specific day or month will be imputed as the start of the year (01/01/yyyy) Demographic and Other Baseline Characteristics See section 6.2 of Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for details on how the baseline characteristics for participants will be presented Compliance with treatment See section 9 of Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for details on compliance with treatment. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 14 of 41

273 18. Analysis of outcomes 18.1 Primary Outcome This SAP only considers the secondary outcomes. See Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for full details on the primary outcome Derivation See section Analysis See section Number of participants failing treatment Derivation See Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for full details on how to derive treatment failure. If a patient has both eyes eligible in the trial then they need to fail treatment on at least one eye to be classed as an event (of treatment failure) Analysis The data will be summarised by the number (and percentage) of patients that failed treatment by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p-value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran-Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. The risk ratio will be calculated as per Appendix I, with the event being treatment failure. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh Incremental cost-effectiveness and cost-utility of adalimumab added to MTX compared with MTX alone This is a health economics outcome and is not considered within this SAP Derivation See section 18.3 Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 15 of 41

274 Analysis See section Health status according to the multi-attribute health utility index, HUI2 This is a health economics outcome and is not considered within this SAP Derivation See section Analysis See section Safety, tolerability and compliance Adverse events (AEs) and serious adverse events (SAEs) Derivation Adverse events can be found on CRF AE Report form. Serious adverse events can be found on CRF SAE report. See section 14.1 of Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data for details on how the S/AEs are reported and presented Analysis See section Laboratory parameters (haematological and biochemical analysis and urinalysis) Derivation The laboratory parameters for haematological and biochemical analysis can be found on subsection Subform Haematological and Biochemical Assessments of the treatment visit CRF under Haematological Assessments and Biochemical Assessments. It can also be found here whether the assessment result was Normal, Abnormal or Not done, and also whether the result was Clinically significant (only applicable if the result was abnormal). The parameters to be reported on for haematological assessments are: Heamatocrit Haemoglobin Red blood cell count White blood cell count Neutrophils Lymphocytes Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 16 of 41

275 Monocytes Basophils Eosinophils Platelet count Erythrocyte sedimentation rate Plasma viscosity (only done if ESR not available The parameters to be reported on for biochemical assessments are: C- Reactive protein (CRP) Urea Creatinine Sodium Potassium Calcium Inorganic phosphate Glucose Chloride Bicarbonate Total bilirubin Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) The laboratory parameters for urinalysis can be found on subsection Subform Urinalysis Test, Physical Exam, Vital Signs and Physician global assessment of disease of the treatment visit CRF under Urinalysis test. It can also be found here whether the assessment result was Normal or Abnormal, and also whether the result of Microscopic urinalysis was Clinically significant (only applicable if the result was abnormal). The parameters to be reported on for urinalysis are: Protein Glucose Blood Leukocyte esterase Specific gravity ph Every item under these sections will be presented at baseline and months 1, 2, 3, 6, 9, 12, 15 and 18 for patients with data at these time points. Patients who withdrew from treatment or failed treatment prior to 18 months will only have their data analysed up to the point of withdrawal/treatment failure and will not contribute further data to the analysis. Any data on Unscheduled visits will not be reported. Due to differences in equipment across the sites, some values may have an upper/lower limit rather than an exact value. For when a value has an upper limit (for example <5 ), then the value of 0 should be used as this is the most extreme value a recording could be. In the Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 17 of 41

276 instances when a value has a lower limit (for example >10 ) then the lower limit should be used (in this example 10 ) as it is not practical to use a value of infinity Analysis No formal analysis will be undertaken for this outcome. Mean profile plots and individual plots by treatment groups will be presented for every haematological and biochemical assessment. 1-standard error bars will be displayed for each visit on the mean profile plots. Summary statistics will also be presented in a table for each time point detailing the number of normal/abnormal/not done assessments, and for the abnormal results the frequency and percentage of clinically significant results for each haematological, biochemical and urinalysis assessment. For the haematological and biochemical assessments, a table will be presented as line listings for each patient detailing the time point, the assessments done and the result. Abnormal values will be highlighted with an asterisk. Separate tables will be presented as line listings for the abnormal values detailing whether they are expected for the patient s condition, whether the result was clinically significant (yes/no) and the free text comments (if completed). For each time point the following will be presented: mean, SD, median, IQR, range, and the number of patients with abnormal values. Tables for each time point will detail the mean change from baseline for each of the haematological and biochemical assessments. For urinalysis, a table will be presented for each time point as line listings for each patient detailing the assessments done, whether the result was abnormal/normal and whether the result was clinically significant (yes/no) Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period Derivation CRF Treatment diary shows the number of injections given for each participant. These are used to determine compliance with the trial treatment. The number of suspected missing doses is the difference between the expected number of doses and CRF Accountability Log shows the number of vials issued and the number returned (both used and unused) Analysis No formal analysis will be undertaken for this outcome. Summary statistics will be presented as line listings per patient by treatment including information of expected number of IMP doses, actual number of IMP doses, number of suspected missing doses, number of vials issued, number of vials returned used and number of vials returned unused. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 18 of 41

277 18.6 Use of Corticosteroids over duration of study period and throughout follow up Total oral corticosteroid dose Derivation Oral corticosteroid dose can be found on CRF Concomitant Medication Form and are defined as all prednisolone medications (under Medication (generic name) ) given orally (Route code 2). To derive the duration of period study period see Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data. If the concomitant medication form does not specify which eye a particular dose is for then it is assumed that the medication is for the eligible eye/eyes. The total dose is calculated by summing the daily doses of each oral treatment on the Concomitant Medication Form from the start date to the end date until 18 months/withdrawal/treatment failure (the cut off date for the primary outcome analysis data set). If no end date is recorded on the Concomitant Medication Form then it will be assumed that the patient is still receiving the treatment until a new oral corticosteroid treatment is recorded or the cut off date for the primary outcome analysis data set is reached. The total dose should be summed across each treatment arm and standardised to per patient years for that treatment. This is calculated by dividing the total oral dose in each arm by the cumulative years all patients in the corresponding arm are on treatment for Analysis The incident rate ratio and 95% confidence intervals will be presented based on Poisson regression. The PROC GENMOD command will be used in SAS, specifying the poission distribution and using the log link function. Including the ILINK option applies the inverse link function to provide rate estimates. The CL option produces confidence intervals for the rates 6. If overdispersion is present (i.e. if the mean and variance are not equal), a negative binomial model will be used instead Reduction in systemic corticosteroid dose from entry dose Derivation The analysis set of this outcome is a subset of all patients, as not everyone will be taking systemic corticosteroids at randomisation. This outcome will have two analyses undertaken: the time to reduction of systemic corticosteroid dose to <5mg/day, and the time to reduction of systemic corticosteroid dose to 0mg/day. Systemic corticosteroids can be found on CRF Concomitant Medication Form and are classed as systemic on the database. The entry dose should be identified by taking the dose of a systemic corticosteroid entry on the Concomitant Medication Form which crosses the randomisation date. If the concomitant medication form does not specify which eye a particular dose is for then it is assumed that the medication is for the eligible eye/eyes. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 19 of 41

278 Analysis Censoring within this time to event outcome will occur at treatment failure. This means that a competing risks model is needed, as patients with treatment failure are informatively censored (at a lower risk than those who do not have treatment failure). Therefore a competing risks model will be used with the two competing events being reduction in systemic corticosteroid dose and treatment failure. The numbers with a reduction in systemic corticosteroid dose will be presented at each time point (baseline and months 1, 2, 3, 6, 9, 12, 15 and 18). The competing risks analysis will be performed using the Fine and Gray model. The cmprsk package in R will be used for this analysis 7. The Cumulative incidence plots will be presented for each arm. Hazard ratios will be calculated and presented with 95% confidence intervals, for each treatment comparison and each risk Rate of systemic corticosteroid dose Derivation Systemic corticosteroids can be found on CRF Concomitant Medication Form and are classed as systemic on the database. If the concomitant medication form does not specify which eye a particular dose is for then it is assumed that the medication is for the eligible eye/eyes. The total dose is calculated by summing the daily doses of each systemic corticosteroid treatment on the Concomitant Medication Form from the start date to the end date until 18 months/withdrawal/treatment failure (the cut off date for the primary outcome analysis data set). If no end date is recorded on the Concomitant Medication Form then it will be assumed that the patient is still receiving the treatment until a new systemic corticosteroid treatment is recorded or the cut off date for the primary outcome analysis data set is reached. The total systemic corticosteroid dose should be summed across each treatment arm and standardised to per patient years for the corresponding treatment. This is calculated by dividing the total systemic corticosteroid dose in each arm by the cumulative years all patients in the corresponding arm are on treatment for. To derive the duration of period study period see Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data Analysis The incident rate ratio and 95% confidence intervals will be presented based on Poisson regression. The PROC GENMOD command will be used in SAS, specifying the poission distribution and using the log link function. Including the ILINK option applies the inverse link function to provide rate estimates. The CL option produces confidence intervals for the rates 6. If overdispersion is present (i.e. if the mean and variance are not equal), a negative binomial model will be used instead. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 20 of 41

279 Topical corticosteroid use (frequency) compared to entry usage Derivation This outcome is the time to reduction to 1 drop for those patients already on >1 drop at baseline. Topical corticosteroids can be found on CRF Concomitant Medication Form and are defined as: prednisolone, dexamethasone, betamethasone, fluorometholone or lotemax (under Medication (generic name) ) given topically (Route code 5). A concomitant medication form should be completed for each patient at baseline and each treatment visit. If the concomitant medication form does not specify which eye a particular dose is for then it is assumed that the medication is for the eligible eye/eyes Analysis Censoring within this time to event outcome will occur at treatment failure. This means that a competing risks model is needed, as patients with treatment failure are informatively censored (at a lower risk than those who do not have treatment failure). Therefore a competing risks model will be used with the two competing events being reduction to 1 drop and treatment failure. The competing risks analysis will be performed using the Fine and Gray model. The cmprsk package in R will be used for this analysis 7. The Cumulative incidence plots will be presented for each arm. Hazard ratios will be calculated and presented with 95% confidence intervals, for each treatment comparison and each risk Need for pulsed corticosteroid Derivation Pulsed corticosteroids can be found on CRF Concomitant Medication Form and are classed as pulsed on the database. A concomitant medication form should be completed for each patient at baseline and each treatment visit. If the concomitant medication form does not specify which eye a particular dose is for then it is assumed that the medication is for the eligible eye/eyes. If a patient has had at least one pulsed corticosteroid at any time during the treatment period then they are classed as yes Analysis The data will be summarised by the number (and percentage) of patients that need pulsed corticosteroids by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p-value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran- Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 21 of 41

280 The risk ratio will be calculated as per Appendix I, with the event being need for pulsed corticosteroids. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh Optic and ocular Number of participants having disease flares (as defined by worsening on SUN criteria) following minimum 3 months disease control Derivation Disease control is when a patient has a score of 0 for the field AC cells (SUN) for 3 months (12 weeks ± 7 days i.e. at least 11 weeks) from randomisation within each eligible eye and has had at least one topical treatment during this time. AC SUN cells can be found on subsection Subform Vision assessment and Slit lamp examination of the treatment visit CRF. Topical treatment is found on CRF Concomitant Medication Form and is defined as any treatment given topically (Route code 5). If the concomitant medication form does not specify which eye a particular dose is for then it is assumed that the medication is for the eligible eye/eyes. Disease flares are defined as an increase in the AC cells (SUN) score at two consecutive visits at least 4 weeks apart. According to section 10 of the SYCAMORE protocol v6.0 17/04/2015 there is an allowance of -7days/+7 days will be allowed for monthly visits and - 15days/+15days for the 3 monthly visits. Therefore, for assessing disease flares at the 3- month scheduled treatment visit (the first visit where the assessment for disease flares requires consecutive visits) an interval of 5 weeks will be used to account for the allowance of 7 days. All scheduled treatment visits following the 3-month treatment visit are 3 monthly so the 4-week interval is sufficient. Unscheduled visits need to be taken into account when assessing disease flares, if this was carried out at the unscheduled visit. If the interval is less than 4 weeks then the next previous visit that is at least 4 weeks prior will be used to assess disease flares against the current visit. If a patient has both eyes eligible in the trial then they must have disease flares on at least one eye to be classed as an event Analysis Two analyses will be performed for this outcome: 3 months disease control and a flare in at least one eye, and 3 months disease control in both eyes and a flare in at least one eye. The numbers and percentages of patients with 3 months disease control in at least 1 eye and patients with 3 months disease control in both eyes will be presented. The data will be summarised by the number (and percentage) of patients that experienced at least one disease flare by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p-value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran- Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 22 of 41

281 The risk ratio will be calculated as per Appendix I, with the event being at least one disease flare. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh 5. The number and percentage of patients who did not have 3 months disease control will be reported by treatment group. Additionally, the number and percentage of patients who experienced at least one disease flare and then went on to later fail treatment will be reported Number of participants having disease flares within the first 3 months Derivation See section for details on how to derive whether a participant has had disease flares. The number of participants having disease flares within the first 3 months should be calculated from randomisation up to 3 months (12 weeks ±7 days i.e. at least 11 weeks) Analysis The data will be summarised by the number (and percentage) of patients that experienced at least one disease flare in the first 3 months by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p- value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran-Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. The risk ratio will be calculated as per Appendix I, with the event being at least one disease flare within the first 3 months. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh 5. The number and percentage of patients who experienced at least one disease flare within the first 3 months and then went on to later fail treatment will be reported Visual acuity measured by Age-appropriate LogMar assessment (change in assessment over time) Derivation This can be found on subsection Subform Vision assessment and Slit lamp examination of the treatment visit CRF under LogMar score for the right and left eye Analysis Summary statistics will also be presented in a table for each time point detailing the mean and median values of the LogMar assessment for each treatment arm and overall. This table will report the scores for the eligible eye only. If a patient was eligible based on both eyes then the table will include their worst score and best score in respective columns. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 23 of 41

282 The following analysis will be applied to two analysis sets to account for patients with two study eyes. The first set will include all patients with one study eye, and for the patients with two study eyes, the worst LogMar score of the two eyes will be taken. The second set will include all patients with one study eye, and for the patients with two study eyes, the best LogMar score of the two eyes will be taken. Mean profile plots and individual plots by treatment groups will be presented. 1-standard error bars will be displayed for each visit on the mean profile plots. This will provide a visual representation of the variation patients may experience in terms of their LogMar score at each scheduled treatment visit between treatment arms. Usually, longitudinal data vs time is plotted (where time goes from 0 to t > 0). However in joint modelling the relationship between longitudinal data and the event of treatment failure should be examined and so longitudinal data vs time backward is plotted since the event had been occurred. By reversing the time-axis, variation in LogMar of an individual prior to treatment failure will be examined. The problem of patients having differing amounts of missing data due to treatment failure (and therefore completing follow-up earlier than patients with a later treatment failure time) will be addressed through a more advanced analysis of joint modelling of the longitudinal data of the LogMar score and the time to treatment failure. Joint modelling accounts for the informative missingness in longitudinal LogMar score due to treatment failure 8. If LogMar score is not normally distributed, then a log with base e transformation is used. Patients who did not fail treatment will be censored at the time of the last treatment visit (month 18). This analysis will be undertaken using the joiner 9 package in R which uses a maximum likelihood estimation approach (using the EM algorithm) with a Cox PH model for the baseline hazards. Estimates from both the longitudinal and event-time sub-models and the corresponding p-values will be presented Number of participants with resolution of associated optic nerve or macular oedema (as assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) (where available) Number of participants with resolution of associated optic nerve Derivation These can be found on subsection Subform Intraocular Pressure, Fundoscopy examination and Optical Coherence Tomography of the treatment visit CRF under the field Optic nerve (tick if yes) for both the right and left eyes. If Normal is selected then this is defined as not having associated optic nerve, and if Neovascularisation or Glaucomatous neuropathy are selected then this is defined as having associated optic nerve. If a patient is recorded as having no associated optic nerve but was recorded as having associated optic nerve at the previous visit then this means it has resolved (and classed as a Yes for this binary outcome. The analysis set for this outcome will be patients who have associate optic nerve at baseline or who develop this at any point during the trial. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 24 of 41

283 Analysis Two analyses will be performed for this outcome: resolution in at least 1 eye, and resolution in both eyes. The numbers and percentages of patients with resolution in at least 1 eye and patients with resolution in both eyes will be presented. The data will be summarised by the number (and percentage) of patients with resolution of associated optic nerve by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p-value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran- Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. The risk ratio will be calculated as per Appendix I, with the event being resolution of associated optic nerve. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh 5. In the analysis set for this outcome the percentage of people with resolution of associated optic nerve will be reported (with the denominator being patients who have associate optic nerve at baseline or who develop this at any point during the trial, and the numerator being those with resolution). The number of people who do not experience this at any point during the trial will also be presented. Alongside this, the number of patients that develop associated optic nerve, is resolved, and then develop this again will be reported Number of participants with resolution of macular oedema Derivation These can be found on subsection Subform Intraocular Pressure, Fundoscopy examination and Optical Coherence Tomography of the treatment visit CRF under the field Macular oedema present? for both the right and left eyes. The analysis set for this outcome will be patients who have macular oedema at baseline or who develop this at any point during the trial. The data for the ocular co-morbidity defined as Macular Oedema (MO) as gauged clinically and where possible by OCT evidence is collected through a fundoscopy assessment and/or OCT assessment. As OCT is more sensitive it can detect macular oedema that is not obvious on fundoscopy. Therefore, if there are conflicting results between fundoscopy and OCT then the OCT result will be used Analysis Two analyses will be performed for this outcome: resolution in at least 1 eye, and resolution in both eyes. The numbers and percentages of patients with resolution in at least 1 eye and patients with resolution in both eyes will be presented. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 25 of 41

284 The data will be summarised by the number (and percentage) of patients with resolution of macular oedema by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p-value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran- Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. The risk ratio will be calculated as per Appendix I, with the event being resolution of macular oedema. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh 5. In the analysis set for this outcome the percentage of people with resolution of macular oedema will be reported (with the denominator being patients who have macular oedema at baseline or who develop this at any point during the trial, and the numerator being those with resolution). The number of people who do not experience this at any point during the trial will also be presented. Alongside this, the number of patients that develop macular oedema, is resolved, and then develop this again will be reported Number of participants with disease control (defined as zero cells, with topical treatment for 3 and 6 months) Derivation See section for details on disease control. This will be assessed separately for 3 months (12 weeks ± 7 days i.e. at least 11 weeks) and for 6 months (24 weeks ± 14 days i.e. at least 12 weeks) Analysis Two analyses will be performed for this outcome: disease control in at least 1 eye, and disease control in both eyes. The numbers and percentages of patients with disease control in at least 1 eye and patients with disease control in both eyes will be presented. The data will be summarised by the number (and percentage) of patients with disease control by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p-value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran-Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. The risk ratio will be calculated as per Appendix I, with the event being disease control. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh 5. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 26 of 41

285 Number of participants entering disease remission (defined as zero cells, without topical treatment for 3 and 6 months) Derivation This will be assessed separately for 3 months (12 weeks ± 7 days i.e. at least 11 weeks) and for 6 months (24 weeks ± 14 days i.e. at least 22 weeks). Disease remission is when a patient has a score of 0 for the field AC cells (SUN) on the subsection Subform Vision assessment and Slit lamp examination of the treatment visit CRF and has not had topical treatment at any point during the 3/6 months. Topical treatment is found on CRF Concomitant Medication Form and is defined as any given topically (Route code 5). If the concomitant medication form does not specify which eye a particular dose is for then it is assumed that the medication is for the eligible eye/eyes Analysis Two analyses will be performed for this outcome: disease remission in at least 1 eye, and disease remission in both eyes. The numbers and percentages of patients with disease remission in at least 1 eye and patients with disease remission in both eyes will be presented. The data will be summarised by the number (and percentage) of patients entering disease remission by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p-value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran-Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. The risk ratio will be calculated as per Appendix I, with the event being disease remission. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh 5. In the analysis set for this outcome the percentage of people with disease remission will be reported. The number of people who do not experience this at any point during the trial will also be presented. Alongside this, the number of patients that enter disease remission more than once (and the number of times disease remission is entered) will be reported Duration of sustaining inactive disease (zero cells, with or without topical treatment) Derivation Inactive disease is when a patient has a score of 0 for the field AC cells (SUN) on subsection Subform Vision assessment and Slit lamp examination of the treatment visit CRF. This is measured at each follow-up visit and unscheduled visits. The duration of sustaining inactive disease is calculated by summing the total consecutive months in which a Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 27 of 41

286 patient has a score of 0 AC SUN cells. If a patient has a score of 0 AC SUN cells for just one visit then this is not classed as sustained inactive disease, i.e. a patient must have consecutive visits with a score of Analysis A random intercept model will be used to account for the correlation between eyes within patients. The outcome variable will be duration of sustaining inactive disease and the covariates will be treatment group and eye. Treatment effect estimates and confidence intervals will be estimated in SAS using the procedure PROC MIXED. The options solution and cl will be added to give the parameter estimates and confidence intervals, respectively Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ)) CHQ Derivation Refer to the PDF held on the CD Child Heath Questionnaire (CHQ) Scoring and Interpretation Manual (pages regarding the CHQ-PF50) 11 for details on how to derive the overall score for the CHQ, as this cannot be reproduced within this SAP due to copyright Analysis This will be analysed using joint modelling as described in section Mean profile plots and individual plots by treatment groups will be presented. 1-standard error bars will be displayed for each visit on the mean profile plots. This will provide a visual representation of the variation patients may experience in terms of their overall CHQ score at each scheduled treatment visit between treatment arms CHAQ Derivation This is the overall score on the CRF CHAQ UK Questionnaire 12. Any component questions are scored as follows: Without any difficulty = 0 With some difficulty = 1 With much difficulty = 2 Unable to do = 3 If not answered or Not applicable is selected then score is left blank for this question. This questionnaire is made up of 10 categories: Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 28 of 41

287 1. Dressing & personal care 2. Getting up 3. Eating 4. Walking 5. Hygiene 6. Reach 7. Grip 8. Activities 9. Pain 10. General evaluation Each category can be given a score out of 3. These are made up from the component questions and whether anything from the Aids or devices and/or Help from another person due to illness for the relevant category is selected. Devices associated with each category: Dressing & personal care o Devices used for dressing (button hook, zipper pull, long handled show horn etc.) Getting up o Special or built up chair Eating o Built up pencil or special utensils Walking o Walking stick o Walking frame o Crutches o Wheelchair Hygiene o Raised toilet seat o Bath seat o Bathrail o Long-handled appliances in bathroom Reach o Long-handled appliances for reach Grip o Jar opener Activities If anything is selected under these sections then the score is 2. The overall score for each category is determined by the highest score given within that category. For example, if someone selected with some difficulty for all the questions in the dressing and personal care category, and also selected Devices used for dressing (button hook, zipper pull, long handled show horn etc.) then the score for the dressing and personal care category would be 2. If someone selected unable to do for anything within the getting up section then the score for this category would be 3. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 29 of 41

288 The Pain and General evaluation categories are scored as a number between 0 and 100. To convert this into a scale of 0 to 3, divide the score by 100 and multiply by 3 and round to the nearest 1 decimal place. The overall index is calculated by summing the overall scores for each of the categories and dividing by the number of categories answered. This will give a score between 0 and Analysis This outcome is being analysed using joint modelling as described in section Mean profile plots and individual plots by treatment groups will be presented. 1-standard error bars will be displayed for each visit on the mean profile plots. This will provide a visual representation of the variation patients may experience in terms of their CHAQ score at each scheduled treatment visit between treatment arms American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels Derivation The 6 paediatric core set criteria assessed at each study visit are: Physician global assessment of disease activity (10 cm visual analogue scale). Parent/patient assessment of overall well-being (10 cm visual analogue scale). Functional ability (Childhood Health Assessment Questionnaire, CHAQ). Number of joints with active arthritis. Number of joints with limited range of movement. Erythrocyte sedimentation rate. The ACR Paediatric 30, 50, 70, 90 and 100 levels 13 are defined as 30%, 50%, 70%, 90% and 100% improvement respectively in a minimum of three variables in the core set with worsening of one variable by no more than 30% as defined in the ACR criteria Physician global assessment of disease activity (10 cm visual analogue scale) This can be found on subsection Subform Urinalysis Test, Physical Exam, Vital Signs and Physician global assessment of disease of the treatment visit CRF under the field Physician global assessment of disease activity Parent/patient assessment of overall well-being (10 cm visual analogue scale) This can be found on the CRF CHAQ UK Questionnaire under the last question General evaluation (point 69) Functional ability (Childhood Health Assessment Questionnaire, CHAQ) See section for details on how to derive the overall score for the CHAQ. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 30 of 41

289 Number of joints with active arthritis This can be found on subsection Subform Recorded pattern of joint involvement on examination and Spinal assessments of the treatment visit CRF. Tabulate number of joints selected from the Active column Number of joints with limited range of movement This can be found on subsection Subform Recorded pattern of joint involvement on examination and Spinal assessments of the treatment visit CRF. Tabulate number of joints selected from the Limited column Erythrocyte sedimentation rate This can be found on subsection Subform Haematological and Biochemical Assessments of the treatment visit CRF Analysis As in section , patients may have differing amounts of missing data due to treatment failure (and therefore completing follow-up earlier than patients with a later treatment failure time). This issue will again be addressed through joint modelling of the longitudinal data of the ACR30, ACR50, ACR70, ACR90 and ACR100, and the time to treatment failure. Patients who did not fail treatment will be censored at the time the last treatment visit (month 18). As the ACR levels are binary outcomes, this analysis will be undertaken using the JMbayes 14 package in R from which the log odds ratio with 95% confidence interval from the longitudinal model will be estimated. This uses a Bayesian MCMC estimation approach, with a spline approximated baseline hazard function. For each treatment arm, the number and percentage of patients with each ACR response will be presented for each time point as a bar graph. Mean profile plots and individual plots by treatment groups will be presented. 1-standard error bars will be displayed for each visit on the mean profile plots. Summary statistics will also be presented in a table for each time point detailing the number and percentage of patients with ACR responses Number of participants undergoing disease flare, in remission on and off medication of their JIA and with minimum disease activity Number of participants undergoing disease flare Derivation For this secondary outcome, disease flare refers to a flare of arthritis rather than the eye (as in section 18.7). The definition of disease flare is a worsening of 30% or more in 3 or more of the 6 variables of the JIA core set, with no more than one variable improving by 30% or more. In addition, the following minimum worsening contingencies apply: if either the number of active joints or the number of joints with limited range of motion are included in the calculation of "flare" then there must be a worsening of at least two joints. If the Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 31 of 41

290 Physician s or parent/legal guardian global rating scores are used in the definition of "flare" then there must be a worsening of at least 2 units on the 10 unit scales. If the ESR is used in the definition of "flare" then the second value for the ESR used in the calculation must be above the upper limit of normal for the ESR. For subjects with sjia, presence of spiking fever (>38 C, occurring on at least 2 consecutive days) due to sjia will be considered alone as flare 15. If a patient has at least one disease flare at any time during the trial then they are classed as a yes. Only patients who don t experience a disease flare at any point are classed as a no Analysis The data will be summarised by the number (and percentage) of patients with at least one disease flare by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p-value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran-Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. The risk ratio will be calculated as per Appendix I, with the event being at least one disease flare. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh 5. Summary statistics will be presented for each point of the number and percentage of patients experiencing at least one disease flare. The number of patients who experience more than 1 disease flare (and the amount of flares) will also be reported Number of participants in remission on and off medication of their JIA Derivation Patients on medication of their JIA will be a withdrawal or treatment failure due to these medications being prohibited in the protocol. Therefore this outcome can only be measured during the post-treatment follow-up phase and will not be discussed within this SAP Analysis See section Number of participants with minimum disease activity Derivation Minimum disease activity is defined for those with Oligoarthritis and Polyarthritis. This information can be found on CRF Inclusion and Exclusion under the field ILAR classification. As this is only defined for Oligoarthritis and Polyarthritis, patients with Systemic arthritis, Psoriatic arthritis, Enthesitis-related arthritis or Undifferentiated arthritis are excluded. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 32 of 41

291 Table shows the threshold values that defines minimum disease activity. If a patient with oligoarthritis/polyarthritis has values less than or equal to the values in the corresponding column at any treatment visit then they are defined as Yes for minimum disease activity. If they have values greater than any of the threshold values at all treatment Table 18-1 Threshold values for juvenile idiopathic arthritis activity measures that best discriminated between states of high and minimal disease activity obtained through the area under the receiver operating characteristic curve analysis. visits then they are defined as No for minimum disease activity. Each of the measures can be found as follows: Physician global assessment: subsection Subform Urinalysis Test, Physical Exam, Vital Signs and Physician global assessment of disease of the treatment visit CRF under the field Physician global assessment of disease activity. Parent global assessment: CRF CHAQ UK Questionnaire under the last question General evaluation (point 69). This is entered as a value of 0 to 100 on the database so divide by 10 for a range of 0 to 10. Parent s pain assessment: CRF CHAQ UK Questionnaire under the question Pain (point 67). This is entered as a value of 0 to 100 on the database so divide by 10 for a range of 0 to 10. CHAQ score: See section for details on how to derive the overall score for the CHAQ. Number of swollen joints: subsection Subform Recorded pattern of joint involvement on examination and Spinal assessments of the treatment visit CRF. Tabulate number of joints selected from the Swollen column. Number of tender joints* Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 33 of 41

292 Number of joints with restricted motion: subsection Subform Recorded pattern of joint involvement on examination and Spinal assessments of the treatment visit CRF. Tabulate number of joints selected from the Limited column. Number of active joints: subsection Subform Recorded pattern of joint involvement on examination and Spinal assessments of the treatment visit CRF. Tabulate number of joints selected from the Active column. Morning stiffness* Erythrocyte sedimentation rate: subsection Subform Haematological and Biochemical Assessments of the treatment visit CRF under Biochemical Assessments. C-reactive protein level: subsection Subform Haematological and Biochemical Assessments of the treatment visit CRF under Haematological Assessments. White blood cells: subsection Subform Haematological and Biochemical Assessments of the treatment visit CRF under Haematological Assessments. Haemoglobin: subsection Subform Haematological and Biochemical Assessments of the treatment visit CRF under Haematological Assessments. Platelets: subsection Subform Haematological and Biochemical Assessments of the treatment visit CRF under Haematological Assessments. *Not collecting this information for SYCAMORE. Assess minimum disease activity as described excluding number of tender joints and morning stiffness Analysis Mean profile plots by treatment groups will be presented for each measure of minimum disease activity for Oligoarthritis and Polyarthritis. 1-standard error bars will be displayed for each visit on the mean profile plots. For each time point the mean, SD, median, IQR and range will be presented for each measure of minimum disease activity. The data will be summarised by the number (and percentage) of patients with at least one case of minimum disease activity by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p-value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran- Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. The risk ratio will be calculated as per Appendix I, with the event being minimum disease activity. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh 5. Proportions of patients with at least one case of minimum disease activity will be presented for each time point. The number of patients with at least one case of minimum disease activity (and the amount of cases if minimum disease activity) will also be reported. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 34 of 41

293 18.11 Number participants requiring change in biologic / Diseasemodifying anti-rheumatic drugs (DMARDs) therapy due to failure to respond from arthritis Derivation This can be found on subsection Subform Trial Intervention of the treatment visit CRF under the field Has participant required a change in biological/dmard therapy since the last visit due to a failure to respond for arthritis? and is given as a binary Yes/No response. If a patient has at least one change at any time during the trial then they are classed as a yes. Only patients who don t have a change at any point are classed as a no Analysis The data will be summarised by the number (and percentage) of patients that required change in biologic/disease-modifying anti-rheumatic drugs (DMARDs) therapy due to failure to respond from arthritis by treatment group. A risk ratio will be computed along with a 95% confidence interval. Also, a chi-squared test will be performed with the p-value being presented. If any of the cells of the 2x2 contingency table have expected counts <5 then Fisher s exact test will be used instead to obtain the p-value. In this case, the Cochran- Mantel-Haenszel estimate of the relative risk and 95% confidence interval will be given which accounts for cells with a value of 0 by adding 0.5 to each cell. The risk ratio will be calculated as per Appendix I, with the event being requiring change in biologic/disease-modifying anti-rheumatic drugs (DMARDs) therapy due to failure to respond from arthritis. The risk ratio and confidence interval will be calculated in SAS using the procedure PROC FREQ with the command relrisk 4 and cmh Missing data and withdrawals The proportion of missing data will be presented overall for each secondary outcome with further detail as to the reason as appropriate. Participants that withdraw from the trial completely (providing they do not withdraw consent to use their data), will contribute outcome data until the point at which they withdrew using an ITT approach. 20 Additional analyses 20.1 Vital signs Derivation The vital signs can be found on subsection Subform Urinalysis Test, Physical Exam, Vital Signs and Physician global assessment of disease of the treatment visit CRF under Vital signs. The parameters to be reported on for vital signs are: Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 35 of 41

294 Resting blood pressure (mm/hg) Respiration rate (breaths/min) Weight (Kg) Pulse (beats/min) Temperature ( C) Height (cm) Every item under these sections will be presented at baseline and months 1, 2, 3, 6, 9, 12, 15 and 18 for patients with data at these time points. Patients who withdrew from treatment or failed treatment prior to 18 months will only have their data analysed up to the point of withdrawal/treatment failure and will not contribute further data to the analysis. Any data on Unscheduled visits will not be reported Analysis No formal analysis will be undertaken. Mean profile plots and individual plots by treatment groups will be presented. 1-standard error bars will be displayed for each visit on the mean profile plots. A table will be presented for each time point as line listings for each patient detailing the assessments done and the value. For each time point the mean, SD, median, IQR and range will be presented for each vital sign Physical exam Derivation The physical exam data can be found on subsection Subform Urinalysis Test, Physical Exam, Vital Signs and Physician global assessment of disease of the treatment visit CRF under Physical exam. It can also be found here whether the assessment result was Normal or Abnormal, whether the result was Clinically significant (only applicable if the result was abnormal), and whether this was expected for patients condition. The parameters to be reported on for physical exam are: Skin Cardiovascular Lungs/chest Abdomen Neurologic Other clinically significant abnormalities Every item under these sections will be presented at baseline and months 1, 2, 3, 6, 9, 12, 15 and 18 for patients with data at these time points. Patients who withdrew from treatment or failed treatment prior to 18 months will only have their data analysed up to the point of withdrawal/treatment failure and will not contribute further data to the analysis. Any data on Unscheduled visits will not be reported. Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 36 of 41

295 Analysis The number of abnormal and normal results will be presented for each time point. A table will be presented as line listings for each patient for the abnormal values detailing whether they are expected for the patient s condition and whether the result was clinically Juvenile Arthritis Disease Activity Score (JADAS) Derivation This outcome is not listed under the secondary outcomes but is described within section of the SYCAMORE protocol v6.0 17/04/2015. The Juvenile Arthritis Disease Activity Score (JADAS) is comprised of four components 17 : physician global assessment of disease activity, parent/patient global assessment of well-being, active joint count, in 27, 71 or 10 joints, erythrocyte sedimentation rate (ESR). The JADAS is calculated as a sum of scores from its four components detailed below, giving global scores of 0-57, and 0-40 for the JADAS-27, JADAS-71 and JADAS-10 respectively. Physician global assessment of disease activity See section for details on how to derive this. Parent/patient global assessment of well-being See section for details on how to derive this. Active joint count, in 27, 71 or 10 joints This can be found on subsection Subform Recorded pattern of joint involvement on examination and Spinal assessments of the treatment visit CRF under the Active column. 27 Joints The joints considered are: 1. Cervical spine 2. Left elbow 3. Right elbow 4. Left wrist 5. Right wrist 6. Left MCP 1 7. Right MCP 1 8. Left MCP 2 9. Right MCP Left MCP Right MCP Left PIP Right PIP Left PIP Right PIP Left PIP Right PIP Left PIP 4 Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 37 of 41

296 19. Right PIP Left PIP Right PIP Left hip 23. Right hip 24. Left knee 25. Right knee 26. Left ankle 27. Right ankle The total number of joints is summed for the relevant joints to obtain a value between 0 and 27. This corresponds to the JADAS-27 score 71 joints All joints are considered within this, excluding Thoracic Spine, Lumbar Spine and Sacroiliac Joints. The total number of joints is summed to obtain a value between 0 and 71. This corresponds to the JADAS-71 score. 10 joints All joints are considered within this, excluding Thoracic Spine, Lumbar Spine and Sacroiliac Joints. The total number of joints are summed however if a patient has >10 active joints then the total number of joints is 10. This will give a value between 0 and 10. This corresponds to the JADAS-10 score. Erythrocyte sedimentation rate (ESR) See section for details on how to derive this. For this outcome, ESR values < 20mm/hour should be converted to 20* and ESR values >120mm/hour should be converted to 120. The ESR values should then be normalised to a 0-10 scale by: ESR (mm/hour) *This formula is taken from Consolaro A, Ruperto N, Bazso A et al., 2009 (reference 17), however it is assumed that ESR values < 20mm/hour should be converted to 20, rather than 0 as stated in Consolaro A, Ruperto N, Bazso A et al, Analysis This will be analysed using joint modelling as described in section Mean profile plots and individual plots by treatment groups will be presented. 1-standard error bars will be displayed for each visit on the mean profile plots. This will provide a visual representation of the variation patients may experience in terms of their overall JADAS-27, JADAS-71 and JADAS-10 score at each scheduled treatment visit between treatment arms. 21 Safety Evaluations 22.1 Data sets analysed The data sets analysed for the safety evaluations are specified in Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 38 of 41

297 22.2 Presentation of the data Details on the presentation of the data for the safety evaluations are specified in Statistical Analysis Plan final analysis for blinded data comparison of primary outcome and safety data 22 Quality Control As this SAP refers to the secondary outcomes only, no quality control is required. 23 References 1. International Conference on Harmonisation. Topic E3 Structure and content of clinical study reports.(cpmp/ich/137/95) International Conference on Harmonisation. Topic E9 Statistical Principles for Clinical Trials (CPMP/ICH/363/96) Guidance on Statistical Analysis Plans m#procstat_freq_sect008.htm 5. m#procstat_freq_sect031.htm Henderson R, Diggle PJ, Dobson A. Joint modelling of longitudinal measurements and event time data. Biostatistics; 1: Philipson P, Sousa I, Diggle PJ, Williamson PR, Kolamunnage-Dona R, Henderson R. Package joiner #mixed_toc.htm 11. Child Heath Questionnaire (CHQ) Scoring and Interpretation Manual 12. Childhood Health Assessment Questionaire: Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40: Rizopoulos D. The R Package JMbayes for fitting joint models for longitudinal and time-to-event data using MCMC. arxiv Prepr 2014;arXiv: Brunner HI, Lovell DJ, Finck BK, Giannini EH. Preliminary definition of disease flare in juvenile rheumatoid arthritis. J Rheumatol 2002; 29(5): Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, Cugno C, Bozzola E, Martini A, Ravelli A. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Rheum 2008;59: Consolaro A, Ruperto N, Bazso A et al. Development and validation of a composite disease activity score for juvenile idiopathic arthritis. Arthritis Rheum 2009; 61(5): Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 39 of 41

298 Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 40 of 41

299 Appendix I The risk ratio is calculated as: Risk for patients on Adalimumab Risk for patients on placebo Where the risk for patients on the Adalimumab arm is: Number of events for patients on Adalimumab Number of patients on Adalimumab Similarly the risk for patients on the placebo arm is: Number of events for patients on placebo Number of patients on placebo Form prepared: 11/04/2016 v0.3 for SYCAMORE Study Page 41 of 41

300 A Randomised Controlled Trial of the Clinical Effectiveness, SafetY and Cost Effectiveness of Adalimumab in Combination with MethOtRExate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis (SYCAMORE) Eudract No Statistical Analysis Plan Secondary outcomes ORIGINATED BY QC PERFORMED BY APPROVED BY Name Naomi Bacon N/A Susie Dodd Title Date Protocol Version and Date Blinded Statistician N/A 21/10/2016 Version /07/2016 Senior Blinded Statistician Form prepared: 21/10/2016 v3.0 for SYCAMORE Study Page 1 of 43