Award Title: Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness. The ASTUTE pragmatic randomized controlled trial.
Funder: Department of Health and Social Care

Abstract: Autoimmune uveitis is a term for several rare eye diseases in which the body’s own immune system causes sight-threatening damage to the light sensitive retina at the back of the eye. Uveitis causes sight loss from inflammation inside the eye, damage to blood vessels in the retina or leakage of fluid into the central, most sensitive area of the retina. Two in 10,000 people are at risk of serious sight loss from uveitis. Usual treatment for autoimmune uveitis involves low dose steroids and one or two other drugs to reduce inflammation. Unfortunately, many patients do not respond to or tolerate usual treatment, or need high dose steroids to control the uveitis. Long term high dose steroids increase the risk of heart attack, stroke, and infection and affect physical and mental health. Adalimumab is an expensive new drug that targets chemicals released by inflamed tissue, neutralizing their damage to the body._x000D_
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Two recent studies suggest fortnightly adalimumab is, on average, an effective way to treat uveitis in some patients. However, drugs like adalimumab can have serious side effects and more evidence is required to identify which patients with uveitis benefit the most from adalimumab, both with respect to their vision and quality of life, including treatment side effects._x000D_
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This study aims, first, to identify patients who are most likely to benefit from adalimumab. All eligible patients who consent will be given adalimumab for a 16 week trial period, if necessary in combination with low dose of steroids; these patients will include those with impaired vision due to uveitis, requiring high dose steroids to bring the disease under control, and those with better vision but who require high dose steroids to keep the uveitis under control. Over the 16 weeks, doctors will aim to reduce the steroid dose to a low level that should not cause side effects._x000D_
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Then, patients who are successfully treated with adalimumab and low dose steroids will enter the main study. They will be given adalimumab or a dummy treatment, in combination with their other medications (including low dose steroids). Chance will determine who receives which treatment and neither patients nor their eye doctors will know. Regular eye examinations, tests and questionnaires will be used to assess how well patients are doing. This part of the study, which will treat and follow up patients for 12 to 30 months, will find out whether adalimumab is better at preventing recurrence of uveitis than the dummy treatment and whether adalimumab is cost -effective compared to the dummy treatment._x000D_
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Patients with uveitis have contributed to the study from the start, helping to: design the protocol to ensure it applies to uveitis patients who may benefit; developing and testing a ‘quality of life’ questionnaire about the side effects of medications, impact on work and mood; co-authoring the lay summary; helping to draft the application, providing feedback on the trial design and participating in a national survey to assess support for the study. They will continue to contribute in these ways and provide support to patients, if funding is awarded. The research team includes eye doctors and researchers with expertise in doing eye studies. A registered clinical trials unit, ophthalmology research networks and patient groups will collaborate to conduct the study. The results will be disseminated through NHS England, patient societies and through medical journals.

Lay Abstract: DESIGN: Phase IV pragmatic placebo-controlled, randomised controlled trial (RCT) with a ‘treatment run-in’ (TRI). After the TRI, responders only (disease remission with <=5mg/day corticosteroid (CS), estimated 50%) will be randomised (1:1) to adalimumab or placebo. An internal pilot (phase 1; 18 months (m) including 6 months (6m) set up) will determine recruitment and responder rates among eligible patients; progression to phase 2 will depend on a) randomising >=80% (n=41) of the target number at this time (n=51), b) having at least 10 sites recruiting to the trial by month 18 and c) <15% of responders at the end of the TRI unwilling to be randomised. The full RCT will evaluate the effectiveness and relative cost-effectiveness of adalimumab vs placebo as add-on therapy to standard care._x000D_
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SETTING: UK tertiary centres treating autoimmune non-infectious uveitis (ANIU)._x000D_
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TARGET POPULATION: Adults with active (incident) or inactive (prevalent) ANIU, requiring/starting >5mg/day corticosteroid (CS) to induce/maintain remission. _x000D_
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Inclusion criteria: Patients with sight threatening ANIU in either or both eyes. ANIU will be diagnosed on the basis of the criteria used to define treatment failure. _x000D_
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Exclusion criteria: Untreated or active tuberculosis, uncontrolled glaucoma, multiple sclerosis, HIV positive, hepatitis B or C, Behcet’s disease, heart failure (NYHA III/IV), anti-TNF drug within 90 days, ocular CS implant within 12 months or an intravitreal steroid injection within the previous 3 months, pregnant, allergy or hypersensitivity to adalimumab or any of its excipients._x000D_
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HEALTH TECHNOLOGIES BEING ASSESSED: 80mg subcutaneous injection of ImraldiTM (licensed biosimilar for adalimumab) at the start of the TRI, then fortnightly 40mg injections starting one week after the initial dose, up to 16 weeks (end of TRI); after randomisation, fortnightly 40mg injections of drug or placebo to the end of the trial (follow-up 12m to 30m). In the event of treatment failure (TF), open label drug will be restarted as per TRI for 16 weeks and, if a participant responds, allocation will be switched and trial treatment restarted, maintaining masking._x000D_
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MEASUREMENT OF OUTCOMES Primary outcome: TF, defined as need for >5mg/day CS to maintain remission (decisions to increase CS made by masked clinicians) or active disease, excluding isolated anterior uveitis and including an increase in cystoid macular oedema.  Clinical TF events will be validated by retinal imaging. Follow-up will be censored when all participants have at least 12m follow-up; following participants recruited earlier to the end of the trial will maintain masking and avoid the ethical issue of withdrawing treatment for participants after 12m follow-up. Secondary outcomes include: Patient reported outcomes (visual function, generic, and symptoms of side effects), individual TF components, retinal morphology, adverse events (AEs), changes in employment, NHS resource use and costs._x000D_
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COST-EFFECTIVENESS ANALYSIS: The main outcome measure for the economic evaluation will be quality adjusted life years (QALYs), estimated using the EuroQol EQ-5D 5L, administered at every visit. Valuations derived from published UK population tariffs will be assigned. The mean number of QALYs per group and incremental QALYs will be calculated._x000D_
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SAMPLE SIZE: Hazard ratios (HRs) in 2 trials of adalimumab to treat active and inactive ANIU were 0.50 and 0.57 respectively.  The TRI design should enhance effectiveness and we have set a target HR of 0.5.  Assuming that 27% in the placebo group survive free from TF at 12m (estimated from placebo groups of the 2 trials with 40:60 active: inactive disease), 174 participants will allow a HR=0.5 (27% vs 52% survival free from TF at 12 months) to be detected with 90% power and 5% 2-tailed significance, with <=10% loss to follow-up._x000D_
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PROJECT TIMETABLE: 48 months comprising 6 months set-up; 23 months recruitment (which includes 4 months TRI and 4 months randomising last recruited participants at end of TRI); minimum 12 months follow-up; 7 months data management, analyses and reporting._x000D_
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EXPERTISE IN TEAM: The multidisciplinary team includes ophthalmologists who treat ANIU, a patient with ANIU, an imaging expert, clinical trials researchers with expertise conducting ophthalmic trials and a health economist.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: EYE;INFLAMMATORY AND IMMUNE SYSTEM