Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness. The ASTUTE pragmatic randomized controlled trial.
A clinical trial is testing whether a cheap, widely available arthritis drug can prevent blindness in people with a rare inflammatory eye condition. Autoimmune uveitis causes the eye’s middle layer to swell, damaging the retina and leading to permanent vision loss if not controlled. Current treatment relies on high-dose corticosteroids, which carry serious side effects including glaucoma, cataracts, and bone thinning. The drug adalimumab, a TNF-inhibitor already used for rheumatoid arthritis, has shown promise in smaller studies but is not yet standard care for uveitis. This trial will determine whether adding adalimumab to standard therapy is more effective than placebo at keeping the disease in remission while allowing patients to reduce their steroid dose. If adalimumab proves effective and cost-effective, it could become a routine add-on treatment for uveitis patients across the NHS. That would mean fewer people losing their sight, fewer steroid-related complications, and lower long-term healthcare costs from avoided hospital visits and disability. The trial also includes a health economics analysis to ensure the NHS can afford any new treatment pathway.
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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. SETTING: UK tertiary centres treating autoimmune non-infectious uveitis (ANIU). TARGET POPULATION: Adults with active (incident) or inactive (prevalent) ANIU, requiring/starting >5mg/day corticosteroid (CS) to induce/maintain remission. 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. 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. 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. 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. 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. 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. 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. 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.
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