Background:

Children with juvenile idiopathic arthritis (JIA) are at risk of uveitis. The role of adalimumab (Humira^®; AbbVie Inc., Ludwigshafen, Germany) in the management of uveitis in children needs to be determined.

Objective:

To compare the efficacy, safety and cost-effectiveness of adalimumab in combination with methotrexate (MTX) versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with JIA.

Design:

This was a randomised (applying a ratio of 2 : 1 in favour of adalimumab), double-blind, placebo-controlled, multicentre parallel-group trial with an integrated economic evaluation. A central web-based system used computer-generated tables to allocate treatments. A cost–utility analysis based on visual acuity was conducted and a 10-year extrapolation by Markov modelling was also carried out.

Setting:

The setting was tertiary care centres throughout the UK.

Participants:

Patients aged 2–18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks).

Interventions:

All participants received a stable dose of MTX and either adalimumab (20 mg/0.8 ml for patients weighing < 30 kg or 40 mg/0.8 ml for patients weighing ≥ 30 kg by subcutaneous injection every 2 weeks based on body weight) or a placebo (0.8 ml as appropriate according to body weight by subcutaneous injection every 2 weeks) for up to 18 months. A follow-up appointment was arranged at 6 months.

Main outcome measures:

Primary outcome – time to treatment failure [multicomponent score as defined by set criteria based on the Standardisation of Uveitis Nomenclature (SUN) criteria]. Economic outcome – incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the NHS in England and Personal Social Services providers. Full details of secondary outcomes are provided in the study protocol.

Results:

A total of 90 participants were randomised (adalimumab, n = 60; placebo, n = 30). There were 14 (23%) treatment failures in the adalimumab group and 17 (57%) in the placebo group. The analysis of the data from the double-blind phase of the trial showed that the hazard risk (HR) of treatment failure was significantly reduced, by 75%, for participants in the adalimumab group (HR 0.25, 95% confidence interval 0.12 to 0.51; p < 0.0001 from log-rank test). The cost-effectiveness of adalimumab plus MTX was £129,025 per QALY gained. Adalimumab-treated participants had a much higher incidence of adverse and serious adverse events.

Conclusions:

Adalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is < 1% at the £30,000-per-QALY threshold.

Future work:

A clinical trial is required to define the most effective time to stop therapy. Prognostic biomarkers of early and complete response should also be identified.

Trial registration:

Current Controlled Trials ISRCTN10065623 and European Clinical Trials Database number 2010-021141-41.

Funding:

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 15. See the NIHR Journals Library website for further project information. This trial was also funded by Arthritis Research UK (grant reference number 19612). Two strengths of adalimumab (20 mg/0.8 ml and 40 mg/0.8 ml) and a matching placebo were manufactured by AbbVie Inc. (the Marketing Authorisation holder) and supplied in bulk to the contracted distributor (Sharp Clinical Services, Crickhowell, UK) for distribution to trial centres.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 09/51/01. The contractual start date was in August 2011. The draft report began editorial review in December 2017 and was accepted for publication in June 2018. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Athimalaipet V Ramanan reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme and Arthritis Research UK during the conduct of the study and others from AbbVie Inc. (Ludwigshafen, Germany) and the University Hospitals Bristol NHS Foundation Trust, outside the submitted work. He has received speaker fees from AbbVie Inc. and lectured in symposia, sponsored by AbbVie Inc.. He has also been on an Advisory Board organised by AbbVie Inc. and has been supported by AbbVie Inc. to attend European and American Rheumatology Society meetings. Andrew D Dick reports other from data and revenue sharing outside the submitted work for consultancy work, paid to University of Bristol by AbbVie Inc., Ashley P Jones, Andrew McKay, Anna Rosala-Hallas, Ben Hardwick, Helen Hickey, Naomi Rainford, Graeme Hickey, Ruwanthi Kolamunnage-Dona and Paula R Williamson report grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study, other from AbbVie Inc. and University Hospitals Bristol NHS Foundation Trust and personal fees from University of Liverpool, outside the submitted work. In addition, Paula R Williamson is the Director of the Clinical Trials Research Centre, which is the Clinical Trials Unit that managed the day-to-day running of this trial. Dyfrig Hughes and Patricia Woo report grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study and other from AbbVie Inc., outside the submitted work. Giovanna Culeddu and Eifiona Wood report grants from Arthritis Research UK during the conduct of the study. Sandrine Compeyrot-Lacassagne reports grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study, and grants and others from AbbVie Inc., outside the submitted work. Clive Edelsten reports grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study, and others and personal fees from AbbVie Inc., outside the submitted work. Michael W Beresford reports grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study and others from AbbVie Inc. and the University Hospitals Bristol NHS Foundation Trust, outside the submitted work.