Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT.

Abstract

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.

• Authors: Athimalaipet V Ramanan, Andrew D Dick, Ashley P Jones, Dyfrig A Hughes, Andrew McKay, Anna Rosala-Hallas, Paula R Williamson, Ben Hardwick, Helen Hickey, Naomi Rainford, Graeme Hickey, Ruwanthi Kolamunnage-Dona, Giovanna Culeddu, Catrin Plumpton, Eifiona Wood, Sandrine Compeyrot-Lacassagne, Patricia Woo, Clive Edelsten, Michael W Beresford
• Journal: Health technology assessment (Winchester, England) (Health Technol Assess) Vol. 23 Issue 15 Pg. 1-140 (04 2019) ISSN: 2046-4924 [Electronic] England
• PMID: 31033434 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antirheumatic Agents
• Adalimumab
• Methotrexate

Topics

• Adalimumab (administration & dosage)
• Adolescent
• Antirheumatic Agents (administration & dosage)
• Arthritis, Juvenile (complications)
• Child
• Child, Preschool
• Cost-Benefit Analysis
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Humans
• Male
• Methotrexate (administration & dosage)
• Outcome Assessment, Health Care
• United Kingdom
• Uveitis (drug therapy, etiology)