TY - JOUR

T1 - Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT

AU - Ramanan, Athimalaipet V.

AU - Dick, A.D.

AU - Jones, Ashley P.

AU - Hughes, Dyfrig

AU - McKay, Andrew

AU - Rosala_Hanna, Anna

AU - Williamson, P.R.

AU - Hardwick, Ben

AU - Hickey, Helen

AU - Rainford, N

AU - Kolamunnage-Dona, R

AU - Culeddu, Giovanna

AU - Plumpton, Catrin

AU - Wood, Eifiona

AU - Compeyrot-Lacassagne, Sandrine

AU - Woo, P.

AU - Eldesten, C

AU - Beresford, Michael W.

PY - 2019/4/10

Y1 - 2019/4/10

N2 - 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.

AB - 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.

U2 - 10.3310/hta23150

DO - 10.3310/hta23150

M3 - Article

C2 - 31033434

VL - 23

SP - 1

EP - 174

JO - Health Technology Assessment

JF - Health Technology Assessment

SN - 1366-5278

IS - 15

ER -