The clinical and cost effectiveness of oraL vErsus intrAmuscular glucocorticoiDs in rhEumatoid aRthritis: LEADER A Randomised Controlled Trial

Research Question In patients with active rheumatoid arthritis (RA) initiating/switching or escalating DMARD therapy (population) is the use of oral glucocorticoids (intervention) more clinically and cost effective than intramuscular glucocorticoids (comparator) therapy whilst limiting toxicity? Background The aim of RA treatment is remission. Rapid target attainment reduces radiographic progression and disability but conventional disease modifying anti-rheumatic drugs (cDMARDs) can take up to 6 months to improve disease activity; glucocorticoid (GC) “bridging” therapy is therefore recommended. Glucocorticoids have a rapid onset of action but are associated with significant adverse effects. British and European guidelines recommend short-term (<3 months) GC therapy in patients commencing cDMARDs. Glucocorticoids can be administered orally or intramuscularly (IM). It remains unknown what method of administration, what dose and for how long GCs should be prescribed in patients initiating/switching or escalating DMARD therapy. Aim To investigate whether the use of oral GC in adult patients with RA initiating, switching or escalating DMARD therapy is more clinically and cost effective than IM GCs whilst limiting toxicity. Primary Objective To compare the mean DAS(CRP)-28 over 12 weeks in adult patients with active RA commencing oral or IM short-term bridging GC therapy who are initiating, escalating or switching DMARD therapy. Secondary Objectives • To compare the effect of oral and IM GC on patient reported outcomes, toxicity and cumulative GC dose • To compare the effect of GC dose regimens on mean 12-week DAS(CRP)-28, cumulative GC dose, toxicity and patient reported outcomes • To conduct an economic evaluation • To conduct a qualitative study of GC bridging therapy acceptability Methods Design: A multicentre randomised open-label assessor-blinded four-arm parallel trial of two oral versus two IM GC strategies for adults with RA, with internal pilot phase, economic evaluation and qualitative study of acceptability. Intervention: Two dose levels of oral prednisolone Comparator: Two dose levels of IM methylprednisolone Setting: 30 rheumatology outpatient sites Population: Adults with active RA initiating/escalating/switching DMARD treatment Primary outcome: Mean DAS(CRP)-28 week 0-12 Key secondary outcomes: Disease activity, cumulative GC dose, toxicity, costs and patient acceptability Sample size: 448 adults with RA (1:1:1:1 randomisation) Timeline Trial duration 41 months. 9 months set-up; 9 months internal pilot, 18 months full recruitment; 6 months follow-up; 8 months data cleaning, analysis, reporting and dissemination. Impact and Dissemination LEADER will be the first randomised controlled trial powered to investigate the efficacy and toxicity of oral versus IM GC bridging therapy in RA patients initiating, escalating or switching DMARD therapy. LEADER will lead to evidence-based practice and cost-effective care for RA patients and evaluate patient acceptability. Additional secondary analysis will provide guidance for clinicians on the most clinically effective dose of GC bridging therapy whilst minimising toxicity at a ratio considered acceptable to patients. With our patient partners and partnership with The National Rheumatoid Arthritis Society (NRAS) we will disseminate the results of the LEADER study through journals, conferences, social media, newsletters and online workshops for patients, stakeholders and clinicians.