Multi-centre randomised open-label assessor-blinded two arm parallel group trial of subcutaneous versus oral methotrexate for rheumatoid arthritis (RA), with internal feasibility assessment, economic evaluation and qualitative study

Research question: Does first line treatment with subcutaneous methotrexate improve disease control in comparison to first line treatment with oral methotrexate in rheumatoid arthritis (RA). Background: Effectiveness and cost-effectiveness of subcutaneous methotrexate as first line treatment of RA is unknown. Aim: To assess effectiveness, cost-effectiveness, and acceptability of subcutaneous methotrexate compared with oral methotrexate as first line treatment for RA. Primary objective: To assess the effectiveness of a treat-to-target protocol using first line subcutaneous methotrexate on remission at 24 weeks. Secondary objectives: To assess the effectiveness of a treat-to-target protocol using first line subcutaneous methotrexate on disease activity, quality of life, mental health, employment, cost effectiveness, and progression to other disease modifying anti-rheumatic drugs including biologics, and to assess the acceptability of first line subcutaneous and oral methotrexate in a treat-to-target protocol. Methods: Pragmatic, multicentre, prospective, assessor-blinded, randomised controlled trial with internal feasibility assessments at 9 and 15 months. Setting: Secondary care rheumatology clinics across the UK. Participants: Methotrexate naïve adults with active RA, meeting the European League Against Rheumatism/American College of Rheumatology classification criteria. Randomisation: 1:1 individual randomisation, minimized by trial centre, 28-joint disease activity score with CRP (DAS-28-CRP), autoantibody status and disease duration. Intervention: subcutaneous methotrexate with 4-weekly dose escalation. Comparator: oral methotrexate with 4-weekly dose escalation. Primary outcome: Remission of RA, defined as DAS-28-CRP <2.6 at week 24. Secondary outcomes: Response and remission of RA, function and quality of life, cost effectiveness, acceptability of treatment, side effects and adverse events and changes to treatment over the 52 weeks of the trial. Sample size: 386 participants (193 in each treatment arm) will allow detection of an absolute difference of 17.5% in the proportion of participants showing remission 24 weeks after randomisation, with 90% power, and a 5% significance level (2-sided). This assumes 30% of participants in the oral methotrexate arm show remission, and that 10% of participants are lost to follow up. Analysis: Evaluation of the primary outcome will be performed on an intention to treat basis using a mixed effects model for binary outcomes which includes factors used in the minimisation. Secondary outcomes will be analysed using appropriate regression models and qualitative methods. Study within a Trial: will be embedded in the main trial and will assess whether the addition of a video link in the Participant Information Sheet explaining the trial and demonstrating subcutaneous injection increases recruitment. Separately funded 2-year follow-up: Separate funding and optional consent will be sought for a postal follow-up at 24 months. This survey will last beyond the time-frame of the proposed trial. Timelines for delivery: 50 months trial. 9 months set up, 22 months recruitment, 12 months follow up, 7 months data cleaning, analysis, write up, dissemination. Anticipated impact and dissemination: The findings will be disseminated to patients, public, and policy makers including NICE and British Society for Rheumatology, where it will have the potential to inform and change guidelines.