Title: Multi-centre randomised open-label assessor-blinded two arm parallel group trial of subcutaneous versus oral methotrexate for rheumatoid arthritis (RA), with feasibility assessment, economic evaluation and qualitative study._x000D_ _x000D_ Short-title: Methotrexate Oral Or SubcutanEous for RA [The MOOSE study].
Funder: Department of Health and Social Care

Abstract: Background: Rheumatoid arthritis (RA) is treated with medicines such as methotrexate that control inflammation and prevent joint damage. In the UK, methotrexate is usually prescribed as weekly tablets for treating RA. Some people may have side effects such as sickness and they may then be prescribed weekly injections of methotrexate. These injections are self-administered to just below the skin in the thigh or the tummy._x000D_ _x000D_ There is a small amount of evidence suggesting that methotrexate injections are more effective in controlling arthritis and cause fewer side-effects than tablets. However, it costs 20 times more than methotrexate tablets. High-quality studies are needed before we can be sure that methotrexate injection is more effective than tablet and should be used as the first-choice treatment for patients with RA._x000D_ _x000D_ Aims: This study will find out whether methotrexate injections are more effective than tablets in controlling RA and for improving wellbeing. It will also find out whether they are acceptable to people with arthritis and value for money for the NHS._x000D_ _x000D_ Methods: A clinical trial will be conducted in 30 hospitals. 386 people with RA who would be started on methotrexate as their RA treatment will be recruited. Whether they are prescribed methotrexate as a tablet or as an injection will be decided randomly i.e. by chance (like tossing a coin), to ensure that a fair comparison can be made at the end of the study._x000D_ _x000D_ Participants will start methotrexate at a low dose, and be seen in the clinic monthly for the next 2-3 months, where the dose may be increased by the rheumatologist, depending on how the participant’s RA is improving and if they are having side effects. Participants may be prescribed other medicines if methotrexate does not control the RA or if side-effects occur. Steroids and medicines such as Ibuprofen will be used to treat flare-ups as required. As there is no reliable method of measuring RA activity without actually examining the participants, it is not possible to change treatment without face-to-face visits. Clinics will ensure the visits are in line with government guidelines and are as brief as possible in the Covid-19 pandemic._x000D_ _x000D_ A research nurse will see participants at the start of the study and 16, 24 and 52 weeks later. They will examine the participant’s joints and collect a blood sample to measure the level of inflammation each time. They will not know which treatment the participant has been taking, so that their assessment cannot be influenced by this. Participants will be sent questionnaires to complete before their hospital visit to reduce their time in the clinic. These questionnaires will ask about their arthritis, ability to do daily activities and work, well-being, fatigue, and mental-health. We will invite up to 20 participants to take part in one-to-one interviews, 1-2 months and 6-8 months into the study to explore their experience of treatment with injections or tablets._x000D_ _x000D_ PPI: We have developed the study processes together with people with RA, including those with experience of methotrexate treatment. A patient advisory group will be involved and a public contributor will help manage this study as part of the team._x000D_ _x000D_ Impact and dissemination: We will share the findings with doctors, nurses, people with RA and patient charities such as the National RA Society. We will engage with NICE and the British Rheumatology Society to update national guidelines for treating RA.

Lay abstract: 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)._x000D_ Background: Effectiveness and cost-effectiveness of subcutaneous methotrexate as first line treatment of RA is unknown._x000D_ _x000D_ Aim: To assess effectiveness, cost-effectiveness, and acceptability of subcutaneous methotrexate compared with oral methotrexate as first line treatment for RA._x000D_ Primary objective: To assess the effectiveness of a treat-to-target protocol using first line subcutaneous methotrexate on remission at 24 weeks. _x000D_ 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._x000D_ _x000D_ Methods: Pragmatic, multicentre, prospective, assessor-blinded, randomised controlled trial with internal feasibility assessments at 9 and 15 months._x000D_ Setting: Secondary care rheumatology clinics across the UK._x000D_ Participants: Methotrexate naïve adults with active RA, meeting the European League Against Rheumatism/American College of Rheumatology classification criteria._x000D_ Randomisation: 1:1 individual randomisation, minimized by trial centre, 28-joint disease activity score with CRP (DAS-28-CRP), autoantibody status and disease duration._x000D_ Intervention: subcutaneous methotrexate with 4-weekly dose escalation._x000D_ Comparator: oral methotrexate with 4-weekly dose escalation._x000D_ _x000D_ Primary outcome: Remission of RA, defined as DAS-28-CRP <2.6 at week 24. _x000D_ 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._x000D_ _x000D_ 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._x000D_ 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. _x000D_ _x000D_ 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._x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM