An international, multicentre, interventional, randomised, assessor-blinded trial to MAXimise the METHotrexate therapy potential in patients with active rheumatoid arthritis (MethMax trial): study protocol for a randomised controlled trial

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BACKGROUND: Methotrexate (MTX) is recommended as first-line therapy in patients with rheumatoid arthritis (RA), proven to be effective, safe and inexpensive. However, a significant proportion of patients does not achieve disease remission with MTX monotherapy. Main reasons include insufficient dose up-titration to the maximal recommended oral dose or the delayed switch to a subcutaneous administration route. We hypothesise, that by dose and route optimisation, a higher proportion of patients can achieve remission. Further, exploratory biomarkers will give new insights on individual MTX metabolism and drug adherence. METHODS: The MethMax trial is a prospective, randomised, assessor-blinded, parallel-group, superiority, low-intervention trial, including 182 patients across 7 European countries. Patients with active RA, naïve to biologic (except tumour necrosis factor alpha inhibitors; TNFi) or targeted synthetic antirheumatic drugs, who have been on a stable oral MTX therapy for the past 3 months are randomised in a 1:1 ratio to 25 mg MTX weekly, either administered orally or subcutaneously. Additionally, both arms receive a short-term glucocorticoid regimen with a four-week tapering and withdrawal protocol. The primary endpoint is the difference in proportion of patients achieving remission defined as the Clinical Disease Activity Index (CDAI) ≤ 2.8 at week 24, comparing the dose/route optimisation and oral dose optimisation. The active study duration for each patient is 24 weeks. Study visits take place at baseline, weeks 4, 12, 16 and 24. Clinical efficacy and safety parameters are obtained at each visit. Patient-reported outcomes, exploratory biomarkers as well as medication adherence are assessed. Written consent is obtained for all participants. The study has received regulatory approval via the Clinical Trials Information System and Medicines and Healthcare products Regulatory Agency and has included the first patient in August 2024. DISCUSSION: The anticipated results will provide insights whether the subcutaneous administration of 25 mg MTX is advantageous in achieving CDAI remission when compared to the oral intake after 24 weeks and inform the community regarding the utility of established and newly developed biomarkers, as well as the potential impact of inadequate drug adherence. The MethMax study is aimed to optimise individual therapy in RA and provide more precise pharmacological MTX management recommendations.

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