Evaluation of Methotrexate Efficacy and Safety in Erosive Inflammatory Hand Osteoarthritis: A Randomized, Placebo-Controlled Clinical Trial

The primary objective of the MERINO trial is to explore whether **methotrexate** can reduce finger joint pain in patients with symptomatic erosive inflammatory hand osteoarthritis. This is clinically relevant as it addresses a significant symptom of the disease, potentially improving patient comfort and quality of life.

Secondary objectives include:

• Exploring whether methotrexate can improve other patient-reported outcomes such as physical function, stiffness, health-related quality of life, markers of pain sensitization, and grip strength.
• Analyzing whether methotrexate reduces joint inflammation as reflected by both imaging and soluble biomarkers, and examining potential associations between symptom reduction and reduced inflammation.
• Determining whether methotrexate treatment reduces structural progression of the disease.
• Exploring person and disease characteristics as predictors for treatment response and identifying sensitive imaging, soluble, and genetic biomarkers for monitoring disease activity.
• Evaluating the cost-effectiveness of methotrexate compared to standard care.

The clinical trial focuses on individuals diagnosed with **erosive hand osteoarthritis**, aiming to assess the efficacy of methotrexate in alleviating finger joint pain. The study population includes both male and female participants, with an age range spanning from 18 to 64 years. Participants were selected based on specific criteria, including experiencing finger joint pain rated between 40-80 on a 0-100 visual analog scale, with inadequate pain relief from or intolerance to oral paracetamol and/or NSAIDs. Additionally, participants must have hand osteoarthritis as per the ACR criteria, with at least one distal or proximal interphalangeal joint showing radiographic pre-erosive or erosive disease, and at least two joints exhibiting power Doppler signal or grey-scale synovitis on ultrasound. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria.

The clinical trial is designed to evaluate the efficacy and safety of **methotrexate** in patients with erosive inflammatory hand osteoarthritis. This is a randomized, placebo-controlled trial with a double-blind design to ensure unbiased results. Participants will be randomly assigned to receive either methotrexate or a placebo, both encapsulated to maintain blinding due to differences in the appearance of the tablets. The trial is expected to last until December 31, 2025, with participant recruitment having commenced on August 12, 2021.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as finger joint pain and radiographic evidence of disease. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and safety. These visits will include assessments of finger joint pain using a visual analogue scale, as well as evaluations of disease activity, hand function, and quality of life. The primary endpoint is the difference in self-reported finger joint pain at six months of treatment. Secondary endpoints include various measures of pain, function, and structural changes assessed through imaging and questionnaires.

The expected duration of participant involvement is up to 52 weeks, with the possibility of early termination if adverse events occur or if the participant withdraws consent. The trial will also monitor the number of adverse events and any withdrawals due to these events. The end-of-study visit will conclude the participant's involvement, with final assessments to evaluate the overall impact of the treatment. This trial aims to provide valuable insights into the potential benefits and risks of methotrexate for this patient population.

The clinical trial involves the administration of **Methotrexate**, a well-established medication used in the treatment of various inflammatory conditions. The specific formulation used in this study is "Methotrexate Pfizer 2.5 mg tabletter," which is provided in tablet form. The active substance, methotrexate, is of chemical origin and is classified under the ATC code L04AX03. Participants will receive a maximum daily dose of 2.5 mg, administered orally. The total treatment period is set for 52 weeks, with a maximum cumulative dose of 52 mg. To maintain blinding, methotrexate tablets will be encapsulated, as identical placebo tablets cannot be produced due to differences in text, color, and shape.

The study also includes a **placebo** group to serve as a comparator. The placebo is formulated as a tablet containing microcrystalline cellulose (85 mg), cornstarch (10 mg), and magnesium stearate (5 mg). Like the methotrexate, the placebo tablets will be encapsulated to ensure blinding. Participants in the placebo group will receive one tablet daily, administered orally, for a total treatment period of 52 weeks. The encapsulation process is crucial to maintain the integrity of the study's double-blind design, ensuring that neither participants nor investigators can distinguish between the active treatment and the placebo.

The efficacy of methotrexate in the treatment of erosive inflammatory hand osteoarthritis will be assessed through a series of primary and secondary endpoints. The primary endpoint is the difference in self-reported finger joint pain over the previous 48 hours, measured on a visual analogue scale (VAS; 0-100 mm) at six months of treatment. Secondary endpoints include a variety of patient-reported outcomes and clinical assessments. These encompass the fulfillment of Outcome Measures in Rheumatology Osteoarthritis Research Society International (OMERACT-OARSI) responder criteria, self-reported pain in fingers and thumbs, and patient-reported disease activity, all measured using VAS at all visits. Additional assessments include the Australian/Canadian hand index (AUSCAN), quality-adjusted life years (QALYs) based on EQ-5D scores, and the Michigan Hand Outcomes Questionnaire (MHOQ) pain and physical function subscales, evaluated at baseline (M00) and six months (M06).

Further secondary endpoints involve the duration of morning stiffness in finger and thumb base joints, Hospital Anxiety and Depression Scales (HADS), Pain Catastrophizing Scale (PCS), and Pain Sensitivity Questionnaire (PSQ), all assessed at M00 and M06. The study will also measure grip strength using a hand dynamometer at M00, M06, and M12, and evaluate pain sensitization through Pressure Pain Thresholds (PPT), temporal summation, and Conditioned Pain Modulation (CPM) at M00 and M06. Imaging techniques such as ultrasound, conventional radiographs, and MRI will be employed to assess structural changes and synovitis. Serum or plasma markers of extracellular matrix turnover and inflammation will be analyzed at M00, M06, and M12. The number of adverse events, serious adverse events, and withdrawals due to adverse events will be recorded at all visits. Additionally, changes in synovial cellular composition and gene expression will be explored using single-cell RNA sequencing analyses in a subgroup of 16 patients at M00 and M06.