Comparison of parenteral to oral split-dose methotrexate in terms of efficacy and intracellular methotrexate polyglutamate levels – A randomized controlled trial

Rheumatoid arthritis (RA) is one of the most common systemic autoimmune disease (estimated to occur in 1%) which commonly presents as polyarthritis, and can lead to deformities if untreated. Methotrexate (low-dose, <25 mg per week) is the gold-standard benchmark conventional synthetic disease modifying anti-rheumatic drug (cs-DMARD) for rheumatoid arthritis. The best efficacy of methotrexate has been proven to be when used parenterally subcutaneous, rather than given orally once a week, as with oral administration absorption of the drug is only around 60-70%. However, methotrexate injection is not patient friendly and many patients do not like taking injections.

Single day oral split-dose methotrexate, i.e., rather than giving the oral methotrexate as a single dose, splitting the dose into two doses given on the same day morning and evening, has been proposed to overcome the problem of intestinal saturation occurring with single weekly dose, and leading to 20-30% higher plasma levels within 24 hours. However, there are no studies which have compared the efficacy of oral split dose methotrexate to parenteral (subcutaneous) methotrexate nor any data on the RBC polyglutamate levels between oral split to parenteral MTX. Hence, we wanted to answer the research question whether oral split-dose methotrexate produce similar efficacy and methotrexate polyglutamate levels compared to subcutaneous methotrexate?

This study is planned be a open-label randomzied controlled trial which is academic investigator initiated and not funded by any drug company. it will enrol patients of rheumatoid arthritis in seven univesity hosiptials in India and randomly assign them to two groups - either receive parenteral methotrexate (subcutaneous injecitons) once a week or recieve oral split dose of methotrexate once a week for 24 weeks. There will be an option to add another medicine for RA in case the disease is not controlled at 16 weeks of the study, like leflunomide or sulfasalazine. We hypothesise that oral split dose will be non-inferior to parenteral methotrexate in terms of efficacy. The patients will have three study visits at 8, 16 and 24 weeks, and each time will have to undergo joint counts, give a blood sample and fill a questionnaire regarding adverse effects (intolerance) as well as their blood test reports for any laboratory abnormality will be assessed.The primary outcome will be improvement in disease activity (based on 28 joint score and EULAR response) at 16 weeks. The secondary outcomes will be other measures of efficacy, RBC levels of methotrexate polyglutamates (done by HPLC) and intolerance and other laboratory adverse effects.