MERIT - Randomized, Double-Blind, Prospective Trial Investigating the Efficacy of Methotrexate in Induction and Maintenance of Steroid Free Remission in Ulcerative Colitis.

There are fewer therapeutic options for patients with active ulcerative colitis (UC) compared to patients with active Crohn's disease (CD) and we are facing a persistent unmet need for additional effective and affordable therapies for patients with UC, Methotrexate (MTX) 25 mg once weekly administered subcutaneously (sq) or intramuscularly (irn) is an efficient therapy to induce and maintain steroid free remission in patients with CD, We conducted a systematic literature research to identify published clinical efficacy data of MTX in patients with UC and found several retrospective and prospective case series demonstrating clinical efficacy of MTX, when the drug was administered in a comparable dose and similar route (irn or sq) as in CD, We therefore hypothesize that MTX presents an effective therapy for patients with UC if administered in a similar fashion as in CD patients. We propose a double-blind, placebo controlled, randomized, multicenter, parallel group trial to investigate the safety and efficacy of 25 mg MTX applied subcutaneously once weekly in patients with active UC, who are either steroid dependent or are intolerant or not responding to azathioprine/6-mercaptopurine therapy or have no response/lost response to infliximab prior to the study inclusion. The study is designed as a drug withdrawal trial and includes two periods, the Induction Period (week 0-16) and the Maintenance Period (week 17-48), In the open label Induction Period every patient will receive a steroid taper, MTX 25 mg sq once weekly + daily folic acid 1 mg tablets for the induction of clinical response or remission. Patients responding to the open label MTX therapy and being off steroids between week 12-16 will be randomized at week 16 1:1 to Placebo sq once weekly + daily folic acid 1 mg tablets + 2.4 g mesalamine or to MTX 25 mg sq once weekly + daily folic acid 1 mg tablets+ 2.4 g mesalamine. The Specific Aims of the trial are: i) To evaluate the safety and tolerability of 25 mg MTX applied sq once weekly over a time period of 48 weeks; ii) To evaluate the relapse-free survival of MTX maintenance therapy compared to placebo over a time period of 32 weeks; iii) To evaluate the efficacy of MTX over a time period of 16 weeks to induce steroid free remission; iiii) To establish a DNA, plasma and serum library to enable the evaluation of clinical and pharmacogenomic models to predict the response to MTX therapy in patients with UC. With 35 participating centers actively enrolling, we anticipate to complete enrollment for this study in a time period of 3 years, Completion of this trial will define the therapeutic value of MTX in UC, potentially changing the current therapeutic strategy in UC.