Methotrexate in Induction and Maintenance of Steroid Free Remission in Ulcerative Colitis
Condition: Ulcerative Colitis
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Intervention: Methotrexate
Intervention description: Induction period (week 1-16) (Open label):
25 mg MTX sq once weekly + Steroid taper + 1 mg folic acid daily
Maintenance period (week 17-48) (Randomization):
25 mg MTX sq once weekly + 1 mg folic acid daily + 2.4 g mesalamine or Placebo sq once weekly + 1 mg folic acid daily + 2.4 g mesalamine
Intervention MeSH terms: Methotrexate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 179.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      There are fewer therapeutic options for patients with active ulcerative colitis (UC) compared
      to patients with active Crohn's disease (CD) and the investigators 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 (im)
      is an efficient therapy to induce and maintain steroid free remission in patients with CD. To
      evaluate the efficacy of a similar approach in patients with active ulcerative colitis the
      investigators conduct 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 either failed 5-ASA therapy, or are 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 25-30 participating centers actively
      enrolling, the investigators 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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed informed consent.

          -  Man or woman between 18 and 70 years of age.

          -  UC diagnosed by routine clinical, radiographic, endoscopic, and pathological criteria.

          -  Active UC with a Mayo score of 6 to 12 points and moderate-to severe active disease on
             sigmoidoscopy (Mayo endoscopic subscore of at least 2)

        and at least ONE of the following criteria:

          -  Steroid dependent UC *

          -  Primary failure or loss of response to an anti-TNF (infliximab, adalimumab, golimumab)
             in the past

          -  Primary failure or loss of response to vedolizumab in the past

          -  Intolerance/failure of azathioprine/6-MP therapy in the past

          -  Failure of 5-ASA therapy

               -  Steroid dependence is defined as a clinical response to treatment with prednisone
                  40 to 60 mg/day and relapse within 30 days after prednisone treatment was
                  completed or as a requirement for a daily dosage of not less than 10 mg of
                  prednisone and impossibility of weaning the patient off steroid without clinical
                  relapses (two attempts to discontinue the medication within the preceding six
                  months of the start of the study).

        Exclusion Criteria:

          -  Failure to respond to 40 mg of prednisone or higher/day in the last 2 weeks before
             inclusion

          -  Concomitant use of azathioprine (AZA) or 6-mercaptopurine (6-MP) must be discontinued
             at least 2 weeks before inclusion into the study (Week 0 visit)

          -  Anti-TNF therapy in the 2 weeks before the Week 0 visit

          -  Failure of cyclosporine therapy in the previous 6 months prior to Screening visit

          -  Patients with serum albumin < 2.5 g/dl at baseline

          -  Low serum folate defined as decrease of >10% below normal range

          -  Patients with WBC< 3.0 x109th/L at baseline

          -  Patients with platelet count < 100 x109th/L

          -  Patients with an underlying infection with C. difficile at Screening visit

          -  Patients with pre-existing hepatic disease

          -  Patients with known non-alcoholic fatty liver disease (NAFLD)

          -  Patients with known Hepatitis B or Hepatitis C

          -  Patients with pre-existing renal dysfunction (creatinine >1.5 mg/dl).

          -  Patients with a pre-existing chronic lung disease other than well controlled asthma

          -  Patients with interstitial lung disease of unknown cause

          -  Patients with a BMI >35

          -  Known previous or concurrent malignancy (other than that considered surgically cured,
             with no evidence for recurrence for 5 years - basal cell does not exclude)

          -  Existing pregnancy, lactation, or planned pregnancy* (men and women) within the next
             12 months. (*Methotrexate should not be used for at least 3 months before planned
             pregnancy for men and women and should not be used during pregnancy or breast feeding)

          -  High alcohol consumption (more than seven drinks per week)

          -  Non - steroidal inflammatory medications (NSAIDs) as long-term treatment, defined as
             use for at least 4 days a week each month

          -  Continuous treatment with one of the following drugs:

          -  Probenecid,

          -  Trimethoprim/sulfamethoxazole

          -  Sulfasalazine

          -  Acitretin

          -  Streptozocin

          -  Non-use of appropriate contraceptives in females of childbearing potential (e.g.
             condoms, intrauterine device {IUD}, hormonal contraception, or other means considered
             adequate by the responsible investigator) or in males with a child-fathering potential
             (condoms, or other means considered adequate by the responsible investigator during
             treatment

          -  Participation in another clinical trial within the last 30 days, simultaneous
             participation in another clinical trial, or previous participation in this trial

          -  Well-founded doubt about the patient's cooperation.