MERIT-UC

Overview

Status: Recruiting
Keywords: Ulcerative Colitis , Methotrexate
IRB Number: 00055276
Specialty: Gastroenterology
Sub Specialties: Inflammatory Bowel Disease/Crohn's/Ulcerative Colitis

Brief Summary

Study Purpose and Objectives:

The therapeutic armamentarium for patients with active UC despite 5-aminosalycilates and steroids is considerably smaller than for patients with CD (therapeutic choices for steroid dependent UC patients: azathioprine, infliximab - therapeutic choices for steroid dependent CD patients: azathioprine, methotrexate, infliximab, adalimumab, certolizumab, natalizumab), there is clearly a need for further exploration of new therapies with a calculable risk profile for this patient group. Currently several new therapeutic approaches investigating the role of different “biologics” e.g. in the inhibition of the co-stimulation of T cells (Abatacept) or selective blockade of interactions between leukocytes and vascular endothelium (MLN 0002 antibody) are being tested in clinical trials. However, given the high costs of biologics, there is an additional need for affordable, easy to administer therapies such as MTX. Additionally, use of small molecules is favorable over biologics as the risk of anti-medication antibody formation is less likely. Since MTX is an old and non-patented drug, it is highly unlikely that this drug will be ever prospectively investigated in patients with UC.

Given the lack of large placebo controlled prospective studies investigating doses of MTX, which were clinically effective in inducing steroid free remission in CD patients, so far neither a negative nor a positive conclusion can be drawn from the published data about the clinical efficacy of MTX in UC. Due to an obvious dose –response relationship observed for MTX in the treatment of rheumatoid arthritis, there seems to be an unmet need for investigating prospectively MTX in higher doses in patients with UC using a subcutaneous or intramuscular application. 

Hypothesis:

MTX applied subcutaneously (sq) once weekly is effective to induce and maintain steroid free remission or response in patients with active ulcerative colitis , who have either failed 5-aminosalicylic acid (5-ASA) therapy, or are steroid dependent or have failed or are intolerant to azathioprine or 6-mercaptopurine therapy or failed to respond or lost response to anti-TNF therapy, compared to placebo.

Principal Investigator: John Valentine
Department: Gastroenterology
Co Investigator:

Contact Information

Name:Andrew Grandemange
Phone: 8015879092
Email: andrew.grandemange@hsc.utah.edu

Inclusion 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 as defined by the Clinical Trials Task Force of the International Organization of Inflammatory Bowel Disease (IOIBD) 2
    • Primary failure or loss of response to an anti-TNF therapy 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

 2Steroid 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

 

Exclusion criteria

Patients who meet one of the following criteria are to be excluded from the trial:

 

  • Failure to respond to 40 mg of prednisone or higher/day in the last 2 weeks before inclusion (Week 0 Visit)
  • Concomitant use of AZA or 6-MP (AZA or 6-MP therapy has to be stopped at least 2 weeks before inclusion into the study) (Week 0 Visit)
  • Anti-TNF therapy (Infliximab (Remicade), Adalimumab (Humira) Golimumab (Simponi)) in the last 4 weeks before inclusion in the study (Week 0 Visit)
  • Concomitant use of vedolizumab (Entyvio) in the last 4 weeks before the Week 0 VisitFailure 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 initial elevation of AST or ALT > 1.5 times above normal limit at baseline
  • 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).  A recent history of basal cell or squamous cell carcinoma does not exclude the subject.
  • 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-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

·            Non - steroidal anti-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:

o   Probenecid

o   Trimethoprim/sulfamethoxazole

o   Sulfasalazine

o   Acitrecin

o   Streptozocin

  • 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