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Methotrexate in Induction and Maintenance of Steroid Free Remission in Ulcerative Colitis (Merit-UC)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by University of North Carolina, Chapel Hill
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Hans Herfarth, MD, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT01393405
First received: July 11, 2011
Last updated: August 20, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Ulcerative Colitis
Drug: Methotrexate
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Randomized, Double Blind, Prospective Trial Investigating the Efficacy of Methotrexate in Induction and Maintenance of Steroid Free Remission in Ulcerative Colitis (MEthotrexate Response In Treatment of UC - MERIT-UC)

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • Relapse free survival [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Relapse-free survival, comprised of three components: total week 32 Mayo score not exceeding 2 points, with all individual subscores not exceeding 1 point and relapse free survival defined by a numerical stable Mayo score throughout 32 weeks of maintenance therapy without increase of 3 or more points in the partial Mayo clinic score (excluding sigmoidoscopy) compared to the partial Mayo score of the individual patient at randomization at week 16 (2) and no steroid use or other immunosuppressive medication throughout the 32 week maintenance period.


Secondary Outcome Measures:
  • Mucosal healing defined as an absolute subscore for endoscopy of 0 or 1 at week 48. [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Relapse of disease [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Relapse of disease in the Maintenance period as defined as an increase of 3 or more points in the partial Mayo clinic score (excluding sigmoidoscopy) with an absolute clinical Mayo score ≥ 4 or need for retreatment with steroids.


Estimated Enrollment: 220
Study Start Date: February 2012
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Methotrexate
25 mg MTX sq once weekly + 1 mg folic acid daily + 2.4 g mesalamine
Drug: Methotrexate

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

Placebo Comparator: Placebo
Placebo sq once weekly + 1 mg folic acid daily + 2.4 g mesalamine
Drug: Methotrexate

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


  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01393405

Contacts
Contact: Hans Herfarth, MD, PhD 919-966-6806 hherf@med.unc.edu
Contact: Susan Jackson, MS 919-843-9071 susan_jackson@med.unc.edu

  Show 37 Study Locations
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Investigators
Principal Investigator: Hans Herfarth, MD, PhD University of North Carolina, Chapel Hill
  More Information

Publications:
Responsible Party: Hans Herfarth, MD, Professor of Medicine, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01393405     History of Changes
Other Study ID Numbers: 09-2044, 1U01DK092239-01
Study First Received: July 11, 2011
Last Updated: August 20, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Additional relevant MeSH terms:
Methotrexate
Colitis
Colitis, Ulcerative
Ulcer
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Inflammatory Bowel Diseases
Pathologic Processes
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014