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

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)

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.

Study Overview

• Status: Completed
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: Methotrexate

• Study Type: Interventional
• Enrollment (Actual): 179
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
  • Colorado
    • Denver, Colorado, United States, 80045
      • University of Colorado
  • Florida
    • Winter Park, Florida, United States, 32789
      • Shafran Gastroenterology
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Atlanta Gastroenterology
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • The University of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University IU Health
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Metropolitan Gastroenterology Group, PC, Chevy Chase Clinical Research
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Novi, Michigan, United States, 48377
      • Henry Ford Health System
  • Minnesota
    • Plymouth, Minnesota, United States, 55446
      • Minnesota Gastroenterology
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth College
  • New York
    • New York, New York, United States, 10029
      • Mt Sinai School of Medicine
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Asheville Gastroenterology Associates
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Charlotte Gastroenterology & Hepatology
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Mentor, Ohio, United States, 44060
      • Great Lakes Gastroenterology
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • State College, Pennsylvania, United States, 17033
      • Penn State University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor University
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98195
      • University of Washington
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University Of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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; Other Names: Placebo
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; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse Free Survival Week 17-48	Relapse-free survival: Total week 48 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 and no steroid use or other immunosuppressive medication throughout the 32 week maintenance period.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mucosal Healing at Week 48.	Mucosal healing is defined as an absolute Mayo subscore for endoscopy of 0 or 1	48 weeks
Relapse of Disease Between Week 17-48	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.	48 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Calprotectin Levels <250 mcg/g Stool in Patients in Response or in Remission at Week 16 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening	Steroid free clinical remission as defined as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point or steroid free clinical response defined as a reduction from baseline in the clinical Mayo score of ≥ 2 points and at least 25%, with an accompanying decrease in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0-1 point and a clinical Mayo score ≤5 and stool calprotectin levels <250 mcg/g stool at week 16 of the induction period in the subgroup of patients with calprotectin >250mcg/g stool at screening.	16 weeks
Calprotectin Levels <250 mcg/g Stool in Patients in Response or in Remission at Week 48 With Calprotectin Levels > 250 mcg/g Stool at Screening	Steroid free clinical remission as defined as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point or steroid free clinical response defined as a reduction from baseline in the clinical Mayo score of ≥ 2 points and at least 25%, with an accompanying decrease in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0-1 point and a clinical Mayo score ≤5 and stool calprotectin levels <250 mcg/g stool at week 32 of the maintenance period in the subgroup of patients with calprotectin ≥ 250mcg/g stool at screening.	48 weeks
Calprotectin Levels < 50 mcg/g Stool in Patients in Remission at Week 16 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening	Steroid free clinical remission as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point and stool calprotectin levels of ≤ 50mcg at week 16 of the induction period in the subgroup of patients with calprotectin ≥ 250mcg/g stool at screening.	16 weeks
Calprotectin Levels < 50 mcg/g Stool in Patients in Remission at Week 48 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening	Steroid free clinical remission as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point and stool calprotectin levels of ≤ 50mcg at week 48 of the induction period in the subgroup of patients with calprotectin ≥ 250mcg/g stool at screening.	48 weeks

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Hans Herfarth, MD, PhD, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• Herfarth HH, Osterman MT, Isaacs KL, Lewis JD, Sands BE. Efficacy of methotrexate in ulcerative colitis: failure or promise. Inflamm Bowel Dis. 2010 Aug;16(8):1421-30. doi: 10.1002/ibd.21246.
• Herfarth H, Barnes EL, Valentine JF, Hanson J, Higgins PDR, Isaacs KL, Jackson S, Osterman MT, Anton K, Ivanova A, Long MD, Martin C, Sandler RS, Abraham B, Cross RK, Dryden G, Fischer M, Harlan W, Levy C, McCabe R, Polyak S, Saha S, Williams E, Yajnik V, Serrano J, Sands BE, Lewis JD; Clinical Research Alliance of the Crohn's and Colitis Foundation. Methotrexate Is Not Superior to Placebo in Maintaining Steroid-Free Response or Remission in Ulcerative Colitis. Gastroenterology. 2018 Oct;155(4):1098-1108.e9. doi: 10.1053/j.gastro.2018.06.046. Epub 2018 Jun 30.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2012
• Primary Completion (Actual): April 1, 2017
• Study Completion (Actual): April 1, 2017

Study Registration Dates

• First Submitted: July 11, 2011
• First Submitted That Met QC Criteria: July 12, 2011
• First Posted (Estimate): July 13, 2011

Study Record Updates

• Last Update Posted (Actual): April 17, 2018
• Last Update Submitted That Met QC Criteria: March 19, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: 09-2044; 1U01DK092239-01 (U.S. NIH Grant/Contract)