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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Hans Herfarth, MD, PhD, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT01393405
First received: July 11, 2011
Last updated: September 12, 2016
Last verified: September 2016
  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.


Other Outcome Measures:
  • Calprotectin levels <250 mcg/g stool at week 16 [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    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.

  • Calprotectin levels <250 mcg/g stool at week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    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.

  • Calprotectin levels of ≤ 50mcg at week 16 [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    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.

  • Calprotectin levels of ≤ 50mcg at week 48 [ Time Frame: 48weeks ] [ Designated as safety issue: No ]
    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.


Enrollment: 179
Study Start Date: February 2012
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: August 2017 (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   (Adult, Senior)
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

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

Publications:
Responsible Party: Hans Herfarth, MD, PhD, 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: September 12, 2016
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Additional relevant MeSH terms:
Methotrexate
Colitis
Ulcer
Colitis, Ulcerative
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Pathologic Processes
Inflammatory Bowel Diseases
Mesalamine
Folic Acid
Vitamin B Complex
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
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
Hematinics

ClinicalTrials.gov processed this record on September 23, 2016