Methotrexate in Induction and Maintenance of Steroid Free Remission in Ulcerative Colitis

NCT01393405 | Completed Phase 2 Results DMC

• 2 other identifiers: 09-20441U01DK092239-01
• Study Type: interventional
• Target: 179
• Locations: 1 country
• Sites: 31

Brief 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.

Conditions

Ulcerative Colitis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Mucosal Healing at Week 48.

  48 weeks

• Relapse of Disease Between Week 17-48

  48 weeks

Other Outcomes (4)

• 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

  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

  48 weeks

• Calprotectin Levels < 50 mcg/g Stool in Patients in Remission at Week 16 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening

  16 weeks

Study Arms (2)

Methotrexate

ACTIVE COMPARATOR

25 mg MTX sq once weekly + 1 mg folic acid daily + 2.4 g mesalamine

Drug: Methotrexate

Placebo

PLACEBO COMPARATOR

Placebo sq once weekly + 1 mg folic acid daily + 2.4 g mesalamine

Drug: Methotrexate

Interventions

Methotrexate DRUG

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

Also known as: Placebo

Methotrexate; Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (31)

University of Southern California

Los Angeles, California, 90033, United States

Location

University of Colorado

Denver, Colorado, 80045, United States

Location

Shafran Gastroenterology

Winter Park, Florida, 32789, United States

Location

Atlanta Gastroenterology

Atlanta, Georgia, 30342, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

The University of Chicago

Chicago, Illinois, 60637, United States

Location

Indiana University IU Health

Indianapolis, Indiana, 46202, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Kentucky

Lexington, Kentucky, 40536, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

Metropolitan Gastroenterology Group, PC, Chevy Chase Clinical Research

Chevy Chase, Maryland, 20815, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Henry Ford Health System

Novi, Michigan, 48377, United States

Location

Minnesota Gastroenterology

Plymouth, Minnesota, 55446, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Dartmouth College

Lebanon, New Hampshire, 03756, United States

Location

Mt Sinai School of Medicine

New York, New York, 10029, United States

Location

Asheville Gastroenterology Associates

Asheville, North Carolina, 28801, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Charlotte Gastroenterology & Hepatology

Charlotte, North Carolina, 28207, United States

Location

Case Western Reserve University

Cleveland, Ohio, 44106, United States

Location

Great Lakes Gastroenterology

Mentor, Ohio, 44060, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Penn State University

State College, Pennsylvania, 17033, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Baylor University

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Harborview Medical Center

Seattle, Washington, 98104, United States

Location

University of Washington

Seattle, Washington, 98195, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

Related Publications (2)

• 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.

  PMID: 20186931 BACKGROUND

• 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.

  PMID: 29964043 DERIVED

MeSH Terms

Conditions

Colitis, Ulcerative

Interventions

Methotrexate

Condition Hierarchy (Ancestors)

Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Inflammatory Bowel Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

There were no limitations for this trial

Results Point of Contact

• Title: Dr. Hans Herfarth
• Organization: University of North Carolina, Chapel Hill, NC

hherf@med.unc.edu

9199666806

Study Officials

• Hans Herfarth, MD, PhD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: July 11, 2011
• First Posted: July 13, 2011
• Study Start: February 1, 2012
• Primary Completion: April 1, 2017
• Study Completion: April 1, 2017
• Last Updated: April 17, 2018
• Results First Posted: April 17, 2018

Record last verified: 2018-03

Locations

US (31)