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

NCT ID: NCT01393405

Last Updated: 2018-04-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 179 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-29
• Study Completion Date: 2017-04-30

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Methotrexate

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

Group Type: ACTIVE_COMPARATOR

Methotrexate

Intervention Type: 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

Placebo

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

Group Type: PLACEBO_COMPARATOR

Methotrexate

Intervention Type: 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

Interventions

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

Intervention Type: DRUG

Other Intervention Names

Placebo

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Hans Herfarth, MD, PhD

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hans Herfarth, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Locations

University of Southern California

Los Angeles, California, United States

University of Colorado

Denver, Colorado, United States

Shafran Gastroenterology

Winter Park, Florida, United States

Atlanta Gastroenterology

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

The University of Chicago

Chicago, Illinois, United States

Indiana University IU Health

Indianapolis, Indiana, United States

University of Iowa

Iowa City, Iowa, United States

University of Kentucky

Lexington, Kentucky, United States

University of Louisville

Louisville, Kentucky, United States

University of Maryland

Baltimore, Maryland, United States

Metropolitan Gastroenterology Group, PC, Chevy Chase Clinical Research

Chevy Chase, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Henry Ford Health System

Novi, Michigan, United States

Minnesota Gastroenterology

Plymouth, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

Dartmouth College

Lebanon, New Hampshire, United States

Mt Sinai School of Medicine

New York, New York, United States

Asheville Gastroenterology Associates

Asheville, North Carolina, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Charlotte Gastroenterology & Hepatology

Charlotte, North Carolina, United States

Case Western Reserve University

Cleveland, Ohio, United States

Great Lakes Gastroenterology

Mentor, Ohio, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Penn State University

State College, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Baylor University

Houston, Texas, United States

University of Utah

Salt Lake City, Utah, United States

Harborview Medical Center

Seattle, Washington, United States

University of Washington

Seattle, Washington, United States

University of Wisconsin

Madison, Wisconsin, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 20186931 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29964043 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

1U01DK092239-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

09-2044

Identifier Type: -

Identifier Source: org_study_id