Low Dose Oral Methotrexate in Pediatric Crohn's Disease Patients Initiating Anti-Tumor Necrosis Factor (Anti-TNF) Therapy

NCT02772965 | Completed Phase 3 Results DMC

• 4 other identifiers: 16-0476PCS-1406-186431U19AR069525-01PCD-MTX-001
• Study Type: interventional
• Target: 306
• Locations: 1 country
• Sites: 32

Brief Summary

The purpose of this study is to determine whether adding low dose methotrexate to anti -TNF therapy is more effective than treatment with anti-TNF therapy alone in inducing and maintaining steroid-free remission for children with Crohn's Disease.

Conditions

Pediatric Crohn's Disease

Outcome Measures

Primary Outcomes (1)

• Percent of Participants Experiencing Treatment Failure

  Treatment failure is defined as follows: 1. Failure to achieve remission (short pediatric Crohn's disease activity index \[SPCDAI\] \< 15) by the week 26 visit; 2. If study initiated on steroids, failure to complete steroid taper by week 16; 3. Short pediatric Crohn's disease activity index (SPCDAI) ≥ 15 attributed to active Crohn's disease, at two or more consecutive visits beyond the week 26 visit. Elevated SPCDAI (≥ 15) due to a non-Inflammatory Bowel Disease (IBD) reason does not count toward this outcome; 4. Hospitalization for active Inflammatory Bowel Disease or abdominal surgery after week 25; 5. Use of oral prednisone or prednisolone, enteral release budesonide, or intravenous (IV) methylprednisolone for over 10 weeks cumulatively, beyond week 16; 6. Discontinuation of anti-TNF agent and/or study drug for lack of effectiveness or toxicity.

  From randomization until treatment failure, assessed up to 3 years.

Secondary Outcomes (5)

• Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-52 Weeks

  Weeks 52 from randomization

• Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-week 104

  104 weeks from randomization

• Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 52

  Week 52 from randomization

• Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 104

  104 weeks from randomization

• Percent of Patients With Positive Anti-TNF Antibody

  Between 6 months and 2 years from randomization

Study Arms (2)

Methotrexate

EXPERIMENTAL

Methotrexate (10, 12.5, or 15 mg), once weekly. Weight-based dosing. Ondansetron (4 mg), twice weekly, 1 hour prior to methotrexate dose and the morning after methotrexate dose. Folic Acid (1 mg) daily

Drug: Methotrexate

Sugar pill (placebo)

PLACEBO COMPARATOR

Placebo for methotrexate, once weekly. Placebo for ondansetron, twice weekly, 1 hour prior to methotrexate placebo dose and the morning after methotrexate placebo dose. Folic Acid (1 mg) daily

Other: Sugar pill (placebo)

Interventions

Methotrexate DRUG

1. Oral methotrexate (MTX): The weekly dose will be 15 mg for children ≥ 40kg, 12.5 mg for children 30 to \<40 kg, and 10 mg for children 20 to \<30 kg. 2. A twice per week, 4mg dose of ondansetron will be provided as pre-treatment to prevent nausea (study provider may opt-out of this component based on clinical judgement). 3. A 1 mg dose of folic acid per day will be provided. This will help to reduce the risk of side effects in the MTX group. Drug kits will contain a 3 month supply of each medication. Refills will be provided every 3 months until week 156 unless there is a failure to induce and maintain remission, development of unacceptable toxicity, pregnancy in a female participant, or failure of the participant to attend scheduled study visits.

Also known as: Methotrexate Sodium

Methotrexate

Sugar pill (placebo) OTHER

1. Placebo for methotrexate: The weekly dose will mimic that of methotrexate. 2. Placebo for ondansetron: The weekly dose will mimic that of ondansetron (study provider may opt-out of this component based on clinical judgement). 3. A 1 mg dose of folic acid per day will be provided to maintain blinding. Drug kits will contain a 3 month supply of each medication. Refills will be provided every 3 months until week 156 unless there is a failure to induce and maintain remission, development of unacceptable toxicity, pregnancy in a female participant, or failure of the participant to attend scheduled study visits.

Sugar pill (placebo)

Eligibility Criteria

• Age: Up to 20 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Pediatric Crohn's Disease (PCD) patients, \< 21 years of age, ≥20 kg, initiating anti-TNF therapy with infliximab or adalimumab (including biosimilars).
• Diagnosis of Crohn's Disease (CD) established confirmed by the treating clinician, and established by standard clinical criteria (radiography, endoscopy, histology).
• Ability to provide parental permission and child assent (where applicable), or adult consent for patients ages 18-20.

You may not qualify if:

• Prior use of anti-TNF or other biological therapy for CD
• Lack of stable home address that study medications can be mailed to
• Anticipated short length of follow up at study center (plans for family to move, transition to adult GI (gastrointestinal) provider, etc.). Patients expected to leave practice \< 12 months from enrollment should not be enrolled.
• Concurrent pelvic or abdominal abscess. A recent history of abdominal or pelvic abscess, which is controlled, does not exclude the subject.
• Prior intra-abdominal surgery without a clinically significant relapse (i.e. patients starting on anti-TNF for post-op prophylaxis or for endoscopic recurrence only should not be included)
• Receipt of a live virus vaccine within the last 30 days
• Pregnancy, planning to become pregnant, or high risk of pregnancy as determined by the local investigator
• Breastfeeding
• Refusal to stay abstinent or utilize 2 forms of birth control while on study medication (for female patients)
• BMI \> 98% for gender and age
• Known previous or concurrent malignancy (other than that considered surgically cured, with no evidence for recurrence for 5 years). A recent history of basal cell or squamous cell carcinoma, which is considered surgically cured, does not exclude the subject.Those with a recent history of colonic adenoma or dysplastic lesions should be excluded.
• Known high alcohol consumption (more than seven drinks per week)
• Patients with serum albumin \< 2.5 g/dl
• Patients with white blood cell count (WBC) \< 3.0 x109th/L
• Patients with platelet count \< 100 x109th/L

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• Patient-Centered Outcomes Research Institute: collaborator
• ImproveCareNow (ICN): collaborator
• The Leona M. and Harry B. Helmsley Charitable Trust: collaborator
• Children's Hospital Medical Center, Cincinnati: collaborator
• Grifols Diagnostics Solutions, Inc: collaborator
• National Institutes of Health (NIH): collaborator
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): collaborator

Study Sites (32)

Children's of Alabama

Birmingham, Alabama, 35233, United States

Location

Stanford Children's Health

Alto, California, 94304, United States

Location

Yale-New Haven Children's Hospital

New Haven, Connecticut, 06510, United States

Location

Nemours Children's Health System - Wilmington

Wilmington, Delaware, 19803, United States

Location

Nemours Children's Health System - Jacksonville

Jacksonville, Florida, 32207, United States

Location

Nicklaus Children's Hospital

Miami, Florida, 33155, United States

Location

Nemours Children's Health System - Orlando

Orlando, Florida, 32827, United States

Location

Children's Healthcare of Atlanta at Egleston/Emory University

Atlanta, Georgia, 30329, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

Location

University of Iowa Children's Hospital

Iowa City, Iowa, 52242, United States

Location

MassGeneral Hospital for Children

Boston, Massachusetts, 02114, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan | CS Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Cardinal Glennon Children's Medical Center

St Louis, Missouri, 63104, United States

Location

St. Louis Children's Hospital | Washington University

St Louis, Missouri, 63110, United States

Location

Children's Hospital and Medical Center Omaha

Omaha, Nebraska, 68114, United States

Location

Mount Sinai Kravis Children's Hospital

New York, New York, 10029, United States

Location

Upstate Golisano Children's Hospital

Syracuse, New York, 13210, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27514, United States

Location

Levine Children's Hospital

Charlotte, North Carolina, 28203, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Rainbow Babies & Children's Hospital

Cleveland, Ohio, 44106, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Dayton Children's Hospital

Dayton, Ohio, 45404, United States

Location

Oklahoma University Medical Center

Oklahoma City, Oklahoma, 73104, United States

Location

Monroe Carell Jr. Children's Hospital at Vanderbilt

Nashville, Tennessee, 37232, United States

Location

The University of Vermont Children's Hospital

Burlington, Vermont, 05401, United States

Location

Pediatric Specialists of Virginia

Fairfax, Virginia, 22031, United States

Location

Children's Hospital of The King's Daughters

Norfolk, Virginia, 23507, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• Kappelman MD, Wohl DA, Herfarth HH, Firestine AM, Adler J, Ammoury RF, Aronow JE, Bass DM, Bass JA, Benkov K, Tobi CB, Boccieri ME, Boyle BM, Brinkman WB, Cabera JM, Chun K, Colletti RB, Dodds CM, Dorsey JM, Ebach DR, Entrena E, Forrest CB, Galanko JA, Grunow JE, Gulati AS, Ivanova A, Jester TW, Kaplan JL, Kugathasan S, Kusek ME, Leibowitz IH, Linville TM, Lipstein EA, Margolis PA, Minar P, Molle-Rios Z, Moses J, Olano KK, Osaba L, Palomo PJ, Pappa H, Park KT, Pashankar DS, Pitch L, Robinson M, Samson CM, Sandberg KC, Schuchard JR, Seid M, Shelly KA, Steiner SJ, Strople JA, Sullivan JS, Tung J, Wali P, Zikry M, Weinberger M, Saeed SA, Bousvaros A. Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial. Gastroenterology. 2023 Jul;165(1):149-161.e7. doi: 10.1053/j.gastro.2023.03.224. Epub 2023 Mar 31.

  PMID: 37004887 DERIVED

MeSH Terms

Conditions

Pediatric Crohn's disease

Interventions

Methotrexate; Sugars

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Michael Kappelman, MD, MPH
• Organization: University of North Carolina at Chapel Hill

michael_kappelman@med.unc.edu

919-966-1343

Study Officials

• Michael D Kappelman, MD

  University of North Carolina, Chapel Hill

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2016
• First Posted: May 16, 2016
• Study Start: October 1, 2016
• Primary Completion: April 7, 2022
• Study Completion: April 7, 2022
• Last Updated: April 12, 2023
• Results First Posted: April 12, 2023

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (32)