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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

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

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.

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)

Michael D Kappelman, MD

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.

Overall study duration: 6 years Multi-center study: up to 42 centers

Number of subjects: 425 Duration of treatment for each subject: up to 156 weeks (3 years)

The primary endpoint is percent of patients who experienced treatment failure over time.

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

A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Pragmatic Clinical Trial To Evaluate The Effectiveness Of Low Dose Oral Methotrexate In Patients With Pediatric Crohn's Disease Initiating Anti-TNF Therapy

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.

T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average pain interference and scores below 50 represent lower than average pain interference. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6.

The investigators will compare the mean of PROMIS Pain Interference T-scores at week 52 between the treatment groups.

T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average pain interference and scores below 50 represent lower than average pain interference. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6.

The investigators will compare the mean of PROMIS Pain Interference T-scores at week 104 between the treatment groups

T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average fatigue and scores below 50 represent lower than average fatigue. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6.

The investigators will compare the mean of PROMIS Fatigue T-scores at week 52 between the treatment groups

T-scores are a continuous variable. The mean in the general population is 50 (SD=10). Scores above 50 represent higher than average fatigue and scores below 50 represent lower than average fatigue. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6.

The investigators will compare the mean of PROMIS Fatigue T-scores at week 104 between the treatment groups

Percent of patients with positive anti-TNF antibody will be compared between the two treatment groups using the chi-squared test.

Patient-Centered Outcomes Research Institute

ImproveCareNow (ICN)

The Leona M. and Harry B. Helmsley Charitable Trust

Children's Hospital Medical Center, Cincinnati

Grifols Diagnostics Solutions, Inc

National Institutes of Health (NIH)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

University of North Carolina, Chapel Hill

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

Methotrexate: 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.

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

Sugar pill (placebo): 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)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Infliximab

Adalimumab

Tumor Necrosis Factor (TNF) Inhibitor at Baseline

Modified Intent to Treat population presented.

Michael Kappelman, MD, MPH

Percent of Participants Experiencing Treatment Failure

Population includes those who completed surveys.

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

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

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

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

Analysis includes participants who provided a blood sample.

Percent of Patients With Positive Anti-TNF Antibody

Overall Study

Spots Global Cancer Trial Database for pediatric crohn's disease