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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
306
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.
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.
Time frame: From randomization until treatment failure, assessed up to 3 years.
Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-52 Weeks
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.
Time frame: Weeks 52 from randomization
Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-week 104
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
Time frame: 104 weeks from randomization
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Children's of Alabama
Birmingham, Alabama, United States
Stanford Children's Health
Alto, California, United States
Yale-New Haven Children's Hospital
New Haven, Connecticut, United States
Nemours Children's Health System - Wilmington
Wilmington, Delaware, United States
Nemours Children's Health System - Jacksonville
Jacksonville, Florida, United States
Nicklaus Children's Hospital
Miami, Florida, United States
Nemours Children's Health System - Orlando
Orlando, Florida, United States
Children's Healthcare of Atlanta at Egleston/Emory University
Atlanta, Georgia, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States
Riley Hospital for Children
Indianapolis, Indiana, United States
...and 22 more locations
Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 52
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
Time frame: Week 52 from randomization
Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 104
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
Time frame: 104 weeks from randomization
Percent of Patients With Positive Anti-TNF Antibody
Percent of patients with positive anti-TNF antibody will be compared between the two treatment groups using the chi-squared test.
Time frame: Between 6 months and 2 years from randomization