Trial Outcomes & Findings for Low Dose Oral Methotrexate in Pediatric Crohn's Disease Patients Initiating Anti-Tumor Necrosis Factor (Anti-TNF) Therapy (NCT NCT02772965)

Last Updated: 2023-04-12

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

306 participants

Primary outcome timeframe

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

Results posted on

2023-04-12

Participant Flow

Participant milestones

Participant milestones
Measure	Methotrexate 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.	Sugar Pill (Placebo) 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.
Overall Study STARTED	162	144
Overall Study Randomized	162	144
Overall Study Withdrew Before Receiving Drug	6	3
Overall Study Modified Intent to Treat	156	141
Overall Study COMPLETED	140	126
Overall Study NOT COMPLETED	22	18

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Methotrexate n=156 Participants 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.	Sugar Pill (Placebo) n=141 Participants 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.	Total n=297 Participants Total of all reporting groups
Age, Continuous	13.8 years STANDARD_DEVIATION 2.5 • n=5 Participants	14.0 years STANDARD_DEVIATION 2.8 • n=7 Participants	13.9 years STANDARD_DEVIATION 2.6 • n=5 Participants
Sex: Female, Male Female	53 Participants n=5 Participants	51 Participants n=7 Participants	104 Participants n=5 Participants
Sex: Female, Male Male	103 Participants n=5 Participants	90 Participants n=7 Participants	193 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	150 Participants n=5 Participants	138 Participants n=7 Participants	288 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	13 Participants n=5 Participants	19 Participants n=7 Participants	32 Participants n=5 Participants
Race (NIH/OMB) White	131 Participants n=5 Participants	113 Participants n=7 Participants	244 Participants n=5 Participants
Race (NIH/OMB) More than one race	8 Participants n=5 Participants	5 Participants n=7 Participants	13 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment United States	156 Participants n=5 Participants	141 Participants n=7 Participants	297 Participants n=5 Participants
Tumor Necrosis Factor (TNF) Inhibitor at Baseline Infliximab	110 Participants n=5 Participants	102 Participants n=7 Participants	212 Participants n=5 Participants
Tumor Necrosis Factor (TNF) Inhibitor at Baseline Adalimumab	46 Participants n=5 Participants	39 Participants n=7 Participants	85 Participants n=5 Participants

PRIMARY outcome

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

Outcome measures

Outcome measures
Measure	Methotrexate n=156 Participants 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.	Sugar Pill (Placebo) n=141 Participants 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.
Percent of Participants Experiencing Treatment Failure	25.64 percentage of participants	34.04 percentage of participants

SECONDARY outcome

Timeframe: Weeks 52 from randomization

Population: Population includes those who completed surveys.

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.

Outcome measures

Outcome measures
Measure	Methotrexate n=119 Participants 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.	Sugar Pill (Placebo) n=107 Participants 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.
Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-52 Weeks	37.5 T-score Standard Deviation 12.0	39.5 T-score Standard Deviation 11.9

SECONDARY outcome

Timeframe: 104 weeks from randomization

Population: Population includes those who completed surveys.

Outcome measures

Outcome measures
Measure	Methotrexate n=91 Participants 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.	Sugar Pill (Placebo) n=77 Participants 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.
Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-week 104	38.1 T-score Standard Deviation 12.4	39.9 T-score Standard Deviation 13.5

SECONDARY outcome

Timeframe: Week 52 from randomization

Population: Population includes those who completed surveys.

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

Outcome measures

Outcome measures
Measure	Methotrexate n=119 Participants 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.	Sugar Pill (Placebo) n=107 Participants 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.
Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 52	41.8 T-score Standard Deviation 14.4	41.8 T-score Standard Deviation 14.0

SECONDARY outcome

Timeframe: 104 weeks from randomization

Population: Population includes those who completed surveys.

Outcome measures

Outcome measures
Measure	Methotrexate n=91 Participants 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.	Sugar Pill (Placebo) n=77 Participants 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.
Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 104	41.1 T-score Standard Deviation 14.5	41.5 T-score Standard Deviation 14.9

SECONDARY outcome

Timeframe: Between 6 months and 2 years from randomization

Population: Analysis includes participants who provided a blood sample.

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

Outcome measures

Outcome measures
Measure	Methotrexate n=112 Participants 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.	Sugar Pill (Placebo) n=100 Participants 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.
Percent of Patients With Positive Anti-TNF Antibody	28.5 percentage of participants	40 percentage of participants

Adverse Events

Methotrexate

Serious events: 23 serious events

Other events: 156 other events

Deaths: 0 deaths

Sugar Pill (Placebo)

Serious events: 28 serious events

Other events: 129 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Methotrexate n=156 participants at risk 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.	Sugar Pill (Placebo) n=141 participants at risk 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.
Gastrointestinal disorders Nausea	20.5% 32/156 • Number of events 38 • From the time of signing informed consent until study completion, up to 3 years.	13.5% 19/141 • Number of events 30 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Abdominal Discomfort	14.7% 23/156 • Number of events 35 • From the time of signing informed consent until study completion, up to 3 years.	12.1% 17/141 • Number of events 23 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Diarrhea	4.5% 7/156 • Number of events 9 • From the time of signing informed consent until study completion, up to 3 years.	8.5% 12/141 • Number of events 15 • From the time of signing informed consent until study completion, up to 3 years.
Hepatobiliary disorders Elevation of Liver Enzymes (AST, ALT)	12.8% 20/156 • Number of events 22 • From the time of signing informed consent until study completion, up to 3 years.	5.7% 8/141 • Number of events 9 • From the time of signing informed consent until study completion, up to 3 years.
General disorders Fever	7.1% 11/156 • Number of events 12 • From the time of signing informed consent until study completion, up to 3 years.	5.7% 8/141 • Number of events 9 • From the time of signing informed consent until study completion, up to 3 years.
General disorders Fatigue	5.1% 8/156 • Number of events 11 • From the time of signing informed consent until study completion, up to 3 years.	6.4% 9/141 • Number of events 12 • From the time of signing informed consent until study completion, up to 3 years.
Nervous system disorders Headache	7.7% 12/156 • Number of events 13 • From the time of signing informed consent until study completion, up to 3 years.	12.8% 18/141 • Number of events 20 • From the time of signing informed consent until study completion, up to 3 years.
Skin and subcutaneous tissue disorders Rash	10.9% 17/156 • Number of events 22 • From the time of signing informed consent until study completion, up to 3 years.	12.1% 17/141 • Number of events 20 • From the time of signing informed consent until study completion, up to 3 years.
Infections and infestations C. Difficile	5.1% 8/156 • Number of events 10 • From the time of signing informed consent until study completion, up to 3 years.	5.0% 7/141 • Number of events 10 • From the time of signing informed consent until study completion, up to 3 years.
Infections and infestations Strep pharyngitis	6.4% 10/156 • Number of events 13 • From the time of signing informed consent until study completion, up to 3 years.	4.3% 6/141 • Number of events 7 • From the time of signing informed consent until study completion, up to 3 years.
Infections and infestations Upper Respiratory Infection	5.1% 8/156 • Number of events 9 • From the time of signing informed consent until study completion, up to 3 years.	5.7% 8/141 • Number of events 11 • From the time of signing informed consent until study completion, up to 3 years.

Additional Information

Michael Kappelman, MD, MPH

University of North Carolina at Chapel Hill

Phone: 919-966-1343

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Methotrexate n=156 participants at risk 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.	Sugar Pill (Placebo) n=141 participants at risk 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.
Gastrointestinal disorders Abdominal Discomfort	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	5.0% 7/141 • Number of events 8 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Acute pancreatitis	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Anemia	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Bowel perforation	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Constipation	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Crohn's disease exacerbation	1.3% 2/156 • Number of events 2 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Diarrhea	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders G-Tube placement	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Ileocecectomy	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Intestinal obstruction	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Nausea	100.0% 3/3 • Number of events 3 • From the time of signing informed consent until study completion, up to 3 years.	1.4% 2/141 • Number of events 2 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders Perirectal abscess	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Gastrointestinal disorders post-operative infection from ileocecectomy	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Musculoskeletal and connective tissue disorders Back pain	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.
Musculoskeletal and connective tissue disorders Tenosynovitis - right ankle	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.
Nervous system disorders Hypertensive emergency	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.
Psychiatric disorders Other Paranoia and mental status change	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Psychiatric disorders Severe major depression	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.
Psychiatric disorders Suicidal ideation	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	1.4% 2/141 • Number of events 2 • From the time of signing informed consent until study completion, up to 3 years.
Psychiatric disorders Suicide attempt	1.9% 3/156 • Number of events 3 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.
Renal and urinary disorders Kidney Stone	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	1.4% 2/141 • Number of events 2 • From the time of signing informed consent until study completion, up to 3 years.
Respiratory, thoracic and mediastinal disorders cervical lymphodenitis	0.64% 1/156 • Number of events 5 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.
Respiratory, thoracic and mediastinal disorders Infection	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Respiratory, thoracic and mediastinal disorders Pneumonia	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.
Skin and subcutaneous tissue disorders acute cellutis	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Skin and subcutaneous tissue disorders Anti-TNF Infusion related reaction	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	1.4% 2/141 • Number of events 2 • From the time of signing informed consent until study completion, up to 3 years.
Skin and subcutaneous tissue disorders Facial abscess	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Skin and subcutaneous tissue disorders Facial flushing	0.00% 0/156 • From the time of signing informed consent until study completion, up to 3 years.	0.71% 1/141 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.
Surgical and medical procedures Tonsillectomy and adenoidectomy	0.64% 1/156 • Number of events 1 • From the time of signing informed consent until study completion, up to 3 years.	0.00% 0/141 • From the time of signing informed consent until study completion, up to 3 years.