Low Dose Oral Methotrexate in Pediatric Crohn's Disease P... | NCT02772965

NCT02772965

Secondary IDs

ID	Type	Description	Link
PCS-1406-18643	Other Grant/Funding Number	Patient-Centered Outcomes Research Institute (PCORI)
1U19AR069525-01	U.S. NIH Grant/Contract		View source
PCD-MTX-001	Other Identifier	UNC

Status Module

Sponsor/Collaborators Module

Name	Class
Patient-Centered Outcomes Research Institute	OTHER
ImproveCareNow (ICN)	OTHER
The Leona M. and Harry B. Helmsley Charitable Trust	OTHER
Children's Hospital Medical Center, Cincinnati

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
Methotrexate	Drug	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. 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). 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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percent of Participants Experiencing Treatment Failure	Treatment failure is defined as follows: Failure to achieve remission (short pediatric Crohn's disease activity index [SPCDAI] < 15) by the week 26 visit; If study initiated on steroids, failure to complete steroid taper by week 16; 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; Hospitalization for active Inflammatory Bowel Disease or abdominal surgery after week 25; Use of oral prednisone or prednisolone, enteral release budesonide, or intravenous (IV) methylprednisolone for over 10 weeks cumulatively, beyond week 16; 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

Measure	Description	Time Frame
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.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

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.

Exclusion Criteria:

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
Patients with initial elevation of liver enzymes (AST or ALT) > 1.5 times above normal limit
Patients with known active infection with Clostridium difficile (C. difficile) (untreated infection based on clinician assessment does not apply to colonization or infection controlled with current or prior treatment.)
Patients with pre-existing hepatic disease
Patients with pre-existing renal dysfunction (creatinine > 0.8 for children age<10, creatinine > 1.2 mg/dl for children age 10-18, and creatinine > 1.5 mg/dl for adults age 18 years and older).
Patients with a pre-existing chronic lung disease other than well controlled asthma
Current treatment with one of the following drugs: Probenecid (Probalan), Acitretin (Soriatane), Streptozocin (Zanosar), Azathioprine (Imuran, Azasan), 6-mercaptopurine (Purinethol, Purixan)
Other concerns about the patient/family's ability to participate in the study

Contacts/Locations Module

Name	Affiliation	Role
Michael D Kappelman, MD	University of North Carolina, Chapel Hill	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Children's of Alabama		Birmingham	Alabama	35233	United States
Stanford Children's Health

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
37004887	Derived	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.

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 23, 2021	Feb 23, 2023

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

Modified Intent to Treat population presented.

Arm/Group Information

ID	Title	Description
BG000	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.
BG001	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.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00013.8± 2.5 BG00114.0± 2.8 BG00213.9± 2.6

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00053 BG00151 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG0005 BG0013 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Region of Enrollment

Count of Participants

Participants

Title

Denominators

Categories

United States

Title	Measurements
	BG000156 BG001141 BG002

Tumor Necrosis Factor (TNF) Inhibitor at Baseline

Count of Participants

Participants

Title

Denominators

Categories

Infliximab

Title	Measurements
	BG000110 BG001102 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percent of Participants Experiencing Treatment Failure

Treatment failure is defined as follows:

Failure to achieve remission (short pediatric Crohn's disease activity index [SPCDAI] < 15) by the week 26 visit;
If study initiated on steroids, failure to complete steroid taper by week 16;
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;
Hospitalization for active Inflammatory Bowel Disease or abdominal surgery after week 25;
Use of oral prednisone or prednisolone, enteral release budesonide, or intravenous (IV) methylprednisolone for over 10 weeks cumulatively, beyond week 16;
Discontinuation of anti-TNF agent and/or study drug for lack of effectiveness or toxicity.

Posted

Number

percentage of participants

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

ID	Title	Description
OG000	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.
OG001	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.

Units	Counts
Participants	OG000156 OG001141

Title

Denominators

Categories

Title	Measurements
	OG00025.64 OG00134.04

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Log Rank		0.08		Hazard Ratio (HR)	0.69			2-Sided	95	0.45	1.05					Superiority

Secondary

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.

Population includes those who completed surveys.

Posted

Mean

Standard Deviation

T-score

Weeks 52 from randomization

ID	Title	Description
OG000	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.

Secondary

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

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

Population includes those who completed surveys.

Posted

Mean

Standard Deviation

T-score

104 weeks from randomization

ID	Title	Description
OG000	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.

Secondary

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

Population includes those who completed surveys.

Posted

Mean

Standard Deviation

T-score

Week 52 from randomization

ID	Title	Description
OG000	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.

Secondary

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

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

Population includes those who completed surveys.

Posted

Mean

Standard Deviation

T-score

104 weeks from randomization

ID	Title	Description
OG000	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.

Secondary

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.

Analysis includes participants who provided a blood sample.

Posted

Number

percentage of participants

Between 6 months and 2 years from randomization

ID	Title	Description
OG000	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.
OG001	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.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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.	0	156	23	156	156	156
EG001	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.	0	141	28	141	129	141

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Abdominal Discomfort	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0018 events7 affected141 at risk
Acute pancreatitis	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0011 events1 affected141 at risk
Anemia	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0010 events0 affected141 at risk
Bowel perforation	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0011 events1 affected141 at risk
Constipation	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0011 events1 affected141 at risk
Crohn's disease exacerbation	Gastrointestinal disorders	Systematic Assessment	EG0002 events2 affected156 at risk EG0011 events1 affected141 at risk
Diarrhea	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0011 events1 affected141 at risk
G-Tube placement	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0010 events0 affected141 at risk
Ileocecectomy	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0011 events1 affected141 at risk
Intestinal obstruction	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0010 events0 affected141 at risk
Nausea	Gastrointestinal disorders	Systematic Assessment	EG0003 events3 affected3 at risk EG0012 events2 affected141 at risk
Perirectal abscess	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0011 events1 affected141 at risk
post-operative infection from ileocecectomy	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0011 events1 affected141 at risk
Back pain	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0010 events0 affected141 at risk
Tenosynovitis - right ankle	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0010 events0 affected141 at risk
Hypertensive emergency	Nervous system disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0010 events0 affected141 at risk
Other Paranoia and mental status change	Psychiatric disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0011 events1 affected141 at risk
Severe major depression	Psychiatric disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0010 events0 affected141 at risk
Suicidal ideation	Psychiatric disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0012 events2 affected141 at risk
Suicide attempt	Psychiatric disorders	Systematic Assessment	EG0003 events3 affected156 at risk EG0010 events0 affected141 at risk
Kidney Stone	Renal and urinary disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0012 events2 affected141 at risk
cervical lymphodenitis	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0005 events1 affected156 at risk EG0010 events0 affected141 at risk
Infection	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0011 events1 affected141 at risk
Pneumonia	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0010 events0 affected141 at risk
acute cellutis	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0011 events1 affected141 at risk
Anti-TNF Infusion related reaction	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0001 events1 affected156 at risk EG0012 events2 affected141 at risk
Facial abscess	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0011 events1 affected141 at risk
Facial flushing	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0000 events0 affected156 at risk EG0011 events1 affected141 at risk
Tonsillectomy and adenoidectomy	Surgical and medical procedures	Systematic Assessment	EG0001 events1 affected156 at risk EG0010 events0 affected141 at risk

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Nausea	Gastrointestinal disorders	Systematic Assessment	EG00038 events32 affected156 at risk EG00130 events19 affected141 at risk
Abdominal Discomfort	Gastrointestinal disorders	Systematic Assessment	EG00035 events23 affected156 at risk EG00123 events17 affected141 at risk
Diarrhea	Gastrointestinal disorders	Systematic Assessment	EG0009 events7 affected156 at risk EG00115 events12 affected141 at risk
Elevation of Liver Enzymes (AST, ALT)	Hepatobiliary disorders	Systematic Assessment	EG00022 events20 affected156 at risk EG0019 events8 affected141 at risk
Fever	General disorders	Systematic Assessment	EG00012 events11 affected156 at risk EG0019 events8 affected141 at risk
Fatigue	General disorders	Systematic Assessment	EG00011 events8 affected156 at risk EG00112 events9 affected141 at risk
Headache	Nervous system disorders	Systematic Assessment	EG00013 events12 affected156 at risk EG00120 events18 affected141 at risk
Rash	Skin and subcutaneous tissue disorders	Systematic Assessment	EG00022 events17 affected156 at risk EG00120 events17 affected141 at risk
C. Difficile	Infections and infestations	Systematic Assessment	EG00010 events8 affected156 at risk EG00110 events7 affected141 at risk
Strep pharyngitis	Infections and infestations	Systematic Assessment	EG00013 events10 affected156 at risk EG0017 events6 affected141 at risk
Upper Respiratory Infection	Infections and infestations	Systematic Assessment	EG0009 events8 affected156 at risk EG00111 events8 affected141 at risk

ID	Term
C536215	Pediatric Crohn's disease

ID	Term
D008727	Methotrexate
D000073893	Sugars

ID	Term
D000630	Aminopterin
D011622	Pterins
D011621	Pteridines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds
D002241	Carbohydrates