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

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.

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