Low Dose Oral Methotrexate in Pediatric Crohn's Disease Patients Initiating Anti-Tumor Necrosis Factor (Anti-TNF) Therapy
- Conditions
- Pediatric Crohn's Disease
- Interventions
- Other: Sugar pill (placebo)Drug: Methotrexate
- Registration Number
- NCT02772965
- Lead Sponsor
- University of North Carolina, Chapel Hill
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 306
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Sugar pill (placebo) 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 Methotrexate 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
- Primary Outcome Measures
Name Time Method Percent of Participants Experiencing Treatment Failure From randomization until treatment failure, assessed up to 3 years. 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.
- Secondary Outcome Measures
Name Time Method Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-52 Weeks Weeks 52 from randomization 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.Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-week 104 104 weeks from randomization 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 groupsMean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 52 Week 52 from randomization 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 groupsMean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 104 104 weeks from randomization 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 groupsPercent of Patients With Positive Anti-TNF Antibody Between 6 months and 2 years from randomization Percent of patients with positive anti-TNF antibody will be compared between the two treatment groups using the chi-squared test.
Trial Locations
- Locations (32)
The University of Vermont Children's Hospital
🇺🇸Burlington, Vermont, United States
Nemours Children's Health System - Wilmington
🇺🇸Wilmington, Delaware, United States
Children's Hospital and Medical Center Omaha
🇺🇸Omaha, Nebraska, United States
Monroe Carell Jr. Children's Hospital at Vanderbilt
🇺🇸Nashville, Tennessee, United States
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Stanford Children's Health
🇺🇸Alto, California, United States
Children's of Alabama
🇺🇸Birmingham, Alabama, United States
Nemours Children's Health System - Jacksonville
🇺🇸Jacksonville, Florida, United States
Children's Healthcare of Atlanta at Egleston/Emory University
🇺🇸Atlanta, Georgia, United States
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
University of Iowa Children's Hospital
🇺🇸Iowa City, Iowa, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
MassGeneral Hospital for Children
🇺🇸Boston, Massachusetts, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Cardinal Glennon Children's Medical Center
🇺🇸Saint Louis, Missouri, United States
St. Louis Children's Hospital | Washington University
🇺🇸Saint Louis, Missouri, United States
Mount Sinai Kravis Children's Hospital
🇺🇸New York, New York, United States
Upstate Golisano Children's Hospital
🇺🇸Syracuse, New York, United States
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Levine Children's Hospital
🇺🇸Charlotte, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Rainbow Babies & Children's Hospital
🇺🇸Cleveland, Ohio, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Oklahoma University Medical Center
🇺🇸Oklahoma City, Oklahoma, United States
Pediatric Specialists of Virginia
🇺🇸Fairfax, Virginia, United States
Children's Hospital of The King's Daughters
🇺🇸Norfolk, Virginia, United States
Yale-New Haven Children's Hospital
🇺🇸New Haven, Connecticut, United States
Nemours Children's Health System - Orlando
🇺🇸Orlando, Florida, United States
University of Michigan | CS Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Children's Mercy Hospital
🇺🇸Kansas City, Missouri, United States