Low Dose Oral Methotrexate in Pediatric Crohn's Disease Patients Initiating Anti-Tumor Necrosis Factor (Anti-TNF) Therapy (COMBINE)
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ClinicalTrials.gov Identifier: NCT02772965 |
Recruitment Status :
Completed
First Posted : May 16, 2016
Last Update Posted : June 23, 2022
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Pediatric Crohn's Disease | Drug: Methotrexate Other: Sugar pill (placebo) | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 306 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Triple (Participant, Care Provider, Investigator) |
Primary Purpose: | Treatment |
Official Title: | 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 |
Study Start Date : | October 2016 |
Actual Primary Completion Date : | April 7, 2022 |
Actual Study Completion Date : | April 7, 2022 |

Arm | Intervention/treatment |
---|---|
Experimental: 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 |
Drug: Methotrexate
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. Other Name: Methotrexate Sodium |
Placebo Comparator: 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 |
Other: Sugar pill (placebo)
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. |
- Time to treatment failure [ Time Frame: From randomization until treatment failure, assessed up to 3 years. ]
Time from randomization to treatment failure defined as follows:
- Failure to achieve remission (SPCDAI < 15) by the week 26 visit;
- If study initiated on steroids, failure to complete steroid taper by week 16;
- 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-IBD reason (i.e., infection, IBS, normal colonoscopy or other test of mucosal inflammation) does not count toward this outcome;
- Hospitalization for active Irritable 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. (Not inclusive of steroids used as premed for anti-TNF administration or steroids used for conditions other than CD);
- Discontinuation of anti-TNF or study drug for lack of effectiveness or toxicity.
- Mean PROMIS (Patient Reported Outcome Measurement and Information System) Pain Interference T score by treatment arm [ Time Frame: Week 52, Week 104, and Week 156 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. The investigators will compare the mean of PROMIS Pain Interference T scores at week 52 and week 104 between the treatment groups. If the patient continues into year 3, the investigators will compare the mean at week 52, week 104, and week 156. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6.
- Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T score by treatment arm [ Time Frame: Week 52, Week 104, and Week 156 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. The investigators will compare the mean of PROMIS Fatigue T scores at week 52 and week 104 between the treatment groups. If the patient continues into year 3, the investigators will compare the mean at week 52, week 104, and week 156. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6.
- Proportion of patients with positive anti-TNF antibody status [ Time Frame: Between week 91 and week 104 from randomization ]Proportion of patients with positive anti-TNF antibody status will be compared between the two treatment groups using the chi-squared test. The year two sample will be collected at a single time point between week 91 and week 104 from randomization.

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Ages Eligible for Study: | up to 20 Years (Child, Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02772965

Study Director: | Michael D Kappelman, MD | University of North Carolina, Chapel Hill |
Responsible Party: | University of North Carolina, Chapel Hill |
ClinicalTrials.gov Identifier: | NCT02772965 |
Other Study ID Numbers: |
16-0476 PCS-1406-18643 ( Other Grant/Funding Number: Patient-Centered Outcomes Research Institute (PCORI) ) 1U19AR069525-01 ( U.S. NIH Grant/Contract ) PCD-MTX-001 ( Other Identifier: UNC ) |
First Posted: | May 16, 2016 Key Record Dates |
Last Update Posted: | June 23, 2022 |
Last Verified: | June 2022 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Crohn Disease Inflammatory Bowel Diseases Gastroenteritis Gastrointestinal Diseases Digestive System Diseases Intestinal Diseases Methotrexate Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents Physiological Effects of Drugs |
Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Dermatologic Agents Enzyme Inhibitors Folic Acid Antagonists Immunosuppressive Agents Immunologic Factors Antirheumatic Agents Nucleic Acid Synthesis Inhibitors |