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

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.

Study Overview

• Status: Completed
• Conditions: Pediatric Crohn's Disease
• Intervention / Treatment: Drug: Methotrexate; Other: Sugar pill (placebo)

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.

• Study Type: Interventional
• Enrollment (Actual): 306
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's of Alabama
  • California
    • Alto, California, United States, 94304
      • Stanford Children's Health
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale-New Haven Children's Hospital
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Nemours Children's Health System - Wilmington
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Health System - Jacksonville
    • Miami, Florida, United States, 33155
      • Nicklaus Children's Hospital
    • Orlando, Florida, United States, 32827
      • Nemours Children's Health System - Orlando
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Healthcare of Atlanta at Egleston/Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Children's Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
    • Boston, Massachusetts, United States, 02114
      • MassGeneral Hospital for Children
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan | CS Mott Children's Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Medical Center
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital | Washington University
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Children's Hospital and Medical Center Omaha
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Kravis Children's Hospital
    • Syracuse, New York, United States, 13210
      • Upstate Golisano Children's Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina at Chapel Hill
    • Charlotte, North Carolina, United States, 28203
      • Levine Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies & Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Monroe Carell Jr. Children's Hospital at Vanderbilt
  • Vermont
    • Burlington, Vermont, United States, 05401
      • The University of Vermont Children's Hospital
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Pediatric Specialists Of Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of the King's Daughters
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 20 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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; 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.; Other Names: 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); Placebo for methotrexate: The weekly dose will mimic that of methotrexate.; Placebo for ondansetron: The weekly dose will mimic that of ondansetron (study provider may opt-out of this component based on clinical judgement).; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 Outcome Measures

Outcome Measure	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.	Weeks 52 from randomization
Mean Patient Reported Outcome Measurement and Information System (PROMIS ) Pain Interference T-score-week 104	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 groups	104 weeks from randomization
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	Week 52 from randomization
Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T Score-week 104	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 groups	104 weeks from randomization
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.	Between 6 months and 2 years from randomization

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Patient-Centered Outcomes Research Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institutes of Health (NIH); Children's Hospital Medical Center, Cincinnati; The Leona M. and Harry B. Helmsley Charitable Trust; ImproveCareNow (ICN); Grifols Diagnostics Solutions, Inc
• Investigators: Study Director: Michael D Kappelman, MD, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start: October 1, 2016
• Primary Completion (Actual): April 7, 2022
• Study Completion (Actual): April 7, 2022

Study Registration Dates

• First Submitted: April 27, 2016
• First Submitted That Met QC Criteria: May 11, 2016
• First Posted (Estimate): May 16, 2016

Study Record Updates

• Last Update Posted (Actual): April 12, 2023
• Last Update Submitted That Met QC Criteria: April 10, 2023
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• 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)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO