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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 : Recruiting
First Posted : May 16, 2016
Last Update Posted : April 21, 2020
Sponsor:
Collaborators:
Patient-Centered Outcomes Research Institute
ImproveCareNow (ICN)
The Leona M. and Harry B. Helmsley Charitable Trust
Children's Hospital Medical Center, Cincinnati
Grifols Diagnostics Solutions, Inc
National Institutes of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Study Description
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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.

Condition or disease Intervention/treatment Phase
Pediatric Crohn's Disease Drug: Methotrexate Other: Sugar pill (placebo) Phase 3

Detailed Description:

Overall study duration: 4 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 time to treatment failure.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 425 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
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Crohn's Disease

Arms and Interventions
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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
  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.

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)
  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.


Outcome Measures
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Primary Outcome Measures :
  1. Time to treatment failure [ Time Frame: Continuous from randomization through week 156 ]
    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); or discontinuation of anti-TNF or study drug for lack of effectiveness or toxicity.


Secondary Outcome Measures :
  1. Mean PROMIS (Patient Reported Outcome Measurement and Information System) Pain Interference T score by treatment arm [ Time Frame: Week 52 and 104 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. We will compare the mean of PROMIS Pain Interference T scores at week 52 and week 104 between the treatment groups. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6.

  2. Mean PROMIS (Patient Reported Outcome Measurement and Information System) Fatigue T score by treatment arm [ Time Frame: Week 52 and 104 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. We will compare the mean of PROMIS Fatigue T scores at week 52 and week 104 between the treatment groups. Minimal important differences (MIDs) for many PROMIS domains are in the range of 2 to 6.

  3. 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. if a sample is not collected in the second year, the sample collected in the first year will be used (week 14).


Eligibility Criteria
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Ages Eligible for Study:   up to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 and Locations
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Information from the National Library of Medicine

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


Contacts
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Contact: Michael D Kappelman, MD (919) 843-5908 michael_kappelman@med.unc.edu
Contact: Ann Firestine (919) 966-0144 annfire@unc.edu

Locations
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Sponsors and Collaborators
University of North Carolina, Chapel Hill
Patient-Centered Outcomes Research Institute
ImproveCareNow (ICN)
The Leona M. and Harry B. Helmsley Charitable Trust
Children's Hospital Medical Center, Cincinnati
Grifols Diagnostics Solutions, Inc
National Institutes of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Investigators
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Study Director: Michael D Kappelman, MD University of North Carolina, Chapel Hill
More Information
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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: April 21, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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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