DOI: 10.3886/icpsr38680.v1
title: Comparative Effectiveness of Anti-TNF in Combination with Low Dose Methotrexate vs Anti-TNF Monotherapy in Pediatrics Crohn's Disease (COMBINE), United States, 2015-2022
title: Version 1

description: The COMBINE study was a longitudinal examination of pediatric Crohn's Disease (CD) patients in the United States with data collected from 2015-2022. This study was a randomized, double blind, placebo controlled pragmatic trial to compare low dose oral methotrexate versus a placebo in children with Crohn's disease initiating anti-TNF (tumor necrosis factor) therapy with Infliximab or Adalimumab. Eligible participants were randomized with a 1:1 allocation and followed for a minimum of 12 months and maximum of 36 months in the context of routine clinical care. The primary outcome was a composite of indicators of treatment failure and/or toxicity. Secondary outcomes included patient reported outcomes of pain interference and fatigue.
Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) that affects approximately 600,000 Americans with estimated direct costs of $3.6 billion annually. Typical symptoms (e.g., abdominal pain, bloody diarrhea) result in substantial morbidity, including hospitalization and surgery, missed work and school, and diminished quality of life. The primary treatment goals for all CD patients are to induce remission by eradicating intestinal inflammation and related symptoms and maintain remission by preventing disease flares and progression. Additional treatment goals for pediatric CD include restoring physical and emotional development.
description: The Principal Investigator and other researchers for this study had four primary objectives.

To determine whether, in children with Crohn's disease (CD) initiating anti-TNF (anti-Tumor Necrosis Factor) biological therapy with Infliximab or Adalimumab, low-dose oral methotrexate (MTX) is more effective than a placebo in the induction and subsequent maintenance of steroid-free remission for a treatment period of up to three years. 
To determine whether, in children with CD initiating anti-TNF biological therapy with Infliximab or Adalimumab, low-dose oral MTX leads to better Patient Reported Outcomes (PROs) as compared to a placebo.
To describe the investigator-reported adverse events (AEs) (Grade 2 or higher) in patients initiating anti-TNF, treated with low dose oral MTX and in a placebo comparison group.
To determine whether low-dose oral methotrexate, in combination with anti-TNF biological therapy, is more effective than anti-TNF monotherapy in reducing anti-TNF antibody formation resulting in higher anti-TNF trough levels.
description: This study utilized a randomization by constrained block within each site, stratified by anti-TNF agent used (Infliximab or Adalimumab), to ensure balanced treatment allocation within individual sites. Sites were randomly assigned 1:1 to the intervention or control group before recruitment begins at each site. A covariate-constrained randomization procedure was used to ensure that the intervention and control sites were balanced at baseline with respect to approximate number of patients with Crohn's Disease started on an anti-TNF agent in the past year. This was important to ensure that a similar number of patients were approached for trial participation at intervention and control sites. Randomization occurred at the site level so that all providers and research staff at a site were assigned to the same randomization condition to increase the feasibility of protocol implementation and decrease risk of contamination across study arms.
Study product, dose, and route: oral MTX (15 mg for respondents greater than or equal to 40 kilograms, 12.5 mg for individuals between 30 - 40 kilograms, and 10 mg for those weighing between 20 - 30 kilograms) given once a week
12 to 36 months.
After study enrollment follow-up with patients took place after four weeks, 14 weeks, 26 weeks, and then quarterly after that.
description: <strong>DS1 Screening / Randomization</strong>: (110 variables / 307 cases) - inclusion and exclusion study criteria, prior IBD medications usage, lab tests and results
<strong>DS2 Screening Conditions</strong>: (3 variables / 371 cases) - condition and body system
<strong>DS3 Supplemental Screening</strong>: (38 variables / 65 cases) - lab tests and results, past week stools and symptoms
<strong>DS4 Early Termination / Completion</strong>: (21 variables / 306 cases) - details regarding the study status for each patient
<strong>DS5 ICN Registry Enrollment</strong>: (15 variables /
325 cases) - diagnosis and CD phenotype, demographics (gender, ethnicity, and race)
<strong>DS6 ICN Registry Hospitalization</strong>: (6 variables / 212 cases) - dates of admission and discharge, was visit IBD related
<strong>DS7 ICN Registry Visits</strong>: (36 variables / 4,445 cases) - current height and weight, lab tests and results, details of stools over the last 7 days
<strong>DS8 Visit Information</strong>: (82 variables / 2,524 cases) - exam and lab results over the course of the entire study
<strong>DS9 Non-Visit Labs</strong>: (11 variables / 6,539 cases) - name of test, test date, and results
<strong>DS10 Anti-TNF Medication</strong>: (15 variables / 1,488 cases) - medication name, dosage, and adjustments made 
<strong>DS11 Other Medications</strong>: (13 variables / 1,121 cases) - medication name, dosage, frequency, route, and dates started and stopped
<strong>DS12 Adverse Events</strong>: (27 variables / 799 cases) - description and details of serious adverse events occurring in the patient's life
<strong>DS13 Colonoscopy</strong>: (24 variables / 405 cases) - results for ileum, right and left colon, transverse colon, and rectum
<strong>DS14 Dose Change</strong>: (9 variables / 244 cases) - type of dose, amount of dose, and reason for change in dosage
<strong>DS15 Pregnancy</strong>: (10 variables / 2 cases) - pregnancy status, outcome, birth length and weight, gender
<strong>DS16 Steroids Before 16 Weeks</strong>: (9 variables / 325 cases) - steroid name, dosage, frequency, route, and dates started and stopped
<strong>DS17 Steroids After 16 Weeks</strong>: (9 variables / 127 cases) - steroid name, dosage, frequency, route, and dates started and stopped
<strong>DS18 Outcomes</strong>: (12 variables / 297 cases) - outcome efficacy of treatment
<strong>DS19 PROMIS</strong>: (43 variables / 1,201 cases) - the affect of pain, tiredness, and happiness on life over the past 7 days
description: None
description: The sample size calculation was based upon the primary aim and outcome -- induction and maintenance of steroid free remission. The estimated sample size was based upon the following assumptions:

Induction and maintenance of steroid-free clinical remission through week 104 will occur in 50% of the monotherapy group. This is based on the two adult trials of anti-TNF combination versus monotherapy in CD.
True difference between the two treatment arms will be 15% or more.
Anticipated loss to follow up of no more than 17%.

Accounting for staggered entry and loss to follow up it was anticipated the study would need to recruit a total of 425 patients to observe required number of treatment failures. The study specified several criteria for inclusion which included:

Confirmed diagnosis of Crohn's Disease by established clinical criteria
Age less than 21 years of age
Weight of patient being more than or equal to 20 kilograms
Willing to initiate anti-TNF therapy with Infliximab or Adalimumab (including biosimilars)

Please see the PI Codebook or protocol document for a list of items that would exclude a person from participation in the study.
description: Datasets: 
DS0: Study-Level Files
DS1: Screening / Randomization
DS2: Screening Conditions
DS3: Supplemental Screening
DS4: Early Termination / Completion
DS5: ICN Registry Enrollment
DS6: ICN Registry Hospitalization
DS7: ICN Registry Visits
DS8: Visit Information
DS9: Non-Visit Labs
DS10: Anti-TNF Medication
DS11: Other Medications
DS12: Adverse Events
DS13: Colonoscopy
DS14: Dose Change
DS15: Pregnancy
DS16: Steroids Before 16 Weeks
DS17: Steroids After 16 Weeks
DS18: Outcomes
DS19: PROMIS
description: Pediatric Crohn's disease patients initiating anti-TNF therapy with Infliximab or Adalimumab (including biosimilars).
description: record abstracts; self-enumerated questionnaireThe variable <strong>COMBINE_ID</strong> is the unique respondent identification number present in each file that can be used to link the files together.Most of the data files contain variables containing full dates (date of lab / test, date of dosage, date of visit). However, all date variables have been shifted in an unknown systematic order by the Principal Investigator to protect patient confidentiality. Dates may still be used to calculate differences in any analysis, but do not reflect the actual date a visit or lab was conducted.For more information on the COMBINE study, please refer to the study website.