Anti-TNF Therapy for Refractory Colitis in Hospitalized Children
Condition: Colitis, Ulcerative; Bowel Diseases, Inflammatory
MeSH terms: Colitis; Colitis, Ulcerative; Inflammatory Bowel Diseases
Study type: Observational

Summary: 
      This multicenter study is being conducted to determine whether infliximab exposure after an
      initial infusion is predictive of early clinical response in hospitalized pediatric patients
      with severe steroid-refractory UC or IBD-U. This pilot and feasibility study will establish
      the infrastructure, demonstrate feasibility, and collect preliminary data to support the full
      study.
    

Detailed description: 
      This is a multicenter prospective non-interventional cohort study to identify clinical and
      biological markers that predict non-response in hospitalized pediatric patients with severe
      corticosteroid-refractory UC or inflammatory bowel disease unspecified (IBD-U) being
      initiated on infliximab.

      Patients hospitalized with severe UC or IBD-U (PUCAI ≥ 65 on admission) and failing
      intravenous corticosteroids will be eligible. Blood, stool, and rectal biopsies (if
      sigmoidoscopy performed for clinical indications) will be collected for translational studies
      (Aim 3). Patients will receive infliximab per the dose and regimen determined by clinical
      physician. No standard dosing regimen will be used and the dose of IFX will be determined by
      the treating physician. Serial PUCAI scores and infliximab levels will be obtained.

      Those who are eligible to participate will have serial blood samples taken in association
      with drug infusions to perform pharmacokinetic/pharmacodynamic modeling of infliximab
      exposure. Clinical response will be determined using the Pediatric UC Activity Index (PUCAI)
      questionnaire.

      Initially, 6 centers will participate with a minimum target enrollment goal of 36 evaluable
      pediatric research participants (to a maximum of 40) age > 4 years or < 18 years old with UC
      or IBD-U (average 6/center).

      The primary endpoint will be the relationship between IFX exposure (area under the curve of
      the PK model) and Day 7 clinical response defined as Pediatric Ulcerative Colitis Activity
      Index (PUCAI) ≤ 35. Secondary endpoints will be Week 8 clinical remission, and Week 26
      steroid-free, colectomy-free remission. We will initially enlist 6 centers, and enroll 36-40
      evaluable patients in 2 years.

      This study described by this protocol is designed as pilot and feasibility study, which we
      anticipate will ultimately be expanded to larger study. Therefore, to demonstrate feasibility
      and begin the development of a biorepository on this patient population, certain biospecimens
      will be collected for this study and anticipated future translational studies as follows:

        -  Blood will be used for IFX pharmacokinetic assays (e.g. levels, antibodies) and future
           biomarker discovery.

        -  Blood DNA we anticipate will be used for genotype/phenotype correlations and genetic
           predictors of rapid infliximab clearance and non-response.

        -  Colon tissue RNA will be used for determining how local gene expression patterns predict
           or explain infliximab clearance or non-response.

        -  Colon tissue DNA we anticipate will be used for studies of how the microbiome or
           epigenetic changes relate to severe UC or response to infliximab.

        -  Colon tissue will be used for determining the relationship between tissue TNF levels (or
           other proteins) and infliximab clearance or non-response.

        -  Stool will be collected for serial measurement of fecal calprotectin and future
           microbiome studies
    

Intervention name(s): Infliximab
Intervention type(s): Drug
Intervention description(s): No standard dosing regimen will be used and the dose of infliximab will be determined by the treating physician
Other intervention name(s): Remicade
Intervention MeSH terms: Infliximab
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Research participants age 4 to 17 will be eligible for this study. Our target is a minimum
        of 36 evaluable research participants (to a maximum of 40) across up to 6 participating
        centers.
      
Biospecimen description: 
      Blood, blood DNA, serum, plasma, colon endoscopic biopsy tissue (RNA/DNA/Formalin-fixed),
      stool (DNA and supernatant)