Anti-TNF Therapy for Refractory Colitis in Hospitalized Children

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

Inclusion Criteria:

1. Age criteria: ≥ 4 or < 18 years of age

2. Diagnosis of UC or IBD-U by established criteria

3. Admitted to the hospital

4. Colitis extending beyond the rectosigmoid colon

5. PUCAI ≥ 65 at admission and ≥ 45 at first dose of infliximab

6. Treatment with infliximab considered by the treating physician

7. Anticipated follow-up ≥ 6 months from infliximab initiation

8. Permission/assent of parent/guardian and research participant.

Exclusion Criteria:

1. Diagnosis of Crohn's disease

2. Enteric infection with a bacterial pathogen (including clostridium difficile), per
review of medical records

3. Colon tissue positive for CMV by PCR, immunohistochemistry, or in situ hybridization,
per review of the medical records

4. Colitis currently extending only to the rectosigmoid colon (proctosigmoiditis)

5. Prior treatment with infliximab or other anti-TNF agent

6. Prior treatment with cyclosporine or tacrolimus

7. PUCAI < 45 the day of first infliximab infusion

8. Pregnancy, per review of medical records and verbal report

9. Other poorly controlled medical condition

10. Hepatic disease (AST or Alk Phos > 3 times the upper limit of normal) in the absence
of IBD associated liver disease

11. Renal disease (BUN and creatinine >1.5 times the upper limit of normal)