Ulcerative colitis (UC) is one of the chronic intestinal disorders known as inflammatory bowel disease (IBD). It affects hundreds of thousands of Americans with about 25-30% being children. UC causes considerable suffering with abdominal pain, diarrhea, bleeding, and weight loss and for unknown reasons is often more severe in children than adults. Longstanding disease carries a high risk of colon cancer. Ideally, UC is adequately controlled with mesalamine, a 5-aminosalicylate with a favorable benefit: risk profile. Unfortunately, mesalamine alone is often not sufficient requiring step-up therapy with corticosteroids (steroids), potent immunosuppressive medications (IM) with major risks, or surgery to remove the colon. There are a lack of controlled data on the treatment of UC in children and virtually no studies that provide guidance to clinicians as to which children are going to do well with mesalamine alone and who is going to do poorly and need increasing medication exposure or surgery. We hypothesize that a combination of clinical, genetic, and immunologic tests performed at diagnosis may allow construction of a model for individualized treatment and thereby improvement of current outcomes. Specifically, we will conduct a clinical trial of standardized medical therapy for 430 children newly diagnosed with UC at 24 pediatric IBD centers in North America (Predicting Response to Standardized Pediatric Colitis Therapy: The PROTECT Study). Using a clinical protocol that is designed to provide optimal care and be responsive to disease severity, as well as state of the art technology to monitor medication adherence, we will subsequently determine the primary clinical outcome of clinical remission at one year on mesalamine only without the concurrent use of steroid medications or the need for more potent immunosuppressive medications or surgery. Biospecimens including blood, stool, and colonic tissue will be obtained at diagnosis and during follow-up, and pre-specified clinical, genetic, environmental, and immune factors will be determined and tested for their impact upon the primary clinical outcome as well as mucosal healing at one year. When possible patients will be followed beyond one year and up to 2-5 years depending upon time of entry into the study. The collective results of the PROTECT study will have a significant and sustained impact upon the field by: 1) providing data regarding response to standardized therapy maximizing the likelihood of response to mesalamine, 2) identifying novel biologic pathways associated with treatment response, and 3) establishing a repository of clinical, genetic, and immune data, as well as biospecimens, that can be used by for future ancillary studies. Ultimately, results of PROTECT will be integrated with those of an ongoing prospective study of 1100 pediatric Crohn's Disease (CD) patients sponsored by the Crohn's and Colitis Foundation of America (CCFA), the RISK study, to provide a powerful new platform for discovering mechanisms which drive pathogenesis and clinical outcomes in pediatric IBD.

Public Health Relevance

The PROTECT Study will, for the first time;describe the course of children newly diagnosed with ulcerative colitis treated with standardized therapy that has been devised to minimize exposure to more toxic drugs. By concomitantly obtaining biospecimens at diagnosis and during the first year following therapy PROTECT will facilitate the understanding of inter-patient variability in response to therapy and provide insights into the pathways that sustain colonic inflammation. This effort will not only improve the health of children newly diagnosed with ulcerative colitis, but will also lessen the likelihood of medication toxicity and the need for colectomy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-S (M1))
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Connecticut Children's Medical Center
United States
Zip Code
Spencer, Elizabeth A; Davis, Sonia M; Mack, David R et al. (2018) Serologic Reactivity Reflects Clinical Expression of Ulcerative Colitis in Children. Inflamm Bowel Dis 24:1335-1343
Boyle, Brendan; Collins, Margaret; Denson, Lee et al. (2018) Histologic Correlates of Clinical and Endoscopic Severity in Children Newly Diagnosed With Ulcerative Colitis. Am J Surg Pathol 42:1127
Schirmer, Melanie; Denson, Lee; Vlamakis, Hera et al. (2018) Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course. Cell Host Microbe 24:600-610.e4
Sauer, Cary G; Loop, Matthew S; Venkateswaran, Suresh et al. (2018) Free and Bioavailable 25-Hydroxyvitamin D Concentrations are Associated With Disease Activity in Pediatric Patients With Newly Diagnosed Treatment Naïve Ulcerative Colitis. Inflamm Bowel Dis 24:641-650
Venkateswaran, Suresh; Prince, Jarod; Cutler, David J et al. (2018) Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis. Inflamm Bowel Dis 24:829-838
Hyams, Jeffrey S; Davis, Sonia; Mack, David R et al. (2017) Factors associated with early outcomes following standardised therapy in children with ulcerative colitis (PROTECT): a multicentre inception cohort study. Lancet Gastroenterol Hepatol 2:855-868
Boyle, Brendan; Collins, Margaret H; Wang, Zhu et al. (2017) Histologic Correlates of Clinical and Endoscopic Severity in Children Newly Diagnosed With Ulcerative Colitis. Am J Surg Pathol 41:1491-1498
Kim, Mi-Ok; Liu, Chunyan; Hu, Feifang et al. (2014) Outcome-adaptive randomization for a delayed outcome with a short-term predictor: imputation-based designs. Stat Med 33:4029-42