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 in addition carries a high risk of colon cancer. While current medical therapies often relieve symptoms, there is currently no cure and many patients require corticosteroids (steroids) or potent immunsuppressive medications (IM) with major risks, or, ultimately surgery to remove the colon. There is a paucity 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 and who is going to do poorly and need increasing medication exposure and possible 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 410 children newly diagnosed with UC at 17 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 follow this cohort for 2 years with a primary clinical outcome of clinical remission at one year without the concurrent use of steroid medications or the need for more potent immunsuppressive 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 mucosal inflammation, and the primary clinical outcome of steroid-free remission. 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 and a more optimal adaptive study design for a clinical trial of early IM use in pediatric UC patients unlikely to achieve steroid-free remission with mesalamine alone, 2) discovering fundamental new knowledge regarding the role of common genetic and environmental factors in the differentiation and function of effector and regulatory lymphocytes, and 3) establishing a repository of clinical, genetic, and immune data, and biospecimens, which can be used by for future ancillary studies. Ultimately, results of PROTECT will be integrated with those of an ongoing prospective study of 1000 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.
The goal of the PROTECT study is improve the long-term outcome of children with ulcerative colitis by discoveries to guide clinical decision making. We plan to develop a model of clinical, genetic, and immunologic information that will allow clinicians to formulate individualized treatment plans to achieve clinical remission and minimize exposure when possible to toxic medications or the need of surgery.
| 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 |
