Development of Patient-Tailored Adaptive Treatment Strategies for Acute Severe Ulcerative Colitis

点击翻译按钮获取中文摘要

Modified Project Summary/Abstract Section This K23 application proposes a focused training and research plan to support the applicant’s career growth into an independent physician-scientist. The proposed plan will ensure the applicant develops expertise in patient-tailored adaptive treatment strategies (ATS) that deliver personalized care to patients with inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis (UC). CONTEXT: Acute severe ulcerative colitis (ASUC) is a life-threatening presentation of UC requiring prompt treatment. Thirty percent of patients with UC will require hospitalization for ASUC during their lifetime. First-line therapy for ASUC, intravenous (IV) corticosteroids, has remained unchanged since the 1950s, despite evidence that up to 30% of patients fail treatment and require emergent colectomy. Cyclosporine and infliximab rescue therapies are effective in treating patients who fail to respond to IV corticosteroids, yet up to 60% of steroid-refractory patients will fail to respond to these rescue therapies as well. A combination of factors, including substantial patient heterogeneity in treatment response and dynamic day-to-day changes in clinical course, have limited our ability to develop effective personalized treatment pathways. There is a critical need to improve the current one-size-fits-all approach to provide more efficacious and safer treatment for ASUC. In this proposal, we hypothesize that ATS, which use prespecified sequential treatment decisions to guide stepwise management changes according to well-defined baseline and longitudinal clinical and laboratory thresholds (tailoring variables) specific to a patient, will reduce the rate of colectomy by guiding clinicians on the type, intensity, and timing of therapy that is most likely to be effective at each stage of treatment. RESEARCH STRATEGY: The objectives of this proposal are to: identify baseline patient characteristics predictive of ASUC treatment response (Aim 1), develop a time-specific risk model to identify pharmacologic treatment failure using tailoring variables to guide treatment decisions (Aim 2), and develop and optimize ATS personalized to patients’ evolving health needs throughout their ASUC hospitalization. We will evaluate the feasibility and acceptability of our ATS using a pilot sequential multiple assignment randomized trial (SMART) (Aim 3). SMARTs, a trial design that sequentially randomizes participants multiple times to one of several interventions at selected time points, have been used successfully to develop, optimize, and test ATS. TRAINING PLAN: To facilitate achievement of the applicant’s long-term career goal – to become an independent physician-scientist and expert in ATS development and optimization – this award will allow the applicant to develop a deeper understanding of the components, principles for optimization, and trial designs that inform the construction of personalized ATS. This will be aided by a deeper understanding of predictive modeling and longitudinal data analysis using machine learning. These objectives will be accomplished through close mentorship from experts in these areas, selected didactic activities, conference attendance, applied research, and grant proposal preparation.