Comparing the Effectiveness of Advanced Therapies in Pediatric Crohn's Disease to Optimize Treatment Decisions

About This Grant

PROJECT SUMMARY/ABSTRACT This proposal will evaluate the comparative effectiveness of advanced therapies (biologics and small molecules) used to treat pediatric Crohn’s Disease using innovative pharmacoepidemiologic methods. Crohn’s Disease, a type of inflammatory bowel disease (IBD), affects over 50,000 children in the U.S. and, when poorly controlled, can lead to pain, fatigue, growth failure, and irreversible surgery. While more than 10 advanced therapies are FDA-approved for adults with Crohn’s Disease, only two—both anti-tumor necrosis factor (Anti- TNF) biologics—are approved for children. This approval gap influences treatment choice, as children with Crohn’s Disease are typically treated initially with FDA-approved anti-TNFs, prior to mechanistically-diverse off- label therapies, despite growing adult data suggesting comparable or even superior safety and effectiveness of alternative agents. These treatment decisions are often influenced by insurers requiring failure of FDA- approved anti-TNFs prior to prescription of second-line off-label therapies, confounding direct comparisons. Innovative risk adjustment methods are needed to overcome these barriers to inform treatment selection and match the right medication to each patient’s unique type of Crohn’s Disease. In Aim 1, Dr. Constant will compare the clinical effectiveness of anti-TNFs and anti-interleukin biologics, an emerging medication class with comparable effectiveness to anti-TNFs in adult studies. Analyses will leverage a validated multicenter retrospective cohort of pediatric patients with Crohn’s Disease to power state-of-the-art causal inference methods which account for demographic and disease-related confounders influencing treatment choice. In Aim 2, he will validate and expand upon these findings through a prospective observational cohort study incorporating patient-reported outcomes to capture a comprehensive view of comparative effectiveness. In Aim 3, he will pilot a pragmatic randomized clinical trial comparing two off-label advanced therapies (risankizumab and upadacitinib) among children with anti-TNF-refractory Crohn’s Disease. This aim will assess the feasibility of comparing off-label therapies within a pragmatic trial structure, allowing for evolving real-world treatment strategies including dose escalation, across a broadly inclusive pediatric Crohn’s Disease population. This research and training plan is supported by a complementary multidisciplinary mentorship team, led by co- primary mentors and nationally recognized pharmacoepidemiologists Dr. James Feinstein and Dr. Frank Scott. Content mentors with aim-specific expertise include Dr. Debashis Ghosh (Aim 1: causal inference), Dr. Lindsey Albenberg (Aim 2: prospective observational research and patient-reported outcomes), and Dr. Calies Menard- Katcher (Aim 3: innovative clinical trial design). This work will advance real-world evidence to inform therapy selection for children with Crohn’s Disease and lay the foundation for future R01-level multicenter pragmatic randomized trials to definitively compare therapies under real-world conditions, launching Dr. Constant’s career as an independent investigator and leader in pediatric IBD comparative effectiveness research.