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Precise Infliximab Exposure and Pharmacodynamic Control to Achieve Deep Remission in Pediatric Crohn's Disease

Award Number: R01DK132408
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Precise Infliximab Exposure and Pharmacodynamic Control to Achieve Deep Remission in Pediatric Crohn's Disease - Project Summary/Abstract Crohn's disease is a chronic illness that results in intestinal inflammation and unwanted gastrointestinal symptoms. The only biologic (monoclonal antibody) approved for moderate to severe Crohn's disease in children (<18 years old) are those that antagonize tumor necrosis factor-alpha (anti-TNF). While there is a high initial response rate to labeled infliximab (anti-TNF) dosing, only half of infliximab exposed patients will achieve clinical remission and less than 40% will achieve endoscopic healing after one year on therapy. Several studies have shown that rates of sustained corticosteroid-free remission are improved when patients receive anti-TNF dose optimizations following reactive or proactive therapeutic drug monitoring. Moreover, anti-TNF dose intensification following pharmacodynamic monitoring has led to improved rates of endoscopic (intestinal) healing. Therefore, given the limited therapeutic options for children with active Crohn's disease, there is a critical unmet need for the development of a data-driven, individualized, and scalable anti-TNF dosing intervention used from drug start and continued throughout therapy to optimize drug exposure and ultimately, improve rates of intestinal healing. Our team has developed a precision dosing strategy that uses an innovative physician decision support dashboard that instantaneously applies pharmacokinetic model-informed precision dosing to generate an individual infliximab dosing regimen starting with induction and targeting phase-specific pharmacokinetic and pharmacodynamic endpoints throughout therapy. The central hypothesis is precision dosing (intervention arm) with infliximab during induction and maintenance will improve rates of deep remission vs. conventional care (pragmatic dosing; control arm). The central hypothesis will be tested with two specific aims. Aim1: Conduct a cluster-randomized (by center) clinical trial to assess rates of deep remission at year1 between Crohn's disease patients receiving infliximab with precision dosing vs. conventional care. Aim2: Refine model- informed precision dosing using a continuous learning approach and identify anti-TNF PK/PD targets from induction to maintenance associated with deep remission. Our approach is conceptually innovative with an emphasis on practical implementation. This is the first clinical trial in children to provide anti-TNF dose optimization during induction to target a specific early (week6) trough concentration while the maintenance regimen is selected by specific treat-to-target pharmacokinetic and pharmacodynamic biomarkers. Additionally, precision dosing regimens are produced with a novel web-based decision support dashboard and the study is being performed within the ImproveCareNow Network to streamline clinical trial logistics. In Aim2, a continuous learning approach will be applied to our published pharmacokinetic model to iteratively refine the model by capturing new real-world data to better describe specific patient populations and further reduce prediction error. The long-term goal is for the precision dosing strategy to generate a paradigm shift as the preferred dosing approach to optimize exposure to all biologics and change the natural history of Crohn's disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $662,152 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/18/2025	NON-COMPETING CONTINUATION	$662,152
														Subtotal = $662,152

Issue Date FY: 2024 ( Subtotal = $642,469 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/3/2024	NON-COMPETING CONTINUATION	$642,469
														Subtotal = $642,469

Issue Date FY: 2023 ( Subtotal = $709,626 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/3/2023	NON-COMPETING CONTINUATION	$709,626
														Subtotal = $709,626

Issue Date FY: 2022 ( Subtotal = $789,670 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/1/2022	NEW	$789,670
														Subtotal = $789,670

Grand Total All Awards = $2,803,917

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Precise Infliximab Exposure and Pharmacodynamic Control to Achieve Deep Remission in Pediatric Crohn's Disease

Award Number: R01DK132408

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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