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Associated Trial(s):- NCT02407236 - A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Protocol to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis
- NCT03464136 - A Phase 3b, Multicenter, Randomized, Blinded, Active-Controlled Study to Compare the Efficacy and Safety of Ustekinumab to That of Adalimumab in the Treatment of Biologic Naïve Subjects With Moderately-to-Severely Active Crohn's Disease
- NCT01369329 - A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Induction Therapy in Subjects With Moderately to Severely Active Crohn's Disease Who Have Failed or Are Intolerant to TNF Antagonist Therapy (UNITI-1)
- NCT01369342 - A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Induction Therapy in Subjects With Moderately to Severely Active Crohn's Disease (UNITI-2)
- NCT01369355 - A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Maintenance Therapy in Subjects With Moderately to Severely Active Crohn's Disease
- NCT00488631 - A Phase 3 Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Golimumab Maintenance Therapy, Administered Subcutaneously, in Subjects With Moderately to Severely Active Ulcerative Colitis
- NCT00036439 - A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
- NCT00096655 - A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
- NCT00207662 - ACCENT I - A Randomized, Double-blind, Placebo-controlled Trial of Anti-TNFa Chimeric Monoclonal Antibody (Infliximab, Remicade) in the Long-term Treatment of Patients With Moderately to Severely Active Crohn's Disease
- NCT00094458 - Multicenter, Randomized, Double-Blind, Active Controlled Trial Comparing REMICADE® (infliximab) and REMICADE plus Azathioprine to Azathioprine in the Treatment of Patients with Crohn's Disease Naive to both Immunomodulators and Biologic Therapy (Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease)
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Status: OngoingResearch Proposal
Project Title: Association Between Adherence to Scheduled Biologic Therapy and Treatment Outcomes in Inflammatory Bowel Disease
Scientific Abstract:
Background: The incidence and prevalence of inflammatory bowel disease (IBD) has risen significantly in developing countries, increasing the global burden. The adherence to scheduled biologic therapy may affect treatment response.
Objective: To investigate the impact of adherence to scheduled biologic therapy on disease control and long-term outcomes in patients with IBD.
Study Design: This is a post-hoc analysis study, including adherence to scheduled therapy analysis for induction and maintenance phase. The major predictors include cumulative absolute deviation and total deviation score.
Participants: Patients with moderate to severe IBD who received >=4 doses during the induction or maintenance phase.
Primary and Secondary Outcome Measure(s): Primary outcome is clinical remission. Secondary outcomes include therapeutic efficacy (such as endoscopic remission, histological remission), and serum drug concentration at the end of induction or maintenance therapy.
Statistical Analysis: We will use multivariate logistic regression, adjusted for potential confounders, to investigate whether deviations from prescribed therapy schedules independently influences treatment outcomes. Spearman's correlation coefficient will be employed to examine pairwise relationships between cumulative absolute deviation at each time point and both serum drug concentration and partial Mayo score. We will utilize bootstrap methods to conduct mediation effect analysis, exploring how drug concentration mediates the relationship between deviations from prescribed therapy schedules and treatment outcomes
Brief Project Background and Statement of Project Significance:
Inflammatory bowel disease (IBD) is a chronic, recurrent, and non-specific intestinal inflammatory disease with an unknown etiology. It mainly includes Ulcerative Colitis (UC) and Crohn's disease (CD). In recent years, the incidence and prevalence of CD and UC has risen significantly, increasing the global burden of IBD.
With the introduction of biological agents and small molecule inhibitors, patients who have not responded to conventional treatments have more treatment options, and the treatment framework for IBD has also undergone significant changes. However, not all IBD patients benefit from treatment with targeted therapies. This reality underscores the importance of investigating the factors influencing treatment response. Adherence to scheduled biologic therapy may be one of the factors affecting treatment response, however, there is no significant and robust evidence currently to confirm this relationship.
Previous studies have shown that patients with IBD have a relatively low adherence to maintenance treatment, ranging from 50% to 70%. Research on CD patients treated with thiopurines and IBD patients on mesalamine demonstrated that better medication adherence was associated with higher drug concentrations and lower relapse risk. Adherence to biologic therapies (e.g., anti-TNF agents) tends to be higher than with conventional treatments. This might be due to the requirement for in-hospital administration. Nevertheless, a significant proportion of patients fail to adhere to the prescribed treatment schedule, with 20%-30% patients delaying their doses. A prospective and a retrospective study revealed that, compared with episodically administered therapy, CD patients receiving regularly scheduled infliximab therapy achieved better outcomes, including mucosal healing, and fewer disease-related hospitalizations. Other studies found that serum infliximab drug levels in CD and UC patients correlated significantly with clinical remission and lower colectomy risk. However, excessively early administration may lead to elevated infliximab trough levels and adverse events. To date, no studies have investigated the relationship between deviations from prescribed therapy schedules (timing inaccuracies in actual administration) and drug concentrations or treatment outcomes.
Patients with IBD require regular clinic visits for scheduled biologic maintenance therapy. However, in real-world practice, deviations from prescribed biologic dosing schedules inevitably occur in IBD management, creating a pragmatic therapeutic window around theoretical treatment intervals. Does the discrepancy between the actual and prescribed dosing interval times affect blood drug concentrations? Does it further influence treatment outcomes? These are the key questions this study aims to explore. This study seeks to investigate whether adherence to scheduled biologic Therapy influences treatment efficacy in patients with IBD, with the goal of providing a scientific basis for standardized drug use, optimizing treatment strategies, and improving treatment responses.
Specific Aims of the Project:
This study aims to investigate the impact of adherence to scheduled biologic therapy on disease control and long-term outcomes in patients with inflammatory bowel disease (IBD).
The scientific hypothesis is that deviations from prescribed dosing schedules may influence treatment outcomes.
Study Design:
Other
Explain:
post-hoc analysis
What is the purpose of the analysis being proposed? Please select all that apply.: Research on clinical prediction or risk prediction
Software Used: R, RStudio
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
All trials are accessed in the Trial List on YODA Project. The specific inclusion and exclusion criteria can be found in the original research.
All trials will be included in adherence to scheduled therapy for maintenance phase, involving patients who received >=4 doses during the maintenance phase.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
The primary outcome is clinical remission at the end of maintenance therapy. The second outcomes include other therapeutic efficacy (such as mucosal healing, endoscopic remission, histological remission, partial Mayo score remission) and serum drug concentration at the end of induction or maintenance therapy. The specific definitions are as follows:
For UC, clinical response is defined as a decrease from baseline in the total Mayo score of >=3 points and >=30% decrease, with an accompanying decrease in the subscore for rectal bleeding of >=1 point or an absolute subscore for rectal bleeding <=1. Clinical remission is defined as a partial Mayo score <= 2 and all subscores <= 1. Endoscopic remission is defined as achieving a Mayo endoscopic subscore (MES) of 0, and endoscopic improvement is defined as MES<=1. Histologic improvement and histologic remission are defined as Geboes grade <=3.0 and <=2.0, respectively. And histo-endoscopic improvement defined as Geboes grade <=3.0 and MES <=1. Partial Mayo score remission is defined as partial Mayo score <= 2 and all subscores =100 points or a CDAI score =50% from baseline, while mucosal healing is defined as SES-CD 16 points and IBDQ >=170 points, respectively.
Main Predictor/Independent Variable and how it will be categorized/defined for your study:
The major predictors include cumulative absolute deviation (defined as the sum days of all deviations from prescribed therapy schedules), and total deviation score (defined as the sum of scores assigned to each deviation, with the scoring criteria based on quartiles and empirical data).
deviations from prescribed biologic dosing schedules
I am investigating the deviations between each actual medication administration time and its planned time. I will perform a series of processing steps on these deviations, such as calculating their sum, mean, cumulative absolute deviation, and absolute mean. Alternatively, by establishing a scoring criterion, I will record the score for each individual deviation and then calculate the total deviation score. All these variables serve as independent variables rather than outcomes. Among them, the main predictors I focus on include cumulative absolute deviation (defined as the sum days of all deviations from prescribed therapy schedules), and total deviation score (defined as the sum of scores assigned to each deviation, with the scoring criteria based on quartiles and empirical data). In the MV logistic regression analysis, they are treated as a continuous variable and an ordinal variable, respectively.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Other variables of interest include other metrics for evaluating deviations from prescribed therapy schedules (e.g., single-dose deviation, cumulative absolute deviation at each time point, cumulative deviation, coefficient of variation based on absolute mean, and proportion of days covered (PDC)), baseline characteristics (e.g., gender, age, disease duration, body mass index, medication history, treatment allocation and concomitant therapy) and baseline disease activity evaluation (e.g. clinical, endoscopic and histological scores, fecal calprotectin and C-reactive protein).
Statistical Analysis Plan:
Continuous and categorical variables are described as median (interquartile range) or frequency (percentage), respectively. Missing data for outcomes will be excluded. Missing data for independent variables will be imputed using multivariable imputation methods.
We will use multivariate logistic regression, adjusted for potential confounders including demographic characteristics (e.g., sex, age), disease manifestations (e.g., disease duration, location), previous medication exposure (e.g., corticosteroids, 5-ASA, and other biologics), and baseline disease activity (e.g., MES, ALB) to investigate whether deviations from prescribed therapy schedules independently influences treatment outcomes. And the Spearman's correlation coefficient will be employed to examine pairwise relationships between cumulative absolute deviation at each time point and both serum drug concentration and PMS (partial Mayo score), with lag effect analysis to understand temporal relationships between variables. Furthermore, we will utilize bootstrap methods to conduct mediation effect analysis, exploring how drug concentration mediates the relationship between deviations from prescribed therapy schedules and treatment outcomes. Sensitivity analyses will be performed by analyzing cases with complete data to verify the robustness of the results.
Statistical significance was set at p-value <0.05. All statistical analysis is performed via R software.
Narrative Summary: Although the introduction of biological agents and small molecule inhibitors gave more treatment options for IBD patients, not all of them benefit from the targeted therapies. Adherence to scheduled biologic therapy may affect treatment response. Previous studies have shown that, compared with episodically administered therapy, CD patients receiving regularly scheduled infliximab therapy achieved better outcomes. Other studies found that serum infliximab drug levels in IBD patients correlated significantly with clinical remission. However, excessively early administration may lead to elevated infliximab trough levels and adverse events. This study seeks to investigate whether adherence to scheduled biologic therapy influences treatment efficacy in patients with IBD, with the goal of providing a scientific basis for standardized drug use.
Project Timeline:
Anticipated project start date: 9/15/2025
Analysis completion date: 3/1/2026
Date manuscript drafted and first submitted for publication: 5/1/2026
Date results reported back to the YODA Project: 5/1/2026
Estimated Analysis Completion Date: 9/15/2026
Dissemination Plan: The products of this project will be submitted to scientific conference, such as Digestive Disease Week, European Crohn's and Colitis Organization and Asian Crohn's and Colitis Organization. A manuscript will also be submitted for publication in peer-reviewed journals, such as Clinical Gastroenterology and Hepatology (CGH), Journal of Crohn's and Colitis (JCC), American Journal of Gastroenterology (AJG) and Inflammatory Bowel Diseases (IBD) and others. The acknowledgement for YODA Project will be presented in all products of this study.
Bibliography:
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