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Status: Withdrawn/ClosedResearch Proposal
Project Title: Efficacy of anti-tumor necrosis factor-? agents on Crohn disease phenotypes and locations: A subgroup meta-analysis of randomize
Scientific Abstract:
Background: Anti-tumor necrosis factor (TNF) agents are widely used to induce remission in patients with active Crohn's disease (CD). However, current guidelines do not differentiate the pharmacological treatment of CD based on location or phenotype, despite evidence suggesting that anti-TNF agents may have differential impacts on subgroups of CD based on location. The objective of this study is to systematically review and analyze the available randomized controlled trials to determine whether the efficacy of anti-TNF agents in inducing remission in patients with active Crohn's disease differs between subgroups based on the location of the disease in the digestive tract.<br />
Objective: The objective of this study is to determine whether the efficacy of anti-TNF agents in inducing remission in patients with active Crohn's disease differs between subgroups based on the location of the disease in the digestive tract.<br />
Study Design: This study is a systematic review and meta-analysis of randomized controlled trials.<br />
Participants: This study includes adult patients with moderate to severe luminal Crohn's disease.<br />
Primary and Secondary Outcome Measure(s): The primary outcome measure is clinical remission (CDAI
Brief Project Background and Statement of Project Significance:
Crohn's disease (CD) is a chronic inflammatory bowel disease that can occur in any part of the digestive tract. Anti-tumor necrosis factor (TNF) agents are widely used to induce remission in patients with active CD. However, current guidelines do not differentiate the pharmacological treatment of CD based on location or phenotype, despite evidence suggesting that anti-TNF agents may have differential impacts on subgroups of CD based on location.
The proposed research project is a systematic review and meta-analysis of randomized controlled trials to investigate the efficacy of anti-TNF agents on subgroups of CD based on location. The project's significance lies in potentially optimizing the pharmacological treatment of Crohn's disease and improving patient outcomes. If successful, the project's findings may help inform clinical practice and provide insights into potential strategies for optimizing pharmacological treatment for different subgroups of Crohn's disease based on location.
Previous research has explored the use of anti-TNF agents in patients with Crohn's disease. However, few studies have investigated the efficacy of these agents on subgroups of CD based on location. This study aims to fill this knowledge gap and provide valuable information on the optimal pharmacological treatment of Crohn's disease based on location
Specific Aims of the Project:
Objective: The objective of this study is to systematically review and analyze the available randomized controlled trials to determine whether the efficacy of anti-TNF agents in inducing remission in patients with active Crohn's disease differs between subgroups based on the location of the disease in the digestive tract
Hypothesis: Anti-TNF agents have different levels of effectiveness on specific Crohn's disease location subgroups for inducing remission in patients with active CD
Study Design:
What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations
Software Used: R
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
This study is a subgroup meta-analysis that will utilize randomized controlled trials (RCTs) comparing an active drug to a placebo in adult patients with Crohn's disease. The analysis will be based on intention-to-treat data and will collect information on specific subgroups of Crohn's disease as well as related outcomes as detailed in the following sections.
Inclusion criteria; adult patients with moderate to severe Crohn's disease, with luminal Crohn's disease only (including ileal, ileocolonic, and colonic), English-written RCTs only.
Exclusion criteria for the study include studies involving the pediatric population, studies including patients with mild active Crohn's disease, extraintestinal Crohn's disease, fistulizing Crohn's disease, and upper gastrointestinal (GI) Crohn's disease.
In addition to NCT00269854 following studies will be incuded; NCT00445939, NCT00105300, NCT00055523, NCT02499783, NCT00552058. Data for those studies are requested through Vivli.org platform.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Main outcome clinical remission (defined as a Crohn?s disease activity index (CDAI) score of less than 150) and Secondary outcomes will be clinical response (defined as a 70 or 100 decrease in CDAI score) at weeks 4, 6, and 8. The outcomes will be evaluated based on the location of Crohn's disease, including ileal, ileocolonic, and colonic disease subgroups, as identified by the Montreal Classification of Crohn's disease.
Main Predictor/Independent Variable and how it will be categorized/defined for your study: The main predictor/independent variable in our study is the location of Crohn's disease, which will be categorized based on the Montreal Classification system. The Montreal Classification system categorizes Crohn's disease into three groups based on the location of the disease: (1) L1, involving the terminal ileum, (2) L2, involving the colon, and (3) L3, involving both the terminal ileum and colon. Additionally, the classification system further subdivides the disease into behavior (B) and age of onset (A) categories. However, as the focus of our study is on the location of the disease, we will only be using the L categories for our categorization of Crohn's disease location. The categorization of Crohn's disease location based on the Montreal Classification system will be obtained from the included studies or extracted from the relevant publications.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: location of the disease: (1) L1, involving the terminal ileum, (2) L2, involving the colon, and (3) L3, involving both the terminal ileum and colon
Statistical Analysis Plan:
Analyses of subgroups (including agent and affected location): A meta-regression analysis will be performed to explorethe heterogeneity. Relevant study-level covariates, defined as those able to decrease inconsistencies measured as Istatistics, will be investigated to identify relevant subgroups.The optimal approach for managing missing data will depend on the extent and pattern of missing data across the included studies. Complete case analysis will beusede if there is minimal missing data and the missingness is random. However, multiple imputation may be necessary if there is a substantial amount of missing data or the missingness is not-at-random.
To account for the differences among studies, we will use a meta-regression analysis approach that will allow us to explore the sources of heterogeneity and identify relevant study-level covariates that may explain the observed variability in treatment effects across studies. We will assess the potential sources of heterogeneity using subgroup analyses, including the location of Crohn's disease (i.e., ileal, colonic, or ileocolonic), and treatment characteristics (i.e., dose, duration).
We will maintain the structure and independence of the studies being requested in our methods by performing separate analyse for each anti-TNF agent and placebo if there are enough number of pateints. If there are not enough studies for each anti-TNF agent, we may not be able to perform separate meta-analyses for each agent. In that case, we will combine all the available studies for anti-TNF agents and perform one meta-analysis, comparing the pooled anti-TNF treatment effect to placebo. We will also use random-effects models, which assume that the true treatment effect varies across studies, to account for the variability in treatment effects across studies. Furthermore, we will assess the robustness of our findings by conducting sensitivity analyses, including leave-one-out analyses and outlier detection, to evaluate the potential influence of individual studies on the overall treatment effect estimates.
Overall, our analytical models will be designed to account for the differences among studies while maintaining the structure and independence of the included studies in our meta-analysis. This approach will allow us to generate more reliable and informative treatment effect estimates for each anti-TNF agent and placebo in Crohn's disease based on location.
Narrative Summary: Crohn's disease is a chronic inflammatory bowel disease that causes inflammation and complications like sores and open wounds in the digestive tract. It affects around 3 million adults in the US and can occur in any part of the digestive system. Anti-TNF agents are drugs that can block the action of a protein called TNF to treat Crohn's disease. However, their efficacy may differ between subgroups based on the location of the disease. This study aims to determine the effectiveness of anti-TNF agents in inducing remission in patients with active Crohn's disease based on the location of the disease.
Project Timeline:
Analysis Comletion date 05/22/2023
Date manuscript drafted 05/27/2023
first submitted for publication 06/12/2023
date results reported back 05/23/2023
Dissemination Plan: The completed research project will be presented as a structured abstract and submitted for presentation at the American College of Gastroenterology (ACG). The manuscript will be submitted for publication in a relevant medical journal such as the Journal of Crohn's and Colitis or the American Journal of Gastroenterology.
Bibliography:
1) Ding, N. S., A. Hart, and Peter De Cruz. “Systematic review: predicting and optimising response to anti?TNF therapy in Crohn’s disease?algorithm for practical management.” Alimentary pharmacology & therapeutics 43.1 (2016): 30-51.
2) Moran, Gordon W., et al. “Phenotypic features of Crohn’s disease associated with failure of medical treatment.” Clinical Gastroenterology and Hepatology 12.3 (2014): 434-442.
3) Feuerstein, Joseph D., and Adam S. Cheifetz. “Crohn disease: epidemiology, diagnosis, and management.” Mayo Clinic Proceedings. Vol. 92. No. 7. Elsevier, 2017.