Biomarkers for predicting long-term outcomes in ulcerative colitis

Lead Investigator: Shenghong Zhang, The first affiliated hospital of Sun Yat-sen University
Title of Proposal Research: Biomarkers for predicting long-term outcomes in ulcerative colitis
Vivli Data Request: 8845
Funding Source: This work was funded by the National Natural Science Foundation of China, grant/award number: 82070538 and 81870374.
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Ulcerative colitis (UC) is a chronic inflammatory disease affecting around 2% of the general population in North America and Western Europe, and its incidence is rising worldwide. Patients with UC have varying prognosis: some patients have good long-term outcomes after initiation treatment, while some will suffer from relapsing and exacerbated (worsening) disease. Therefore, predicting the prognosis of UC patients is important for selecting the best treatment approaches and conducting personalized management. Nowadays, identifying effective indicators for predicting the prognosis in UC is receiving considerable attention. Biomarkers (biological molecules found in blood, other body fluids, or tissues) are non-invasive, easy-available and promising indicators for assessing disease activity and predicting prognosis in UC. This study aims at identifying useful biomarkers and investigating their predictive ability for long-term outcomes in UC.

The primary objective of this study is to investigate the relationship between potentially useful biomarkers and long-term outcomes, such as endoscopic remission (when there is no inflammation visible during examination of the affected area with a small camera), histological remission (when there is no detectable disease seen in a piece of tissue removed and examined under a microscope) and colectomy (surgical removal of part of the large bowel/colon).

This analysis will assess the relationship between potentially useful biomarkers and the likelihood of achieving long-term outcomes. The analysis will also assess the ability of the chosen biomarkers to predict disease outcomes. Further analysis by treatment allocation, disease activity at baseline, age and gender will be performed. The results will explore useful biomarkers and may help in selecting treatment approaches for patients with different prognosis in UC.

Statistical Analysis Plan:

In our project, we will use data from one or more studies to explore the potential biomarkers, which can predict therapeutic outcomes in UC. Further, we will use data from other studies to validate the biomarker’s predictive ability. In this step, we will perform meta-analysis to pool the odds ratio/hazard ratio of the biomarkers from different studies. We pooled effect estimates for each predictor through inverse variance analysis using random effects meta-analysis. Statistical heterogeneity as assessed with the I2 statistic, whose values higher than 50% indicate a substantial level of heterogeneity.

Continuous and categorical variables are described as median (interquartile range, IQR) and proportion (percentage), respectively. The Mann-Whitney test and χ2 test were performed to evaluate the difference for continuous and categorical variables, respectively. A p-value less than 0.05 was considered as statistical significance. Univariate logistic or cox regression analysis will be conducted to analyse the association of candidate predictors and outcomes. Multivariate logistic or cox regression analysis will be performed to adjusted potential confounders (like disease duration, treatment allocation). The receiver operating characteristic (ROC) analysis is performed to calculate the area under ROC curve (AUROC). The cut-off value is determined by the Youden index. AUROC, sensitivity, specificity, positive predictive value and negative predictive value are used to assess the predictive capacity of the predictors for predicting specific outcomes. Furthermore, we will perform subgroup analyses by treatment allocation, disease activity at baseline, age and gender. Missing value for major outcome will be excluded from statistical analysis. Missing values for other variables will be imputed by simple imputation, using the mice package in R.

Taking account of differences among studies, we will (1) compare baseline characteristics, like age, sex, race, disease duration and disease activity, among different trails. If some covariates are found different among trials, we will adjust them in the multivariate regression model; (2) perform subgroup analysis stratified by different trials to assess the interaction between predictors and trials; (3) conduct sensitivity analyses in patients with same disease activity, range of age, disease duration or type of biologics (anti-TNF agents, vedolizumab or ustekinumab) to verify the consistency of our results.

Requested Studies:

A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by MLN0002 in Patients With Moderate to Severe Ulcerative Colitis
Data Contributor: Takeda
Study ID: NCT00783718
Sponsor ID: C13006

A Randomized, Double-Blind, Double-Dummy, Multicenter, Active-Controlled Study to Evaluate the Efficacy and Safety of Vedolizumab IV Compared to Adalimumab SC in Subjects With Ulcerative Colitis
Data Contributor: Takeda
Study ID: NCT02497469
Sponsor ID: MLN0002-3026

A Multicenter, Randomized, Double-blind Placebo-controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction of Clinical Remission in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: AbbVie
Study ID: NCT00385736
Sponsor ID: M06-826

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction and Maintenance of Clinical Remission in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: AbbVie
Study ID: NCT00408629
Sponsor ID: M06-827

A Phase 3, Open-label Study to Determine the Long-term Safety and Efficacy of Vedolizumab (MLN0002) in Subjects With Ulcerative Colitis and Crohn’s Disease
Data Contributor: Takeda
Study ID: NCT00790933
Sponsor ID: C13008

A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study, With a Vedolizumab IV Reference Arm, to Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis Who Achieved Clinical Response Following Open-Label Vedolizumab Intravenous Therapy
Data Contributor: Takeda
Study ID: NCT02611830
Sponsor ID: MLN0002SC-3027

A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Study ID: NCT00036439
Sponsor ID: CR004777

A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Data Request ID: 00008845
Sponsor ID: CR004783

A Phase 2/3 Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Golimumab Induction Therapy, Administered Subcutaneously, in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Study ID: NCT00487539
Sponsor ID: CR014176

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
Data Contributor: Johnson & Johnson
Study ID: NCT00488631
Sponsor ID: CR014179

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
Data Contributor: Johnson & Johnson
Study ID: NCT02407236
Sponsor ID: CR106920

A Phase 2/3 Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Golimumab Induction Therapy, Administered Intravenously, in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Study ID: NCT00488774
Sponsor ID: CR014188

Public Disclosures:

Zheng, J., Zhang, X., Zhang, L., Li, L., Chen, M., Chen, R. and Zhang, S., 2024. Serum Albumin and Its Trajectory Are Associated with Therapeutic Outcomes in Ulcerative Colitis. Clinical Gastroenterology and Hepatology. Doi: 10.1016/j.cgh.2024.10.036