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Associated Trial(s):- 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
- 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
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Status: OngoingResearch Proposal
Project Title: Impact of Baseline Fecal Calprotectin and Histologic Activity Thresholds on Clinical and Endoscopic Outcomes in Ulcerative Colitis
Scientific Abstract:
Background: Clinical trials in ulcerative colitis (UC) often report high placebo response rates, which can mask the true effectiveness of new treatments. One proposed strategy to improve trial outcomes is to include only patients with high levels of inflammation at the start of the study--measured using fecal calprotectin (FC), a stool biomarker, or the Geboes histologic score, which assesses inflammation under the microscope.
Objective: To evaluate whether applying various baseline thresholds of fecal calprotectin (FC) or histologic activity (Geboes score) as inclusion criteria impacts the clinical and endoscopic outcomes in UC clinical trials.
Study Design: Post-hoc analysis using pooled, individual patient-level data from five phase 3, randomized, placebo-controlled clinical trials in moderate-to-severe ulcerative colitis (UC).
Participants - individual-patient level data
Primary and Secondary Outcome Measure(s): Clinical Remission (CR) - modified Mayo score consisting of: Stool Frequency Subscore (SFS): 0 or 1, with a decrease of at least 1 point from baseline Rectal Bleeding Subscore (RBS): 0, Endoscopic Subscore: 0 or 1. Endoscopic Improvement (EI) - Defined as a Mayo endoscopic subscore of 0 or 1. Histologic and Endoscopic Mucosal Improvement (HEMI) - Defined as the simultaneous achievement of: Geboes Score < 3.1 (indicating histologic improvement or remission), and Mayo Endoscopic Subscore (MES) of 0 or 1. Clinical Remission with FC (CR + FC <150).
Statistical Analysis: Differences in CR and EI between active drug and placebo will be calculated.
Brief Project Background and Statement of Project Significance:
Clinical trials for moderate-to-severe ulcerative colitis (UC) are essential for developing new therapies, but patient selection often relies on clinical scores that may not fully capture underlying mucosal inflammation. This can lead to high placebo response rates and may dilute the observed treatment effect, making it difficult to assess a drug's true efficacy. Objective biomarkers, such as fecal calprotectin (FC) and histologic activity (e.g., Geboes score), offer a more direct measure of intestinal inflammation and have been proposed as tools to refine trial enrollment. However, the precise impact of implementing specific biomarker thresholds on trial outcomes has not been extensively quantified across different therapies.
This project addresses this critical knowledge gap through a large-scale, post-hoc analysis of pooled, individual-level data from five pivotal phase 3 trials. By simulating the application of various baseline FC and histologic thresholds for trial eligibility, this study will provide robust, generalizable evidence on the relationship between baseline inflammatory burden and treatment efficacy. The significance of this work is threefold: 1) It will clarify whether enriching trial populations for patients with higher objective inflammation leads to a greater separation between active therapy and placebo, potentially allowing for more efficient and conclusive trial designs. 2) The findings will provide data-driven guidance for researchers, sponsors, and regulatory agencies on optimizing inclusion criteria for future UC trials. 3) By analyzing outcomes across multiple advanced therapies with different mechanisms of action, this research will generate broadly applicable scientific knowledge to enhance the precision of clinical drug development in gastroenterology, ultimately helping to accelerate the delivery of effective treatments to patients in need.
Specific Aims of the Project:
Primary Aim: To evaluate whether applying various baseline thresholds of fecal calprotectin (FC) or histologic activity (Geboes score) as inclusion criteria impacts the clinical and endoscopic outcomes in UC clinical trials.
Objective 1: To assess whether higher baseline FC or Geboes thresholds reduce placebo response rates.
Objective 2: To determine whether these thresholds improve the absolute difference in treatment response between active therapy and placebo groups.
Objective 3: To explore these outcomes within key subgroups, including biologic-naïve patients and corticosteroid users.
Study Design: Individual trial analysis
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: STATA
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
This is a post-hoc analysis using pooled, individual patient-level data from five phase 3, randomized, placebo-controlled clinical trials in moderate-to-severe ulcerative colitis (UC). The included trials are GEMINI 1, LUCENT-1/2, PURSUIT, U-ACCOMPLISH, and UNIFI. Patients received standard doses of various advanced therapies or placebo during the induction phase. Baseline biomarker (FC) and histologic (Geboes score) data were analyzed to simulate the impact of hypothetical inclusion thresholds on treatment outcomes.
Individual patient-level data obtained from five phase 3 (on YODA and Vivli), randomized, placebo-controlled clinical trials in patients with moderate-to-severe UC will be obtained. The trials will include GEMINI 1 (ClinicalTrials.gov Identifier: NCT00783718), LUCENT-1/2 (NCT03518086, NCT03524092), PURSUIT (NCT00488631), U-ACCOMPLISH (NCT03653026), and UNIFI (NCT02407236)
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
Primary Outcomes
Clinical Remission (CR) - Defined as a modified Mayo score consisting of: Stool Frequency Subscore (SFS): 0 or 1, with a decrease of at least 1 point from baseline Rectal Bleeding Subscore (RBS): 0, Endoscopic Subscore: 0 or 1.
This definition aligns with commonly accepted remission criteria in phase 3 trials of moderate-to-severe UC.
Endoscopic Improvement (EI) - Defined as a Mayo endoscopic subscore of 0 or 1, indicating mild or no endoscopic inflammation.
Secondary Outcomes
Histologic and Endoscopic Mucosal Improvement (HEMI) - Defined as the simultaneous achievement of: Geboes Score < 3.1 (indicating histologic improvement or remission), and Mayo Endoscopic Subscore (MES) of 0 or 1.
Clinical Remission with Normalized Fecal Calprotectin (CR + FC <150) - Defined as: Meeting all criteria for Clinical Remission, and Having a fecal calprotectin (FC) level 150, >200, >250, and >500 ug/g, Baseline Geboes score thresholds: >=3.1 and >=3.2, Biologic-naïve status: Yes vs. No, Concomitant corticosteroid use: Yes vs. No
Main Predictor/Independent Variable and how it will be categorized/defined for your study:
Main Predictor: Baseline inflammatory activity, as defined by FC and Geboes histologic score.
Categorization:
Fecal Calprotectin thresholds: >150 ug/g, >200 ug/g, >250 ug/g, >500 ug/g
Geboes score thresholds: >=3.1 and >=3.2
These thresholds represent increasing degrees of inflammation and were applied to simulate "gating" eligibility for trial participation.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:
Treatment Group: Active therapy (vedolizumab, mirikizumab, golimumab, upadacitinib, or ustekinumab) vs. placebo.
Clinical Remission (CR): Modified Mayo score with:
Stool frequency subscore (SFS) of 0 or 1 (with >=1 point drop from baseline)
Rectal bleeding subscore (RBS) of 0
Endoscopic subscore of 0 or 1
Endoscopic Improvement (EI): Mayo endoscopic subscore of 0 or 1
Histologic and Endoscopic Mucosal Improvement (HEMI): Geboes score <3.1 and MES 0--1
CR with FC <150 ug/g: Defined as above plus FC level below 150 ug/g post-induction
Biologic Exposure: Biologic-naïve vs. biologic-experienced
Concomitant Steroid Use: Yes vs. No at trial baseline
Baseline Disease Severity: Partial Mayo score, endoscopic subscore, rectal bleeding score, albumin level
Demographics: Age, sex, and other baseline characteristics
Statistical Analysis Plan:
Descriptive statistics will be used to summarize baseline characteristics and compare across treatment groups using chi-square tests for categorical variables and t-tests for continuous variables. For each active therapy and placebo group, the proportion of patients achieving CR and EI will be calculated for both the unrestricted cohort and for cohorts restricted by FC and Geboes thresholds.
Primary analysis will involve calculating absolute differences in CR and EI between active drug and placebo, both overall and within biomarker-restricted subgroups. Subgroup analyses will be performed among biologic-naïve patients and those using concomitant corticosteroids. Additional exploratory endpoints (HEMI and CR with FC <150 ug/g) will be evaluated using the same methodology.
All statistical analyses will be performed using Stata IC Version 15, and statistical significance set at p-value < 0.05.
Narrative Summary:
Clinical trials in ulcerative colitis (UC) often report high placebo response rates, which can mask the true effectiveness of new treatments. One proposed strategy to improve trial outcomes is to include only patients with high levels of inflammation at the start of the study--measured using fecal calprotectin (FC), a stool biomarker, or the Geboes histologic score, which assesses inflammation under the microscope. This study will use data from five large UC trials to see if requiring high FC or histologic inflammation at trial entry would reduce placebo responses and increase the observed treatment effect. The findings may suggest that this approach does not significantly improve trial results, and may not be beneficial for future UC trial designs.
Project Timeline:
Start date - December 2025
Completion date - Janaury 2026
Manuscript draft / submitted - February 2026
Results reported - March 2026
Dissemination Plan:
The study will be submitted to a high-impact, peer-reviewed medical journal specializing in gastroenterology or clinical trial methodology, such as Gastroenterology, The American Journal of Gastroenterology, or Journal of Crohn's and Colitis.
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