Ulcerative Colitis Clinical Trials Research Articles

Adaptive Steroid Tapering Impedes Corticosteroid-free Remissions Compared with Forced Tapering in Clinical Trials of Ulcerative Colitis.

It is unclear if steroid tapering protocols can affect clinical trial outcomes in ulcerative colitis [UC], particularly fixed versus adaptive steroid tapering. Fixed steroid tapering involves incremental dose decreases at prespecified intervals, and adaptive steroid tapering uses investigator discretion as determined by the patient's response. In this post-hoc analysis from six clinical trials of UC [VARSITY, ACT 1, PURSUIT, GEMINI1, OCTAVE, and ULTRA2], responders to induction therapy with baseline corticosteroid use were considered as the primary population of interest. Adjustments were made to account for treat-through versus re-randomisation designs, and multivariate regression was performed to account for other potential confounding variables. The primary outcome was corticosteroid-free clinical remission [CR] at 1 year, and secondary outcomes were CR and endoscopic improvement. There was a total of 861 patients who had achieved clinical response after induction and were using corticosteroids. Within multivariate analysis, patients using adaptive steroid tapering regimens were less likely to achieve corticosteroid-free CR at 1 year (odds ratio [OR] 0.66 [95% confidence interval, CI, 0.48-0.92], p = 0.015) but had increased odds for achieving CR at 1 year (OR 1.9 [95% CI 1.43-2.52], p < 0.001). The steroid tapering regimen was not associated with achievement of endoscopic improvement at 1 year. Among patients with UC on corticosteroids in clinical trials, patients using adaptive steroid weaning regimens were less likely to achieve corticosteroid-free CR at 1 year but more likely to achieve CR at 1 year. Consideration should be given to implementing mandatory fixed steroid weaning protocols in future clinical trials of UC.

Differences Between the 2016 and 2022 Food and Drug Administration Guidance-Implications for Design and Interpretation of Clinical Trials in Ulcerative Colitis.

In 2022, the Food and Drug Administration (FDA) updated its draft guidance for drug development in ulcerative colitis, replacing the version from 2016. Several changes from the 2016 version merit further discussion as they impact clinical trial design and the interpretation of trial results. We compared both documents and critically appraised the changes and implications for future clinical trials. The 2022 guidance recommends full colonoscopy, rather than flexible sigmoidoscopy, to document disease activity in all involved segments of the colon. The concordance between the findings of the 2 procedures is very high and there is little evidence to support colonoscopy over sigmoidoscopy. The use of colonoscopy, rather than sigmoidoscopy, is also associated with a higher burden to trial participants who must undergo full bowel preparation, cost, and a potential for more adverse events. The definition of the Mayo endoscopic score of 0 was changed from the original publication to "normal appearance of mucosa," which suggests that endoscopic signs of prior disease, such as pseudopolyps and scarring, are incompatible with a score 0, even though they are not associated with active disease. The term "mucosal healing" has been abolished and histologic outcomes defined as exploratory. A welcome change is that shorter washout periods than 5 half-lives will be considered to reduce patient exposure to corticosteroids as bridging therapy. The 2022 FDA draft guidance includes changes which for the most part are not informed by empirical evidence, which may ultimately complicate interpretation of future trials and preclude comparisons with past trials.

P213 ArgesMES: A high-performance, generalizable AI model for scoring Ulcerative Colitis severity from endoscopy videos

Abstract Background The Mayo endoscopic subscore (MES) is widely used to assess endoscopic disease severity assigned by human readers in Ulcerative Colitis (UC) clinical trials. AI-based automation of the MES could reduce inter-rater variability and allow for the development of more sensitive endoscopic measures. This report assesses whether a previously trained (locked) algorithm is suitable for automating full colon or segment-level MES scoring on a prospective UC clinical trial. Methods Endoscopy videos from two UC clinical trials (UNIFI: NCT02407236, Phase 3, 965 subjects, 3128 videos; and JAK-UC: NCT01959282, Phase 2, 211 subjects, 448 videos) were used to train an AI-based MES classifier, where 20% of the total data was retained as a holdout set. This AI model training had two steps: 1) training a feature extraction module using self-supervised learning (SSL), and 2) supervised training of a small transformer network with an attention-based classifier using SSL features to estimate full colon MES. Videos from an independent, prospective UC trial (QUASAR: NCT04033445, Phase 2b induction study, 313 subjects, 615 videos) were used to validate the locked AI model. MES scoring in QUASAR included full colon MES values and additional MES values for three left colon segments: descending colon, sigmoid colon, and rectum. Comparisons between AI-model and human reader scores were performed using AUC, Accuracy, F1 score, and Fleiss kappa. A non-inferiority test was also conducted to determine interchangeability between AI- and human-derived full colon MES values. Results Full colon MES on the QUASAR data showed AUC, Accuracy, and F1 scores of 0.810, 0.687, and 0.693, respectively, comparable to results obtained on the UNIFI holdout data (0.803, 0.645, and 0.647). The Fleiss kappa score was 0.682, comparable to the inter-rater agreement between two human readers-local and central readers (Fleiss kappa = 0.712). The non-inferiority test (p-value &amp;lt; 0.05) indicated that the AI-computed full colon MES readout was interchangeable to that of human readers. Similar performance was observed for the AI-computed segment-level MES: descending colon, sigmoid colon, and rectum as shown in Table 1. This result demonstrates the model's effectiveness at scoring the segment-level MES despite not being trained with segment level ground truth. Conclusion ArgesMES, an AI-based model, underwent successful prospective validation, demonstrating proficiency in automating full colon and segment-level MES scores. ArgesMES has the potential to facilitate rapid, reliable, and reproducible MES scoring at full colon and segment levels in prospective clinical trials.

P689 Adaptive steroid tapering impedes corticosteroid-free remissions compared to forced tapering in UC clinical trials

Abstract Background Protocols for managing steroids in clinical trials of ulcerative colitis (UC) vary. Most trials mandate steroid tapering at the beginning of maintenance phase. Adaptive steroid tapering allows for some discretion on whether to taper steroids for a patient. It remains unclear what impact steroid tapering protocols have on trial outcomes. Methods This post-hoc analysis from many clinical trials of advanced therapies in UC (VARSITY, ACT 1/2, PURSUIT, GEMINI1, OCTAVE and ULTRA2) was carried out under protocols with Vivli (00007656) and YODA (20224882). Responders to induction therapy with baseline corticosteroid use were considered as the primary population of interest. Adjustments were made to account for re-randomization designs and treatment exposure. Univariate analyses were conducted to identify baseline variables that had an association with the primary outcome of interest, one-year corticosteroid-free clinical remission (CR). All covariates with a significant univariate association (p &amp;lt; 0.05) were considered for inclusion in the multivariate model. Logistic regression was used to assess the impact of steroid-weaning regimen on the outcome of interest. Secondary outcome of interest was one-year CR. Results There was a total of 861 patients from the seven included trials who had achieved clinical response after induction and were using corticosteroids. Within multivariate analysis, patients using adaptive steroid weaning regimens were less likely to achieve one year corticosteroid-free CR (odds ratio (OR) 0.66 (95% CI 0.48-0.92), p=0.015). Patients with higher partial Mayo scores were also less likely to achieve one year corticosteroid-free CR (OR 0.88 (95% 0.8-0.97), p=0.012). Other variables found significant on univariate analysis were no longer significant once considered within the multivariate model (smoking, race, albumin, endoscopic Mayo score). For the secondary outcome of one year CR, patients using adaptive steroid weaning regimens had increased odds for achieving one year CR as compared to those using fixed regimens (OR 1.9 (95% 1.43-2.52), p&amp;lt;0.001). Several other variables were also found to have an association with one year CR within the multivariate model (Table 1). Conclusion Among patients with UC on corticosteroids at the time of study enrolment, adaptive steroid weaning regimens were less likely to achieve one-year corticosteroid-free CR but more likely to achieve one-year CR. This may help explain the findings within the VARSITY study, where patients treated with vedolizumab had increased odds for one-year CR but were less likely to achieve one-year corticosteroid-free CR. Consideration should be given to implementing mandatory steroid weaning protocols in future clinical trials of UC.

P905 Symptomatic remission and IUS improvements in a multi-national real-world cohort of UC patients treated with Upadacitinib - First results from the IBD-DACH study EUROPE

Abstract Background Upadacitinib (UPA) is an oral, reversible and selective Januskinase-inhibitor (JAKi) that was approved for the treatment of several immune-mediated inflammatory diseases, including moderate to severe ulcerative colitis (UC) (1). While the efficacy of UPA has been demonstrated in clinical trials in UC, real-word (RW) evidence on the effectiveness and safety of UPA in UC remains scarce (2). Here, we shed light on the clinical and sonographic results after 2 and 8 weeks of UPA induction in a large, multinational RW cohort of UC patients. Methods EUROPE is an ongoing, prospective, non-interventional, multi-country study in patients with active UC who initiate therapy with UPA. The study assesses the early clinical effectiveness and the predictive value of early disease improvements including sonographic parameters for the long-term outcome after 52 and 104 weeks. For this interim analysis, we report clinical and sonographic results at baseline (BL), week 2 (2W) and week 8 (8W) of 124 UC patients with a visit after 8W until August 2023. For 75 patients, sonographic BL data for the most affected bowel segment was available. Results Of the 124 UC patients, most were male (60.5%, n = 75) with a median age and disease duration of 37.5 years (27.5 – 50.9) and 6.58 years (2.40–12.13). Almost half of all patients had a pancolitis (48.4%, n = 60) The vast majority of patients was bio-experienced (85.5%, n = 106), a third had been exposed to ≥ 3 biologicals (28.2%, n = 35). At BL, patients had a median bowel wall thickness (BWT) of 5.0 mm (3.8-7.0) in the sigmoid colon. It was the most affected segment in 44.4% of patients (n = 55). Disease activity per paMayo score was 3.0 (2.0-5.0) points, with 72.6% (n = 90) and 38.8% (n = 48) of patients reporting ≥ 3 more stools than usual/day and blood in most stools or bleeding without stool, respectively. At 2W after UPA induction, stool frequency and rectal bleeding substantially improved as reflected by the rate of patients in symptomatic remission significantly increasing from 16.9% (n = 21) at BL to 43.5% (n = 54) at 2W and to 64.5% (n = 80) at W8 (both p &amp;lt; 0.001 vs. BL, fig.1). BWT was reduced significantly as early as 2W (n = 48; p &amp;lt; 0.001) and was ≤ 3mm in more than half of all patients. Considering the overall population, 156 patients were included in the safety analysis. Of these, 23.7% (n = 37) experienced an adverse event of which most were non-serious. Conclusion In this first interim analysis of the EUROPE study, UPA treatment in UC was associated with early clinical and sonographic improvement, with most patients achieving symptomatic remission and/or normalization of BWT by week 8 of treatment. 1-SmPC Upadacitinib 2-Danese, Vermeire et al. Lancet. 2022 Jun 4;399(10341):2113-2128

P356 Long-term outcome of UC patients in clinical remission with different level of mucosal activity: real world, retrospective, multicontinental study

Abstract Background In contrast to the increasingly rigorous endpoints of clinical trials of ulcerative colitis (UC), Mayo endoscopic score (MES) ≤ 1 is mostly set as target during clinical follow-up, but long-term outcomes may differ according to different level of healing. Therefore, our study aimed to compare the long-term outcomes of UC patients in clinical remission with different MES and UCEIS scores in real-life condition. Methods UC patients in clinical remission (defined by pMayo&amp;lt;2 with no rectal bleeding) who underwent colonoscopy between 2016-2020 were consecutively enrolled in this multicenter retrospective study. Mayo and UCEIS endoscopic scores were evaluated and clinical and demographic data were collected at baseline. Clinical flare, colectomy, hospitalization and treatment modifications were recorded during at least 3 year of follow-up. Primary outcome was the clinical flare, while secondary outcomes were hospitalization, colectomy, new biological initiation and biological dose escalation during follow-up. Outcomes were compared with Log-rank test and survival characteristics were plotted. Results In total, 156 UC patients were enrolled with a median age of 46.0 (IQR 35.5-58.0), while male/female ratio was 49.4 % (Table 1.). Near to half of the patients (44.9%) had MES&amp;gt;0 endoscopic activity at baseline. Non zero baseline MES (Figure 1.; p = 0.002; MES 0 vs 1 p = 0.004) and UCEIS (p &amp;lt; 0.001; UCEIS 0 vs. 1 p = 0.016) scores were associated with higher rate of clinical flare. Higher baseline MES (p = 0.042) and UCEIS (p = 0.008) scores were coupled with increased risk of hospitalization. Colectomy rates were low. Increased baseline UCEIS (p = 0.003), but not MES score was coupled with new biological treatment initiation, while only UCEIS score was associated with biological treatment intensification (&amp;gt;4; p = 0.008). Conclusion Our study suggests differentiating between complete MH from MES 1 as long-term outcomes were more favorable in case of lower endoscopic scores. Consequently, targeting complete MH should be considered to achieve deep remission and disease clearance.

P974 Incidence of Perianal Complications in Clinical Trials for Therapies for Moderate to Severe Inflammatory Bowel Disease

Abstract Background Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) with distinct clinical consequences. Distinct from patients with UC is that nearly 25% of patients with CD patients have or will develop perianal disease. Predictors for the development of new perianal disease or complications from existing perianal disease are not well described but such occurrences are included as adverse events (AEs) in clinical trials for IBD. We performed a systematic review and meta-analysis of perianal AEs in pivotal trials of therapies for IBD. Methods We conducted a search of PubMed, EMBASE, MEDLINE, Medline Plus, and CDSR library databases for registry and pivotal Phase II-III clinical trials of therapies for IBD. Safety data from clinicaltrials.gov was reviewed to identify incidence of perianal AEs using the terms "abscess" and "fistula." Reported perianal AEs included the following: anal abscess, fissure, fistula; perianal abscess, fistula; perineal abscess; perirectal and rectal abscess; subcutaneous (gluteal) abscess. Results Perianal AE incidence across all trials reviewed was 0.47% (91/19,327 patients). Perianal AEs were more likely to occur in patients with CD (0.77%, 70/9,046) than UC (0.20%, 21/10,281). Perianal AEs occurred more frequently in populations of drug-exposed patients than in patients exposed to placebo. In drug-exposed patients with UC, 0.22% (16/7,415) of patients experienced a perianal AE vs 0.17% (5/2,935) of patients exposed to placebo. In drug-exposed patients with CD, 0.76% (55/7,271) of patients experienced a perianal AE vs 0.61% (15/2,465) of patients exposed to placebo. The results are summarized in Table 1. Conclusion We found that perianal AEs occur in pivotal UC and CD clinical trials. Expectedly, the frequency of perianal AEs was higher in trials of CD than those for UC. However, the development of perianal AEs in trials of UC suggests that these patients may have been misclassified and have CD. Available data do not allow distinction between development of a perianal AE in a patient with known perianal disease or progression of undiagnosed clinical or subclinical perianal disease, nor does it allow for distinction in a patient not responding to the experimental agent. The finding that perianal AEs occurred more frequently with drug exposure than placebo may be due to fistula healing with consequential abscess formation or unique mechanistic effects that worsen perianal disease. These results highlight a probable rate of misclassification of patients with UC in pivotal trials, and suggest the possibility of subclinical perianal disease in some patients. Further clarification and study of these AEs and their implications are warranted.

Clinical Trial Design in Ulcerative Colitis: Interpreting Evolving Endpoints Based on Post Hoc Analyses of the Vedolizumab Phase 3 Trials GEMINI 1 and VISIBLE 1.

The 12-point total Mayo score including a Physician's Global Assessment (PGA) of disease activity has been used to assess outcomes in clinical trials for ulcerative colitis (UC). In 2016, the US Food and Drug Administration (FDA) issued guidance advising the removal of the PGA in future trials. We examined how endpoints in UC trials have evolved and conducted a post hoc analysis of the GEMINI 1 and VISIBLE 1 trials to understand how the use of a 9-point modified Mayo score, excluding PGA, compares with the total Mayo score. Endpoint definitions of clinical remission in phase 3 trials were extracted from published literature and ClinicalTrials.gov. The difference (%Δ) between the proportions of patients in GEMINI 1 and VISIBLE 1 achieving clinical remission with vedolizumab versus placebo at week 52 was measured according to 4 endpoint definitions. Trials completed up to the end of 2019 used the total Mayo score to assess clinical remission. Most trials that were completed or estimated to be completed by June 2020 or later used modified Mayo scores. Post hoc analysis revealed decreasing endpoint stringency was associated with increasing %Δ values. The modified Mayo score definition most like the definition recommended by the FDA produced %Δ values like those reported using the total Mayo score in GEMINI 1 and VISIBLE 1. Endpoint definitions for UC clinical trials have evolved following FDA guidance. The efficacy of vedolizumab, measured using modified Mayo scoring, was comparable to values reported using the total Mayo score.

Using Computer Vision to Improve Endoscopic Disease Quantification in Therapeutic Clinical Trials of Ulcerative Colitis

Endoscopic assessment of ulcerative colitis (UC) typically reports only the maximum severity observed. Computer vision methods may better quantify mucosal injury detail, which varies among patients. Endoscopic video from the UNIFI clinical trial (A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis) comparing ustekinumab and placebo for UC were processed in a computer vision analysis that spatially mapped Mayo Endoscopic Score (MES) to generate the Cumulative Disease Score (CDS). CDS was compared with the MES for differentiating ustekinumab vs placebo treatment response and agreement with symptomatic remission at week 44. Statistical power, effect, and estimated sample sizes for detecting endoscopic differences between treatments were calculated using both CDS and MES measures. Endoscopic video from a separate phase 2 clinical trial replication cohort was performed for validation of CDS performance. Among 748 induction and 348 maintenance patients, CDS was lower in ustekinumab vs placebo users at week 8 (141.9 vs 184.3; P < .0001) and week 44 (78.2 vs 151.5; P < .0001). CDS was correlated with the MES (P < .0001) and all clinical components of the partial Mayo score (P < .0001). Stratification by pretreatment CDS revealed ustekinumab was more effective than placebo (P < .0001) with increasing effect in severe vs mild disease (-85.0 vs -55.4; P < .0001). Compared with the MES, CDS was more sensitive to change, requiring 50% fewer participants to demonstrate endoscopic differences between ustekinumab and placebo (Hedges' g= 0.743 vs 0.460). CDS performance in the JAK-UC replication cohort was similar to UNIFI. As an automated and quantitative measure of global endoscopic disease severity, the CDS offers artificial intelligence enhancement of traditional MES capability to better evaluate UC in clinical trials and potentially practice.

Alternative Endoscopy Reading Paradigms Determine Score Reliability and Effect Size in Ulcerative Colitis.

Central reading of endoscopy is advocated by regulatory agencies for clinical trials in ulcerative colitis [UC]. It is uncertain whether the local/site reader should be included in the reading paradigm. We explore whether using locally- and centrally-determined endoscopic Mayo subscores [eMS] provide a reliable final assessment and whether the paradigm used has an impact on effect size. eMS data from the TURANDOT [NCT01620255] study were used to retrospectively examine seven different reading paradigms (using the scores of local readers [LR], first central readers [CR1], second central readers [CR2], and various consensus reads [ConCR]) by assessing inter-rater reliabilities and their impact on the key study endpoint, endoscopic improvement. More than 40% of eMS scores between two trained central readers were discordant. Central readers had wide variability in scorings at baseline (intraclass correlation coefficient [ICC] of 0.475 [0.339, 0.610] for CR1 vs CR2). Centrally-read scores had variable concordance with LR (LR vs CR1 ICC 0.682 [0.575, 0.788], and LR vs CR2 ICC 0.526 [0.399, 0.653]). Reading paradigms with LR and CR which included a consensus, enhanced ICC estimates to >0.8. At Week 12, without the consensus reads, the CR1 vs CR2 ICC estimates were 0.775 [0.710, 0.841], and with consensus reads the ICC estimates were >0.9. Consensus-based approaches were most favourable to detect a treatment difference. The ICC between the eMS of two trained and experienced central readers is unexpectedly low, which reinforces that currently used central reading processes are still associated with several weaknesses.

P206 Artificial Intelligence reproduces central reading for automated scoring of colonoscopies from multiple clinical trials in Ulcerative Colitis

Abstract Background Using Artificial Intelligence (AI) for the automated scoring of colonoscopy videos with Mayo Clinic Endoscopic Subscore (MCES) has been successful in several models [1]. However, no study to date has evaluated the performance of such algorithms on a new cohort obtained from a separate clinical trial. In this study, we aimed to build an AI scoring algorithm able to reproduce central reading from three Phase III clinical trials in Ulcerative Colitis (UC). Methods As a training dataset, still frames were automatically extracted from sigmoidoscopy videos of two Etrolizumab clinical trials: Hickory NCT02100696 [2] and Laurel NCT02165215 [3]. A quality control AI algorithm [4] was applied and the resulting dataset (N=1897 videos) was paired with central reading MCES for each colon section. The training was achieved on a multiclass MCES scoring algorithm [4] with the challenging task of assigning a multiclass score (MCES between 0 - 3) instead of a binary score (MCES &amp;lt;=1 or not). The performance was assessed on 2,292 videos from independent cohorts (Hibiscus I NCT02163759, Hibiscus II NCT02171429 [5], Gardenia NCT02136069 [6]). Videos were pre-processed in an identical manner as those from the training dataset (N= 637, 636 and 1019 videos for Hibiscus I, Hibiscus II and Gardenia, respectively). This dataset constitutes the largest cohort to date for the evaluation of a MCES scoring algorithm. Results The Area Under the Receiver Operator Characteristic curve (AUROC) was evaluated independently for each trial. Table 1 summarizes AUROC values per MCES for each clinical trial. The resulting mean AUROC values were 0.79 for Hibiscus I and 0.77 for both Hibiscus II and Gardenia. The average Cohen’s kappa between the automatic measurements and the central readings is 0.40, in contrast to 0.41 between central and local readers. Conclusion Our automated MCES scoring algorithm efficiently reproduces central reading in three independent clinical trials cohorts. In addition, algorithm evaluation was performed on data from independent trials, different from the ones used for the development of the algorithm. This is the first study evaluating, on such an extended cohort, the use of AI based automated MCES scoring in UC.

P123 Development of an end-to-end Mayo endoscopic score machine learning algorithm for use in clinical trials of ulcerative colitis

Abstract Background Scoring colonoscopy videos of UC patients requires a high level of expertise, but even among trained expert readers there are disagreements. In clinical trials, this can negatively impact both subject selection and assessment of treatment response. Consistency among central readers might be improved by algorithms that automatically process videos to identify salient features and estimate the level of disease activity using established scoring methods. Methods We propose an end-to-end system using machine learning (ML) models to process colonoscopy videos, both shortening the time required for a human expert reader to score a video by filtering out non-informative parts and supplying a second-opinion of Mayo Endoscopic Score (MES) on each informative frame and the full video. Our dataset included videos from UC patients with a representative range of disease activity acquired at a Ukrainian hospital (n=505) and an Israeli hospital (n=227). Video annotation was performed by 12 reviewers, trained and supervised by an expert gastroenterologist (DM) with &amp;gt;10 years central reading experience. Out of almost 3 million frames over ~34% were classified by human reviewers as non-informative (e.g., out of focus, motion blurring, stool). The remaining informative frames were further annotated by the reviewers as containing ulcers (6%) and hence classified as MES=3, erosions (22%) as MES=2, loss of vascularity or erythema (23%) as MES= 1, or none of the above (49%) classified as MES=0. Informative frames were split to 80% training set, 10% validation set and 10% test set. The data set included low quality frames on which the reviewers could still estimate the MES. Models consisting of image processing algorithms, Convolutional Neural Networks (CNN), CNN+Long Short Term Memory (LSTM) model and classical ML classifiers were trained to filter out non-informative frames and score independently each frame and the full video for MES. Results Model performance was evaluated using Cohen’s Quadratic Weighted Kappa (QWK) with 95% Confidence Interval [95% CI]..Model agreement with humans is shown in the middle column. Inter-reviewer agreement based on a subset of ‘clear frames’ from various videos of the test set is shown in the last column. Conclusion We developed a full end-to-end pipeline for processing colonoscopy videos that estimated MES with accuracy comparable to human-human agreement. Such a model has the potential to make human readers more efficient by highlighting frames with relevant pathology. It can also aid inter-reader agreement by providing a second-opinion MES. Future work will expand model training and testing with new data sources and explore paradigms to combine the model with human readers to improve clinical trial central reading.

P854 Race and ethnicity in ulcerative colitis clinical trial enrolment: a post hoc analysis of patient demographics and clinical characteristics from GEMINI 1, VARSITY, and VISIBLE 1

Abstract Background The incidence of inflammatory bowel disease (IBD) has risen among Black individuals and Hispanic or Latino individuals in the USA in recent decades; however, these patients are underrepresented in clinical trials of IBD therapies. We aimed to perform a post hoc analysis of the baseline demographics and clinical characteristics in three phase 3 clinical trials of vedolizumab for ulcerative colitis (UC) to identify differences between racial and ethnic groups. Methods The baseline demographics and clinical characteristics of patients with UC who were enrolled in GEMINI 1, VARSITY, and VISIBLE 1 were pooled and stratified by race and ethnicity, which were self-reported. The inclusion criteria for these trials included adult patients with moderately to severely active UC who had a prior inadequate treatment response, loss of response, or intolerance to conventional therapies or anti-tumour necrosis factor α treatment. Data were analysed using descriptive statistics, with mean or median values calculated for continuous variables, and the number and proportion of patients reported for categorical variables. T-tests and exact tests were used to compare continuous and categorical variables, respectively, between Black and White patients and between Hispanic or Latino patients and those who were not Hispanic or Latino. Results We included 1,358 patients, of whom 1,171 (86.2%) were White, 148 (10.9%) were Asian, 14 (1.0%) were Black, and 25 (1.8%) were of multiple or unspecified racial groups (Table 1). Black patients had significantly higher mean weight (87.9 kg vs 74.8 kg, p &amp;lt; 0.01) and body mass index (30.5 kg/m2 vs 25.2 kg/m2, p &amp;lt; 0.01), but lower albumin (38.5 g/L vs 41.2 g/L, p &amp;lt; 0.05) and haemoglobin levels (115.5 g/L vs 126.1 g/L, p &amp;lt; 0.05) than White patients (Table 1). Ethnicity data were recorded for 465 patients (34.2%). Hispanic or Latino patients were shorter in height (166.6 cm vs 171.0 cm, p &amp;lt; 0.01) and had shorter mean disease duration (4.6 years vs 7.6 years, p &amp;lt; 0.01) than those who were not Hispanic or Latino (Table 2). A non-significant, but numerically greater proportion of Hispanic or Latino patients had pancolitis than those who were not Hispanic or Latino (50.0% vs 35.8%). Conclusion In this post hoc analysis of vedolizumab clinical trials, Black patients and Hispanic or Latino patients with UC had differences in certain demographic and disease characteristics versus White patients and patients who were not Hispanic or Latino, respectively. These differences may have implications for therapy. Thus, inclusion of a more diverse patient population that reflects the demographics of the general population is warranted to adequately ascertain drug efficacy across racial and ethnic groups.

P578 Exploring duration of corticosteroid withdrawal in definitions of corticosteroid-free remission endpoints in ustekinumab clinical trials: results from the IM-UNITI, UNIFI, and SEAVUE trials

Abstract Background Remission off steroids is a major treatment goal in inflammatory bowel disease. In the recent CORE-IBD consensus,1 the preferred definition of “corticosteroid-free” remission in clinical trials was withdrawal ≥12 weeks before the assessment timepoint. We evaluated the rates of corticosteroid-free remission according to three different definitions (ie, cross-sectional, ≥30, and ≥90 days) in the analysis of the corticosteroid-free remission endpoint using data from the IM-UNITI and SEAVUE trials of patients with Crohn’s disease (CD) and the UNIFI trial of patients with ulcerative colitis (UC). Methods In IM-UNITI and UNIFI, patients with moderate-to-severe CD and UC, respectively, who had previously responded to ustekinumab (UST) induction were randomized to placebo (PBO), UST 90mg SC q12w, or UST 90mg SC q8w. In SEAVUE, biologic naïve patients with moderate-to-severe CD were randomized to adalimumab 160mg SC at week 0, 80mg SC at week 2, and 40mg SC q2w or UST ~6mg/kg IV at week 0 and 90mg SC q8w. Each trial included protocols for mandatory corticosteroid tapering after the induction phase unless medically inappropriate (required in IM-UNITI and UNIFI starting at week 8 and recommended in SEAVUE starting at week 8 but required starting at week 16). Corticosteroid-free remission was defined as clinical remission (CDAI&amp;lt;150 in IM-UNITI and SEAVUE and a Mayo score ≤2 with no individual subscore &amp;gt;1 in UNIFI) and not receiving steroids at the assessment timepoint or ≥30 or ≥90 days before the assessment timepoint. Corticosteroid-free remission at week 44 was a major secondary endpoint in IM-UNITI and UNIFI (both cross-sectional). Corticosteroid-free remission (≥30 days before week 52) was a major secondary endpoint in SEAVUE. Results The proportions of patients who achieved corticosteroid-free remission were consistent, regardless of the corticosteroid-free duration used in the assessment (Tables 1 and 2). The results were consistent for both ustekinumab treatment groups (q12w and q8w) and placebo in the pivotal IM-UNITI and UNIFI studies (Table 1) and for both ustekinumab and adalimumab groups in the SEAVUE study (Table 2). Conclusion In CD and UC clinical trials of ustekinumab maintenance, which included protocol-mandated corticosteroid tapering regimens, corticosteroid-free remission results at 1 year were similar regardless of the corticosteroid-free duration used in the outcome definition.

P227 Patient experiences in ulcerative colitis: conceptual model and review of patient-reported outcome measures

Abstract Background Symptoms of ulcerative colitis (UC) negatively affect patients’ health-related quality of life (HRQoL). The aim of this study was to identify symptoms and impacts experienced by patients with UC, develop a conceptual model (CM) and evaluate available patient-reported outcome (PRO) measures for appropriateness for inclusion in UC clinical studies. Methods We conducted a landscape assessment that included: targeted literature reviews (TLRs) to identify concepts of interest and frequently used PRO measures among patients with UC; label claims searches for US and European regulatory and health technology assessment (HTA) submissions; and US and European clinical trial database searches to identify PRO measures used as primary and secondary endpoints in ongoing clinical trials. Results from the TLR informed a CM of UC. Concepts from the CM were mapped to selected PRO measures. Appropriateness of selected PRO measures for UC populations was evaluated via a gap analysis. Results Fifty-two symptoms and 72 impacts of UC were identified from the TLR. The most frequently reported symptoms were diarrhoea, incontinence/leaking/lack of bowel control, urgency, rectal bleeding, frequent bowel movements and fatigue. The most frequently reported impacts were anxiety, depression, inability to conduct daily activities, embarrassment and affected relationships with others. The CM grouped the 52 symptom concepts into eight dimensions, the 29 impacts proximal to UC into two dimensions and the 43 impacts distal to UC into five dimensions (Figure 1). Of the 69 PRO measures identified, eight were selected for conceptual analysis based on being disease-specific and having evidence of use in regulatory label claims, HTA submissions, as UC clinical trial endpoints and/or having US Food and Drug Administration (FDA) qualification status. The five PRO measures that covered the most concepts when mapped against the CM and included in the gap analysis were: the Inflammatory Bowel Disease Questionnaire (IBDQ); Symptoms and Impacts Questionnaire for UC (SIQ-UC); UC-PRO symptoms modules (UC-PRO-Signs and Symptoms [UC-PRO/SS] and UC-PRO-Systemic Symptoms); UC-PRO impact modules (UC-PRO-Daily Coping [UC-PRO-DC], UC-PRO-Daily Life Impact [UC-PRO-DLI] and UC-PRO-Emotional Impact [UC-PRO-EI]); and Crohn’s and Ulcerative Colitis Questionnaire (CUCQ) (Table 1). All five PRO measures had good or excellent support for content validity; the UC-PRO/SS fully met FDA PRO guidance for content validity and most psychometric properties. Conclusion Based on the CM and PRO measures review, the IBDQ plus UC-PRO/SS are recommended to capture UC symptoms and IBDQ plus UC-PRO impact modules to capture proximal impacts. All PRO measures reviewed require further psychometric evaluation.

Definition of mild to moderate ulcerative colitis in clinical trials: A systematic literature review.

We performed a systematic review to investigate the definition of mild to moderate active ulcerative colitis (UC), and to describe predictors of good response to treatment in clinical trials assessing 5‐ASA and/or budesonide. Thirty‐nine randomized controlled trials were included. The UC Disease Activity Index (UCDAI) was the most frequent score used for defining mild to moderate active UC (16 studies, 41%), followed by Clinical Activity Index in 11 studies (28.2%). Four different cut‐offs were used to define mild to moderate active UC using the UCDAI. The most frequently reported predictors of good response to treatment was a mild and moderate disease activity. There is heterogeneity in the definition of mild to moderate active UC in randomized clinical trials. A standardized definition of mild to moderate active UC used for inclusion of patients in clinical trials is needed.

Predictors of Placebo Induction Response and Remission in Ulcerative Colitis

High placebo response rates in clinical trials of ulcerative colitis (UC) have been reported previously. However, data from patient-level analyses are lacking. We assessed factors associated with clinical and endoscopic placebo response among placebo-treated patients in clinical trials of UC. We performed a post hoc analysis of pooled clinical trial data from GEMINI-1, ACT-1, ACT-2, PURSUIT, ULTRA-2, OCTAVE-1, and OCTAVE-2. Predictors were assessed in placebo-treated patients for their association with end of induction (week 6 of 8) clinical response (reduction in total Mayo score of ≥3 and ≥30% from baseline with ≥1 point decrease in rectal bleeding subscore [RBS] or absolute RBS ≤1); clinical remission (total Mayo score ≤2 and no subscore >1); endoscopic healing (Mayo endoscopic subscore ≤1); partial Mayo score of 0; patient-reported outcome 2-item remission (RBS of 0 and stool frequency ≤1), resolution of rectal bleeding, and stool frequency normalization. Predictors on univariate analyses with P < .05 were included in multivariate logistic regression models. Placebo-treated patients with normal serum C-reactive protein and albumin levels were more likely to attain clinical response (71 of 437 [16.3%] vs 49 of 660 [7.4%]; adjusted odds ratio, 2.76; 95% confidence interval, 1.19-5.41; P= .018). Compared with patients with a Mayo endoscopic score of 2, patients with a Mayo endoscopic score of 3 were less likely to attain clinical response (105 of 556 [18.8%] vs 179 of 675 [25.9%]; adjusted odds ratio, 0.33; 95% confidence interval, 0.16-0.68; P= .003). Similar findings were observed for clinical remission and resolution of rectal bleeding. Biomarkers such as normal serum C-reactive protein and albumin and baseline endoscopic severity were found to affect placebo response rates in clinical trials of UC. These findings have implications for clinical trial design in UC.

Racial Difference in Efficacy of Golimumab in Ulcerative Colitis.

Observational studies have described racial differences in inflammatory bowel disease (IBD) genetics, clinical manifestations, and outcomes. Whether race impacts response to biologics in IBD is unclear. We conducted a post hoc analysis of phase 2 and 3 randomized clinical trials in ulcerative colitis to evaluate the effect of race on response to golimumab. We analyzed pooled individual-level data from induction and maintenance trials of golimumab through the Yale Open Data Access Project. The primary outcome was clinical response. Secondary outcomes were clinical remission and endoscopic healing. Multivariable logistic regression was performed comparing White vs racial minority groups (Asian, Black, or other race), adjusting for potential confounders. There were 1006 participants in the induction (18% racial minority) and 783 participants in the maintenance (17% racial minority) trials. Compared with White participants, participants from racial minority groups had significantly lower clinical response (adjusted odds ratio [aOR], 0.43; 95% confidence interval [CI], 0.28-0.66), clinical remission (aOR, 0.41; 95% CI, 0.22-0.77), and endoscopic healing (aOR, 0.48; 95% CI, 0.31-0.74) at week 6. Participants from racial minority groups also had significantly lower clinical remission (aOR, 0.46; 95% CI, 0.28-0.74) and endoscopic healing (aOR, 0.63; 95% CI, 0.41-0.96) at week 30. There were no racial differences in placebo response rates. Ulcerative colitis participants from racial minority groups were less likely to achieve clinical response, clinical remission, and endoscopic healing with golimumab compared with White participants in induction and maintenance trials. Further studies are needed to understand the impact of race on therapeutic response in IBD.

End of induction patient reported outcomes predict clinical remission and endoscopic improvement with vedolizumab and adalimumab in ulcerative colitis

Background Patient-reported outcomes (PROs) are increasingly emphasized as endpoints in clinical trials of ulcerative colitis (UC). However, the prognostic value of early improvement in PROs for long-term outcomes remains unclear. Methods This was a post-hoc analysis of 611 vedolizumab-treated or adalimumab-treated patients in the VARSITY trial (Clinicaltrial.gov: NCT02497469). Stool frequency (SF) and rectal bleeding score (RBS) as reported in the Mayo score at post-induction (week 6 and 14) was assessed for their association with one-year endoscopic improvement (EI), defined as Mayo endoscopic subscore <2; histo-endoscopic mucosal improvement (HEMI), defined as EI and Geboes highest grade <3.2, clinical remission (CR), defined as total Mayo score ≤2; and PRO-2 remission, defined as RBS of 0 and SF ≤1. Multivariable logistic regression models adjusted for confounders assessed the relationships between post-induction PROs and outcomes of interest at one-year. Results Patients with severe SF at week 6 were significantly less likely to achieve one-year EI compared to those with non-severe SF [aOR 0.40 (95% CI: 0.24–0.68), p < .001]. Absence of rectal bleeding at week 6 was associated with greater odds of achieving EI at one-year [aOR 2.21 (95% CI: 1.58–3.09), p < .001]. These findings were consistent across comparisons at week 14. Similar findings were observed for the outcomes of one-year HEMI, CR and PRO-2 remission. No difference was observed between the modified partial Mayo score and modified PRO-2 score. Conclusions Post-induction PROs strongly predict the odds of CR and EI in UC and simplified evaluations can be used to assess early response to UC therapies.

Update on ozanimod for ulcerative colitis.

Treating moderate to severe ulcerative colitis (UC) has been enriched by the increasing number of drugs available for this disease. However, failure of conventional therapies, an incomplete response, or loss of response to biologics is experienced in many UC patients. Thus, there is still a growing need for new drugs in the therapeutic arsenal for UC. Ozanimod is a sphingosine-1-phosphate (S1P) receptor modulator which has been recently approved for UC therapy. In this review, we focus on the mechanism of action of ozanimod hydrochloride in preclinical studies of intestinal inflammation as well as its clinical effectiveness and safety in moderate to severe UC patients. In this population, ozanimod was shown to be significantly more effective than placebo to induce clinical remission. Additionally, in terms of clinical response, corticosteroid-free remission, endoscopic improvement and mucosal healing, ozanimod performed significantly better than placebo in this population. No significant safety concerns about ozanimod emerged from clinical trials in UC.