Ulcerative Colitis Trials Research Articles

P0964 The effect of alarms on completion of electronic diaries in patients with inflammatory bowel disease

Abstract Background Clinical trials have contributed substantially to the development of novel therapies for inflammatory bowel disease, including Crohn’s disease (CD) and ulcerative colitis (UC). The Food and Drug Administration (FDA) recommends the use of the Crohn’s Disease and Activity Index (CDAI) and the modified Mayo Score (mMS) to measure primary endpoints in CD and UC trials, respectively. Both assessments use composite scores requiring the completion of a daily diary by subjects to report on symptoms, including stool frequency (SF), rectal bleeding, abdominal pain, and general well-being. In order to ensure the timely completion of diaries, and to limit missing days, it has been recommended to implement device alarms or reminders. The objective of this study was to investigate how device alarms and/or reminders can influence completion times of the daily electronic diaries (eDiaries) in CD and UC studies. Methods More than 3.7 million eDiary entries from 12 153 patients across 11 studies in CD and UC were evaluated. Only completed entries were included. Patients were required to complete eDiaries daily, either on their personal device or a provisioned device, throughout their participation in a specific study. Daily alarms were programmed to remind patients to complete their eDiary. For this analysis, the difference between the patient’s eDiary alarm time and the time the eDiary was first opened was determined. Results For CD trials, 65% (n=1 079 823) of eDiaries were opened after the programmed alarm time. Of these eDiary entries, 39% (n=652 138) were answered 30 minutes after the alarm time, and 8% (n=127 711) were answered between 30 minutes and an hour after the alarm time. In UC trials, 60% (n=1 277 090) of eDiaries were opened after the programmed alarm time. Similarly, 38% (n=822 552) of eDiaries were completed after 30 minutes of the alarm time, and 8% (n=170 433) were completed between 30 minutes and an hour after the alarm time. Conclusion The implementation of eDiary alarms is essential to support patient compliance in clinical trials and drive reliable inferences. The analysis performed here suggests that eDiary alarms are useful to encourage patients to answer their eDiary within an hour reporting window of their scheduled alarm time. Nevertheless, sites and study teams should continue to educate patients on the importance of eDiary completion.

P0541 Placebo rates in randomised clinical trials of Ulcerative Colitis: An individual patient data meta-analysis

Abstract Background Information on placebo rates is important for designing clinical trials. We aimed to assess placebo rates and associated factors using individual patient data from multiple randomised clinical trials in ulcerative colitis. Methods We conducted a meta-analysis of individual participant-level data from nine randomised trials using Vivli and Yale University Open Data Access data-sharing platforms. Phase 2 and 3 placebo-controlled randomised clinical trials of advanced biologic therapies in adults with moderate-to-severe active ulcerative colitis published since 2010 were included. Pooled placebo rates and 95% CIs were estimated using one-stage and two-stage meta-analytical approach. Significant patient-level factors (P<0.05) associated with placebo rates were identified using regression analyses. The pre-specified primary outcomes were placebo clinical response and remission. Results Outcome data were available for 1,703 patients from nine studies (three induction-only, one maintenance-only, and five including both phases). For induction trials, overall placebo response and remission rates were 33% (95% CI 29-38%) and 9% (95% CI 7-11%), respectively (Figure). Overall placebo response and remission rates in maintenance trials were 28% (95% CI 17%-41%) and 14% (95% CI 9-20%), respectively (Figure). A lower body mass index reduced odds of placebo response and remission, while higher baseline albumin levels and left-sided UC (compared to extensive) increased the odds of these outcomes. A one-point increase in the Mayo Clinic Score and adapted Mayo Clinic Score was associated with a 26% and 27% reduction in the odds of clinical remission. For induction trials, prior exposure to biologics or tumour necrosis factor antagonist therapy was associated with lower odds of both response and remission. Multi-centre trials have lower placebo effect than single-centre trials. Conclusion These results will enable future trials that include placebo to incorporate design elements that enable reduction of placebo rates as well as a precise benchmark for expected rates in clinical trials that do not include placebo.

DOP078 Machine learning assessment of endoscopic severity in Ulcerative Colitis trials: Model evaluation against the 2 + 1 reference standard

Abstract Background Regulatory guidance recommends the endoscopy subscore, a component of the modified Mayo Score, as a primary endpoint in ulcerative colitis (UC) therapeutic trials. The endoscopy subscore is typically assessed via the 2 + 1 central reading paradigm, a workflow involving independent video review by multiple readers and, most commonly, statistical methods in cases of disagreement1. Disagreement in centrally read endoscopic assessments can impact the reliability and reproducibility of trial results2. Machine learning (ML) provides an opportunity for standardization. The objective of this study is to evaluate a novel ML model to assess the endoscopy subscore in UC trials compared to a 2 + 1 reference standard. Methods Endoscopic videos from the mirikizumab Phase 2 (NCT02589665) and Phase 3 induction (NCT03518086) trials in UC were added to a database of endoscopic recordings from routine practice to create a cohort of 18,169 videos. 639 videos (~25%) from the Phase 3 induction trial (week 0 and 12 procedures) with a 2 + 1 centrally read endoscopy subscore, per protocol, were randomly selected with a distribution of endoscopic severity similar to the overall study population (82.2% moderate-to-severe) and held out to evaluate performance of the final, locked model. Remaining videos were used to develop a state-of-the-art multi-stage deep learning algorithm to assess the endoscopy subscore on full-length UC endoscopic videos. Quadratic weighted kappa (QWK) was used to evaluate the inter-rater agreement between the model-assessed endoscopy subscore and the 2 + 1 reference standard. Results In the holdout test cohort (n=639) there was 62.4% agreement rate between the first two human readers (local vs central reader 1) in determining the centrally read endoscopy subscore with 2.5% cases of disagreement by 2 classes, in line with published data3,4. QWK between the model-assessed endoscopy subscore and the 2 + 1 reference standard was 0.77 (95% confidence interval (CI) 0.74-0.80). Disagreement by 2 classes occurred in 1.9% of videos. Binary accuracy for inactive-to-mild vs moderate-to-severe disease and inactive vs mild-to-moderate-to-severe disease, definitions of endoscopic improvement and remission in trials, was 89.8% (95% CI 87.5-92.2%) and 94.2% (95% CI 92.4-96.0%), respectively. Conclusion This ML algorithm effectively assesses the endoscopy subscore on full-length endoscopic videos in UC. Given the performance, ML models such as this could potentially standardize the assessment of inflammation, addressing a notable challenge currently posed in UC therapeutic development programs due to inconsistencies among human readers. Future research will investigate ML-based reading paradigms for the assessment of endoscopic endpoints in trials. References Food and Drug Administration. Ulcerative Colitis: Developing Drugs for Treatment [Internet]. 2022 [cited 2024 Oct 17]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ulcerative-colitis-developing-drugs-treatment Wils, P., Jairath, V., Sands, B. E., Magro, F., Reinisch, W., Rubin, D., . . . & Peyrin-Biroulet, L. (2023). Comparison of treatment effect between phase 2 and phase 3 trials in patients with inflammatory bowel disease. United European Gastroenterology Journal, 11(8), 797-806. Hashash, J. G., Yu Ci Ng, F., Farraye, F. A., Wang, Y., Colucci, D. R., Baxi, S., . . . & Melmed, G. Y. (2024). Inter-and intraobserver variability on endoscopic scoring systems in crohn’s disease and ulcerative colitis: A systematic review and meta-analysis. Inflammatory Bowel Diseases, izae051. Feagan, B. G., Khanna, R., Sandborn, W. J., Vermeire, S., Reinisch, W., Su, C., . . . & Sands, B. E. (2021). Agreement between local and central reading of endoscopic disease activity in ulcerative colitis: Results from the tofacitinib OCTAVE trials. Alimentary Pharmacology & Therapeutics, 54(11-12), 1442-1453.

P0307 Application of a machine learning model in the 2 + 1 central reading paradigm to assess endoscopic severity in ulcerative colitis trials

Abstract Background The 2 + 1 human central reader paradigm is the most common workflow to measure the endoscopy subscore, a component of the modified Mayo Score, in ulcerative colitis (UC) trials1. This workflow involves independent endoscopy video reviews by a local site investigator (LR) and central reader (CR1), with discrepancies typically addressed through an additional independent central read (CR2). Inter-rater disagreement in assessments remains a challenge, impacting study results2. Machine learning (ML) models have demonstrated the potential to aid in assessment standardization of the endoscopy subscore. Paradigms for the use of these models in endpoint assessments are currently under investigation. The objective of this study is to explore the application of an ML model to assess the LR and CR1 in the 2 + 1 central reader paradigm. Methods Endoscopy video recordings from the mirikizumab trials and routine practice were used to develop a state-of-the-art multistage deep learning algorithm to assess the endoscopy subscore on full-length UC videos. 639 videos (~25%) from the Phase 3 LUCENT1 (NCT03518086) induction trial for mirikizumab in UC (week 0 and 12 procedures) with a 2 + 1 centrally read endoscopy subscore per protocol, were held out to evaluate performance of the final locked model and this analysis. Videos in this cohort were randomly selected with a distribution of endoscopic severity similar to the overall study population (82.2% moderate-to-severe). Quadratic weighted kappa (QWK) was used to evaluate inter-rater agreement in pairwise comparisons between the ML model, LR, and CR1 assessments. Results QWK between ML model-assessed endoscopy subscore and the final 2 + 1 reference standard endoscopy subscore was 0.77 (95% confidence interval (CI) 0.74-0.80). In the baseline comparison between LR and CR1 assessments, the initial two reads in the 2 + 1 central reading paradigm, QWK was 0.71 (95% CI 0.67-0.75) and the agreement rate was 62.4%. Independent comparison of the ML model to the LR (ML vs LR) and CR1 (ML vs CR1) demonstrated similar findings: QWK was 0.69 (95% CI 0.64-0.73) and 0.72 (95% CI 0.68-0.76) and agreement rate was 59.5% and 66.5%, respectively. Conclusion We demonstrate that this ML model can be used effectively in the 2 + 1 central reading paradigm for evaluation of the endoscopy subscore in UC and automate one of the two initial assessments. The high discord between human reviewers creates a ceiling effect when comparing the ML model to any single human read, with performance measurements capped by the variability in the human read. Future studies will evaluate the ML model and human reviewers against alternative ground truth definitions to inform higher-quality paradigms for the assessment of endoscopic endpoints in trials. References Food and Drug Administration. Ulcerative Colitis: Developing Drugs for Treatment [Internet]. 2022 [cited 2024 Oct 17]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ulcerative-colitis-developing-drugs-treatment. Wils, P., Jairath, V., Sands, B. E., Magro, F., Reinisch, W., Rubin, D., . . . & Peyrin-Biroulet, L. (2023). Comparison of treatment effect between phase 2 and phase 3 trials in patients with inflammatory bowel disease. United European Gastroenterology Journal, 11(8), 797-806.

P0694 Clinical response trajectories identify distinct subpopulations of ulcerative colitis patients and are linked to disease outcome across different therapy classes. Patient level analysis of 2378 participants from 6 randomized controlled trials in moderate-severe UC representing 8 different mechanisms of action.

Abstract Background In randomized placebo-controlled trials (RCTs) for ulcerative colitis (UC), remission rates below 40% (wk52). Landmark analyses using independent endpoints provide approvable estimands for overall efficacy but overlook individual variability.Notably, a subset of patients achieves deeper remission levels. Post hoc analysis of the SELECTION trial (filgotinib) demonstrated that treating daily PRO2 scores (stool frequency, rectal bleeding) as time-series data reveals discrete subpopulations.Patients with in the faster response trajectory groups achieve wk52 endpoints at higher rates including disease control. Methods In a cross-industry/academic collaboration, data from 2,378 UC responders from RCTs of adalimumab, brepocitinib, etrasimod, etrolizumab, ozanimod, ritlecitinib, ustekinumab, and vedolizumab in UC were analyzed for PRO2-based treatment response trajectories using Group-based trajectory modeling (GBTM). Using random-effects logistic regression, trajectory groups were linked to wk 12 and 52 outcomes, including comprehensive disease control (CDC), defined as achieving remission in endoscopy, symptoms, lab markers, and histology. Meta-analyses of baseline demographics/disease characteristics examined predictors of trajectory group affiliation and CDC at wk 52. Results GBTM identified 3–5 distinct response trajectories for each mechanism of action (MOA), ranging from super-fast responses to slow and incomplete responses or relapse, based on PRO2 dynamics. Meta-analysis revealed baseline factors associated with faster response, including prior biologic failure, lower endoscopic activity (Mayo-ES 2 vs. 3), lower Robarts Histology Index, lower baseline disease activity and male sex (0.78 [0.66, 0.93]) (Fig1). Across therapies, remission, mucosal healing, and comprehensive disease control (CDC) were most frequently achieved in fast and super-fast responders (15–37%), compared to slow or non-responders (2.6–8.1%). Random-effects logistic regression confirmed better clinical outcomes for faster responders (Tab1). Conclusion Distinct subgroups (response trajectories) with specific PRO2-based response dynamics were consistently identified. In all trials, patients with (super)fast responses had significantly higher odds of achieving mucosal healing, deep remission, and comprehensive disease control (CDC) at wk52. While some baseline characteristics were linked to faster responses, they only partially account for the observed separation of patient groups. Response trajectories likely reflect underlying heterogeneity in disease biology in the interaction with the different MOA (i.e. endotypes). RNASeq analysis of transcriptome regulation in these patients aims to further explore this hypothesis. References Schreiber S et al. UEG Journal, doi:10.1002/ueg2.12686

P0430 Central reading of ulcerative colitis endoscopic disease activity: Automated but with a human in the loop (2M+1H)

Abstract Background Central reading in ulcerative colitis (UC) trials has high interobserver variability, typically managed through 2 + 1 adjudication when 2 readers disagree on the endoscopic subscore (40% of cases)1,2. While artificial intelligence (AI) models show high agreement with human readers3, relying solely on AI in medical imaging raises concerns. Our novel 2M+1H approach uses human adjudication (H) only when two independently developed AI models (2M) disagree, preserving human oversight while affording the reproducibility and efficiency provided by AI4. The models’ independent development and performance characteristics ensure distinct “personalities,” similar to independent human readers. Methods Both models 1 and 2 were previously developed and validated deep learning models. In addition to distinct approaches, training was conducted by separate teams utilizing different training data. Model 1 was trained using a self-supervised feature extractor while model 2 was trained on supervised severity models consisting only of human-identifiable features. A panel of 10 blinded central readers (CRs) were selected and randomly assigned to provide independent human reads. 150 lower endoscopy videos from routine practice with a confirmed diagnosis of UC were independently assessed through the traditional 2 + 1 approach and the 2M+1H approach. The “final score” generated by each reading workflow was compared using quadratic weighted kappa (QWK). Noninferiority was determined if the lower bounds of the 95% confidence intervals (CIs), computed via bootstrapping, exceeded the QWK margin-adjusted threshold (set at -10%). Results The 2M+1H approach achieved good agreement with traditional 2 + 1 human central reading (QWK 0.78, 95% CI 0.69-0.84) and is statistically noninferior (Fig 1). Binary classification of endoscopic improvement and endoscopic remission was very good (agreement rate 82.7% (95% CI 76.7%-88.7%) and 89.3% (95% CI 84.7%-94.0%). Comparison of the two ML models showed statistically similar behavior to that of the first two human CRs in the 2 + 1 approach (QWK model 1 vs model 2: 0.74 (95% CI 0.66-0.80), QWK CR 1 vs CR2: 0.78 (95% CI 0.70-0.85), p = 0.80). The 2M+1H approach reduced the total number of human reads from 349 (2 + 1) to 67 (2M+1H), an 81% decrease, decreasing the total number of human reads per video (0.45 vs 2.33, p < 0.001) (Fig 2). Conclusion Our data demonstrates that 2M+1H central reading achieved comparable performance to traditional 2 + 1 human central reading and is statistically noninferior while significantly reducing human workload. Prospective studies may adopt this approach to leverage ML as a regulatory-aligned alternative to the 2 + 1 human reading approach in UC clinical trials. References Food and Drug Administration. Ulcerative Colitis: Developing Drugs for Treatment [Internet]. 2022 [cited 2024 Oct 17]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ulcerative-colitis-developing-drugs-treatment Gottlieb, K., Daperno, M., Usiskin, K., Sands, B. E., Ahmad, H., Howden, C. W., . . . & Reinisch, W. (2021). Endoscopy and central reading in inflammatory bowel disease clinical trials: Achievements, challenges and future developments. Gut, 70(2), 418-426. Rimondi, A., Gottlieb, K., Despott, E. J., Iacucci, M., Murino, A., & Tontini, G. E. (2023). Can artificial intelligence replace endoscopists when assessing mucosal healing in ulcerative colitis? A systematic review and diagnostic test accuracy meta-analysis. Digestive and Liver Disease, 56(7):1164-1172. Cohen, I. G., Babic, B., Gerke, S., Xia, Q., Evgeniou, T., & Wertenbroch, K. (2023). How AI can learn from the law: Putting humans in the loop only on appeal. npj Digital Medicine, 6(1), 160.

P0451 Using a machine learning model to assess agreement between inflammation in the rectosigmoid and entire colon in patients with ulcerative colitis

Abstract Background Limited endoscopy of the rectosigmoid colon is sometimes used to assess endpoints in clinical trials for ulcerative colitis (UC). However, there is inherent inter- and intra-rater variability in endoscopic assessment of inflammation, and regulatory agencies have suggested that full colonoscopy is preferred1,2,3. We used a machine learning (ML) model to compare the degree of inflammation of full-length endoscopy videos to that seen in the distal colon and rectum. Methods We used a previously developed ML model that predicts the endoscopy subscore4, a component of the modified Mayo Score, and applied it to 49 full-length endoscopy videos randomly selected and stratified by endoscopic severity from the Phase 3 induction trial for mirikizumab in UC (NCT03518086). Each video was preprocessed by a human reviewer to identify the point of maximal extent and the end of the procedure. The withdrawal portion of the videos were divided into 15, 30, or 60 second clips (a series of smaller segments of video), and the ML model generated an endoscopy subscore for each clip (clip-level endoscopy subscore) and for the entire video (video-level endoscopy subscore). We assigned the final two clips during withdrawal as an assessment of the sigmoid and rectum. Therefore, in this analysis, we compared the ML endoscopy subscore grade of the final two clips to the video-level endoscopy subscore. Kappa statistics of variability between scores were performed. Results There was substantial agreement between the video-level endoscopy subscore and that of the last 2 clips (Table 1). For 60-second clips, the agreement rate between the video-level endoscopy subscore and clip 1 was 0.67 and that with clip 2 was 0.76. When comparing the video-level endoscopy subscore to clip 1 or clip 2, the agreement rate was 0.86, and this was greater than the agreement rate when looking at the higher grade of clip 1 or clip 2 (0.73). The 60 second clips had greater agreement rates than 30 second or 15 second clips (Table 1 and 2). The endoscopy subscores of clip 1 or clip 2 had excellent agreement with video-level grades 0-3 (Table 2), and this was best observed with 60 second clips (Table 2A, kappa 0.944). Conclusion The ML model demonstrated excellent agreement between clip-level endoscopy subscore assessments of the distal most portion of the withdrawal videos compared to the video-level endoscopy subscore, and this was best observed with 60 second clips. These findings support the use of distal colon and rectum assessment to determine the grade degree of endoscopic inflammation of the full colonoscopy. We propose further prospective study of the use of this ML model in this setting. References Feagan, B. G., Khanna, R., Sandborn, W. J., Vermeire, S., Reinisch, W., Su, C., . . . & Sands, B. E. (2021). Agreement between local and central reading of endoscopic disease activity in ulcerative colitis: Results from the tofacitinib OCTAVE trials. Alimentary Pharmacology & Therapeutics, 54(11-12), 1442-1453. Hashash, J. G., Yu Ci Ng, F., Farraye, F. A., Wang, Y., Colucci, D. R., Baxi, S., . . . & Melmed, G. Y. (2024). Inter-and intraobserver variability on endoscopic scoring systems in crohn’s disease and ulcerative colitis: A systematic review and meta-analysis. Inflammatory Bowel Diseases, izae051. Food and Drug Administration. Ulcerative Colitis: Developing Drugs for Treatment [Internet]. 2022 [cited 2024 Oct 17]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ulcerative-colitis-developing-drugs-treatment Rubin, D. T., Gottlieb, K., Colombel, J. F., Schott, J. P., Erisson, L., Prucka, B., . . . & McGill, J. (2023). Development of a novel ulcerative colitis Endoscopic Mayo Score prediction model using machine learning. Gastro Hep Advances, 2(7), 935-942.

The Stability-Indicating Ultra High-Performance Liquid Chromatography with Diode Array Detector and Tandem Mass Spectrometry Method Applied for the Forced Degradation Study of Ritlecitinib: An Appraisal of Green and Blue Metrics.

Janus kinase inhibitors open new horizons for small-molecule drugs in treating inflammatory bowel disease, with ritlecitinib demonstrating significant efficacy in clinical trials for ulcerative colitis and Crohn's disease. Ritlecitinib, a second-generation JAK3 inhibitor, is a novel therapeutic agent for alopecia areata and other autoimmune conditions. A new stability-indicating UHPLC-DAD-MS/MS method was developed, validated, and applied for a forced degradation study of ritlecitinib under ICH guidelines. The method demonstrated high specificity, sensitivity (LOD: 0.04 µg/mL; LOQ: 0.14 µg/mL), precision (RSD ≤ 0.15%), and accuracy (99.9-100.3%). Forced degradation studies under acidic, basic, oxidative, thermal, and photolytic conditions revealed four novel degradation products. Basic degradation followed second-order kinetics, while oxidative degradation followed zero-order kinetics. The validated method reliably characterized ritlecitinib's stability and degradation products, providing essential data for optimizing formulation, determining proper storage conditions, anticipating drug-excipient interactions, and ensuring quality control. The eco-friendliness and applicability of the developed forced degradation procedure were evaluated using various green and blue metric tools. Incorporating green analytical principles underscores its potential for sustainable pharmaceutical analysis.

An Analysis of the Effectiveness and Safety of Upadacitinib in the Treatment of Inflammatory Bowel Disease: A Multicenter Real-World Study.

Background and Aims: Inflammatory bowel disease (IBD) requires effective treatment options. Upadacitinib, a Janus kinase 1 (JAK1) inhibitor, has shown effectiveness in trials for Crohn's disease (CD) and ulcerative colitis (UC). This study evaluates its real-world effectiveness and safety. Methods: We conducted a multicenter retrospective cohort study in tertiary care centers, involving patients treated with upadacitinib from January 2023 to September 2024. The study included adult patients aged 18 years or older, diagnosed with UC or CD, who received at least 8 weeks of upadacitinib therapy. Treatment outcomes were evaluated using established clinical, endoscopic, imaging, histological, and laboratory parameters. Results: A total of 236 IBD patients received upadacitinib treatment. In 80 UC patients at 8 weeks, 64.0% achieved steroid-free remission, 57.6% clinical remission, and 81.8% response. Endoscopic remission was 35.8% (p = 0.039), with 63.3% response and 35.8% mucosal healing. Histological remission reached 29.2% (p = 0.009). For 156 CD patients at 12 weeks, 76.8% achieved steroid-free remission (p < 0.001), 77.8% clinical remission (p < 0.001), and 81.0% response. Mean CDAI decreased from 214.9 to 117.5 (p < 0.001). Endoscopic remission was 19.4%, with 48.9% response and 4.9% mucosal healing. Radiological remission was 9.1% with 85.7% response. Intestinal ultrasound showed 5.7% remission and 56.7% response. Conclusions: Upadacitinib demonstrates significant real-world effectiveness and safety in IBD, particularly in biologic-resistant cases, as evidenced by high rates of steroid-free remission and clinical response. These outcomes are likely due to its targeted JAK1 inhibition, which effectively reduces inflammation and promotes mucosal healing. Future research should focus on long-term safety, comparative effectiveness with other biologics, and its application in diverse patient populations. These findings support the integration of upadacitinib into IBD management strategies.

Assessment and reporting of extraintestinal manifestations and fatigue in phase 3 inflammatory bowel disease clinical trials.

Extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) are frequently experienced by patients and may lead to severe symptoms and fatigue. However, the reporting patterns of these outcomes in IBD randomized controlled trials (RCTs) are not clear. We searched placebo-controlled phase 3 RCTs of advanced therapies in IBD and assessed the frequency and means of reporting EIM and fatigue data in these studies. Thirty-three phase 3 RCTs for Crohn's disease (CD) (n = 16) or ulcerative colitis (UC) (n = 16) were identified between 2002 and 2023. While all trials (16/16) in CD collected some EIM data, we could only ascertain 6/16 (38%) collected EIM data in UC trials. Fewer than one-third (9/32, 28%) reported EIM prevalence at baseline; fewer reported the improvement with active treatment (9%). Fatigue was measured in 20/32 trials (63%). EIM and fatigue data are inconsistently collected in RCTs of IBD. Standardizing collection methods across RCTs would provide greater insight on these agents and their efficacy in treating these manifestations of disease.

Medical Therapies for Prevention and Treatment of Inflammatory Pouch Disorders-A Systematic Review and Meta-Analysis.

Pouchitis and Crohn's-like disease of the pouch (CLDP) are common in patients who undergo ileal pouch anal anastomosis for ulcerative colitis. We conducted separate systematic reviews to evaluate the effectiveness of available interventions to prevent and treat pouchitis and CLDP. Through systematic literature reviews, we identified studies that evaluated the effectiveness of probiotics, antibiotics, 5-aminosalicylates, nonsystemic oral corticosteroids, and advanced therapies for prevention and treatment of pouchitis and CLDP for meta-analysis. Primary outcomes were occurrence of pouchitis for pouchitis prevention and clinical response for pouchitis and CLDP treatment. We estimated the relative effectiveness of these interventions using the existing placebo response rates or hypothetical spontaneous improvement rates derived from clinical trials of pouchitis, ulcerative colitis, and Crohn's disease. Probiotics were effective for primary (relative risk [RR] 0.18; 95% confidence interval [CI] 0.05-0.62) and secondary prevention (RR 0.17; 95% CI 0.09-0.34) of pouchitis. Antibiotics were effective for treatment of acute and chronic pouchitis (12 cohorts; RR 1.67; 95% CI 1.34-2.01; response rate 65%; 95% CI 52-75) with ciprofloxacin and metronidazole-based regimens being more effective than rifaximin. Advanced therapies were effective for treatment of chronic antibiotic-refractory pouchitis (31 cohorts; RR 1.71; 95% CI 1.28-2.56; response rate 50%; 95% CI 43-57) and CLDP (10 cohorts; RR 2.49; 95% CI 1.87-3.73; response rate 74%; 95% CI 68-79) without significant difference between classes. Multiple medical interventions are effective for prevention and treatment of pouchitis and CLDP. Given the overall low quality of data, further research is needed to confirm these findings.

Review article: Novel therapies in inflammatory bowel disease - An update for clinicians.

Several new treatments including small molecules and biologics have been approved for the treatment of inflammatory bowel diseases in recent years. Clinicians and patients now have a wide variety of therapeutic options to choose from and these novel therapies provide several advantages including oral administration, lower immunogenicity, better selectivity and arguably better safety profiles. An increase in treatment options has increased the complexity of decision-making. Both patients and clinicians have had to become rapidly familiar with efficacy of new medications balanced against a range of pre-initiation requirements, dosing schedules and adverse event profiles. To provide a simple guide to practising clinicians on recently approved and emerging therapies and address key challenges around treatment strategies such as optimal sequencing and timing of treatment. We comprehensively searched the published literature and major conference abstracts to identify phase III placebo-controlled and active comparator trials for Crohn's disease and ulcerative colitis. Data for recently approved therapies including selective Janus kinase inhibitors, sphingosine-1 receptor modulators and p19 interleukin (IL)-23 inhibitors have demonstrated improved patient outcomes in both Crohn's disease and ulcerative colitis. Further comparative head-to-head studies have improved our understanding of when and how to optimally use newer therapies, specifically for IL-23 inhibitors. Data for emerging treatment options and novel treatment strategies such as early effective treatment, combinations of treatments and implications for sequencing are continuing to transform IBD care continually. Recently approved novel therapies have expanded the range of medical options available to treat IBD. However, further data from long-term extension studies, real-world studies and head-to-head trials are warranted to better inform the long-term safety and optimal sequencing of treatments for patients living with IBD.

Analysis of the outcomes in treatment of ulcerative colitis with acupuncture and moxibustion

To clarify the key outcomes of acupuncture-moxibustion treatment of ulcerative colitis. The clinical randomized controlled trials (RCTs) for ulcerative colitis treated with acupuncture and moxibustion were searched from CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, and Web of Science, from the inception of each database to March 20th, 2023. The basic information of literature, intervention measures and outcome indexes were collected. The selection of primary and secondary outcomes, the use frequency of each index and the combination of them in utility were analyzed; and index domains of acupuncture and moxibustion for ulcerative colitis were summarized. A total of 215 RCTs were included and 54 outcomes were involved, classified into 6 categories, i.e. TCM syndromes, symptoms/physical signs, physical and chemical tests, quality of life, long-term prognosis and safety events. The top 3 outcomes with high use frequency were clinical effect evaluation, adverse reactions of acupuncture and moxibustion and the score of main symptoms. Only 3 articles clearly reported the primary outcome and the secondary ones, 180 articles used two types of outcomes simultaneously, 3 articles clearly described the time points of the observation indexes, and 126 articles determined the sources of the evaluation criteria of therapeutic effect, with 57 criteria involved. At present, the outcomes have not been standardized in RCTs of acupuncture and moxibustion for ulcerative colitis. It needs to clarify the primary one and the secondary ones. The criteria have not been unified for the evaluation of therapeutic effects and there is less consideration on the quality of life in patients, the follow-up visit and safety events. The attention should be paid to develop the outcome set, in which, the endoscopic score is taken as the objective, and the improvements in the symptoms/physical signs and the biochemical examination as the supplementary.

Defining mucosal healing in randomized controlled trials of inflammatory bowel disease: A systematic review and future perspective.

Mucosal healing (MH) is an established treatment goal in inflammatory bowel disease (IBD). However, various definitions of MH exist. We aimed to identify how MH is defined in randomized controlled trials (RCTs) in ulcerative colitis (UC) and Crohn's disease (CD). We searched MEDLINE, EMBASE, and the Cochrane library from inception to December 2023 for phase 2 and 3 RCTs of advanced therapies in IBD. One hundred forty-four studies were included, 72 in UC and 72 in CD, published between 1997 and 2023. In UC, 64% (46/72) RCTs reported MH as an endpoint. 12 definitions of MH were found, from endoscopic assessment alone (35/46; 76%) to the more recent combination of histology and endoscopy (10/46; 22%). 96% (44/46) of studies used the Mayo Endoscopic Subscore. In CD, reporting of MH lagged behind UC, with only 12% (9/72) of trials specifically defining MH as an endpoint, 7 as "absence of ulceration," 2 as Simplified Endoscopic Score for CD score ≤2 or 0. Histological assessment was performed in 3 RCTs of CD. Centralized reading of endoscopy was used in 48% (35/72) of RCTs of UC and 22% (16/72) of CD. Only 1 RCT included transmural healing as an endpoint. A standard definition of MH in IBD is lacking. Definitions have evolved particularly in UC, which now includes the addition of histological evaluation. Transmural healing holds promise as a future target in CD. We support a greater standardization of definitions as we expect endpoints to become increasingly stringent and multimodal with computers automating the assessment.

S899 The Role of Video Quality in Central Reader Disagreement in Assessment of the Endoscopic Mayo Score in Ulcerative Colitis Trials

S899 The Role of Video Quality in Central Reader Disagreement in Assessment of the Endoscopic Mayo Score in Ulcerative Colitis Trials

Screen Failures and Causes in Inflammatory Bowel Disease Randomized Controlled Trials: A Study of 16913 Screened Patients.

While recruitment rates in inflammatory bowel disease (IBD) trials are continuously decreasing, the underlying reasons are likely multifactorial but remain poorly defined. Screen failure (SF) proportions and causes have not been extensively explored in IBD. We assessed SF proportions and underlying SF reasons in IBD phase 2 and 3 clinical trials. We analyzed SF-related data from 17 randomized controlled phase 2 or 3 IBD trials. Twelve trials were in ulcerative colitis (UC) and 5 trials were in Crohn's disease (CD) operated by a single contract research organization, IQVIA. Differences between patient groups were tested for significance by Mann-Whitney and Fisher's tests when appropriate. We analyzed a total of 11 161 patients with UC and 5752 patients with CD. The mean SF proportion was 0.43 per trial in UC. The primary reason for SFs in UC was not meeting the overall (modified) Mayo score inclusion threshold and/or the endoscopic subscore of at least 2 (33.8% of all SF). In CD clinical trials, the mean SF proportion was at 0.53. The primary cause for SFs was not meeting the CDAI eligibility criteria (23.1% of all SFs). SF proportions were significantly higher in CD versus UC trials (P = .027). Clostridium difficile or any other intestinal infection and not meeting tuberculosis screening criteria were other major reasons for SFs both in UC and CD. High SF proportion in IBD clinical trials, particularly for CD studies, pose obstacles to patient recruitment. While underlying causes are diverse, arbitrarily defined clinical and/or endoscopic eligibility criteria remain the major limiting factors.

Efficacy and Safety of Etrasimod in Patients with Ulcerative Colitis in Japan: Data from the Phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN Trials

Introduction: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we report the primary analysis of a phase 3 trial evaluating the efficacy and safety of etrasimod in patients from Japan with moderately to severely active UC. Methods: Patients from Japan who completed the 12-week ELEVATE UC 12 induction trial could enroll in the 40-week ELEVATE UC 40 JAPAN maintenance trial for a combined 52-week treatment period. Patients in this Japan cohort continued their baseline assigned treatment (etrasimod 2 mg QD or placebo) from ELEVATE UC 12. Efficacy was assessed at week 12 and week 52. Treatment-emergent adverse events (TEAEs) pooled from both trials were assessed up to 52 weeks of exposure. Results: The Japan cohort comprised 32 and 16 patients who received etrasimod and placebo, respectively. A numerically greater proportion of patients who received etrasimod versus placebo achieved clinical remission at week 12 (etrasimod: 14.3%; placebo: 7.1%) and week 52 (etrasimod: 25.0%; placebo: 7.1%); a similar trend was observed for all key secondary efficacy endpoints. TEAEs occurred in 84.4% (27/32) and 62.5% (10/16) of patients who received etrasimod and placebo, respectively. No new safety signals were detected. Conclusion: In these induction and maintenance trials evaluating etrasimod in patients from Japan with UC, numerically higher proportions of patients who received etrasimod versus placebo achieved efficacy endpoints. Efficacy and safety findings were consistent with those from the global ELEVATE UC trial populations.

HLA-DQA1*05 Associates With Anti-Tumor Necrosis Factor Immunogenicity and Low Adalimumab Trough Concentrations in Inflammatory Bowel Disease Patients From the SERENE Ulcerative Colitis and Crohn's Disease Studies.

Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's disease (CD) and ulcerative colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADAs). Understanding the factors associated with immunogenicity in anti-TNF-treated patients can help guide treatment. The Humira SERENE studies were Phase 3 trials investigating adalimumab induction regimens in CD and UC patients. We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We then tested these alleles for association with time to immunogenicity. Subsequently, we tested loci significantly associated with immunogenicity for their association with patients who had consistently low drug serum concentrations. This study replicated the association of HLA-DQA1*05 with time to immunogenicity (hazard ratio [HR] 1.42, p = 2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, p = 2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, p = 2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 was associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05: odds ratio [OR] 1.98, p = 0.0049; HLA DRB1*01:02: OR 7.06, p = 7.44E-05). We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug serum concentrations in large clinical studies of CD and UC patients. This work extends previous findings in CD to UC and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest that genetic screening could be a useful tool for clinicians concerned with patient anti-TNF immunogenicity. SERENE CD (NCT02065570), SERENE UC (NCT02065622).

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.

Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme.

Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. Patients, including those with isolated proctitis (<10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p < 0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52. Clinicaltrials.gov: NCT03945188; NCT03996369.