Ulcerative Colitis Trials Research Articles

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.

Quality of reporting of integrative Chinese and Western medicine intervention in randomized controlled trials of ulcerative colitis: a review

BackgroundIntegrative Chinese and Western medicine (ICWM) is commonly used for the treatment of ulcerative colitis (UC) in clinical practice. However, it is unclear whether the details of ICWM interventions, such as selection rationale, implementation design, and potential interactions, were adequately reported. Therefore, this study aimed to assess the quality of reporting in the ICWM interventional randomized controlled trials (RCTs) of UC and to identify the common problems if any.MethodsThrough a search of 10 international electronic databases, we identified RCTs of UC with ICWM interventions published in English or Chinese from the inception date of each database up to 16 June 2023. Literature screening was strictly conducted based on the inclusion and exclusion criteria of the Population, Concept, and Context (PCC) framework. The general characteristics of the included studies were described. The quality of reporting was assessed according to three checklists, including the CONSORT (Consolidated Standards of Reporting Trials) with 36 items (except for one item 1b about abstract), the CONSORT for s (17 items), and a self-designed ICWM-related checklist (27 items covering design rationale, intervention details, outcome assessments, and analysis). The reporting scores of RCTs published before and after 2010 were compared.ResultsA total of 1458 eligible RCTs were included. For the reporting compliance, the median score (interquartile ranges) of the CONSORT (72 score in total), the CONSORT for (34 score), and ICWM-related (54 score) items was 21 (18–25), 13 (12–15), and 18 (15–21), respectively. Although the time period comparisons showed that reporting quality of included publications improved significantly after the CONSORT 2010 issued (P < 0.01), more than 50% of items were evaluated as poor quality (reporting rate < 65%) among each checklist, especially in the CONSORT for and ICWM-specific items.ConclusionAlthough CONSORT appears to have enhanced the reporting of RCTs in UC, the quality of ICWM specifics is variable and in need of improvement. Reporting guidelines of the ICWM recommendations should be developed to improve their quality.

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.

Managing Ulcerative Colitis and Crohn's Disease: Should the Target Be Endoscopy, Histology, or Both?

In inflammatory bowel disease (IBD), mucosal healing is the primary long-term treatment goal, encompassing both endoscopic and histological outcomes. This paper aims to overview the ability of new treatment options to promote endoscopic and histological healing and to discuss the prognostic significance of endoscopic and histological outcomes. The analysis included randomized-controlled trials (published since 2020) focused on the impact of pharmacological interventions on endoscopic and histological remission in IBD. Even though the Mayo endoscopic subscore is routinely used, the application of validated scoring systems for ulcerative colitis is uncommon. In Crohn's disease (CD), the application of endoscopic scores remains limited to clinical studies. The standardized evaluation of histological features has been performed in several recent ulcerative colitis trials, resorting mostly to the Geboes score and the Nancy histological index. Still, the use of histological scores for CD remains elusive. Current evidence underscores that histological remission conveys the best long-term prognosis, supporting the inclusion of histology as a treatment guide in ulcerative colitis. In CD, data are promising but originated from a few retrospective studies. Further efforts are warranted to: (1) use validated histological indexes for ulcerative colitis, aiming their adoption as treatment targets; (2) promote the validation and utilization of histological scores for CD, at least in clinical studies; (3) confirm the prognostic impact of histological remission in CD; (4) integrate artificial intelligence assets to support grading, particularly in the setting of histology; (5) prospectively define the monitoring frequency of IBD patients who achieved histological remission.

Generation and Characterization of Mirikizumab, a Humanized Monoclonal Antibody Targeting the p19 Subunit of IL-23.

Interleukin (IL)-23 exists as a heterodimer consisting of p19 and p40 and is a key cytokine for promoting inflammatory responses in a variety of target organs. IL-23 plays a key role in the differentiation and maintenance of T helper 17 cells, and deregulation of IL-23 can result in autoimmune pathologies of the skin, lungs, and gut. This study describes the generation and characterization of mirikizumab (miri), a humanized IgG4 monoclonal antibody directed against the p19 subunit of IL-23. Miri binds human and cynomolgus monkey IL-23 with high affinity and binds rabbit IL-23 weakly but does not bind to rodent IL-23 or the other IL-23 family members IL-12, IL-27, or IL-35. Miri effectively inhibits the interaction of IL-23 with its receptor, and potently blocks IL-23-induced IL-17 production in cell-based assays while preserving the function of IL-12. In both local and systemic in vivo mouse models, miri blocked IL-23-induced keratin mRNA or IL-17 production, respectively. These data provide a comprehensive preclinical characterization of miri, for which efficacy and safety have been demonstrated in human clinical trials for psoriasis, ulcerative colitis, and Crohn's disease. SIGNIFICANCE STATEMENT: This article describes the generation and characterization of mirikizumab, a high affinity, neutralizing IgG4 variant monoclonal antibody that is under development for the treatment of ulcerative colitis and Crohn's disease. Neutralization of interleukin (IL)-23 is achieved by preventing the binding of IL-23 p19 subunit to the IL-23 receptor and does not affect the IL-12 pathway.

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.

A Comparison of Treatment Effect Sizes in Matched Phase 2 and Phase 3 Trials of Advanced Therapeutics in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.

Phase 2 trials are fundamental to the rational and efficient design of phase 3 trials. We aimed to determine the relationship of treatment effect size estimates from phase 2 and phase 3 clinical trials on advanced therapeutics in inflammatory bowel disease. MEDLINE, EMBASE, CENTRAL, and the Cochrane library were searched from inception to December 19, 2022, to identify paired phase 2 and 3 placebo-controlled induction studies of advanced therapeutics for Crohn's disease (CD) and ulcerative colitis (UC). Treatment effect sizes were expressed as a risk ratio (RR) between the active arm and placebo arm. For the same therapeutics, RRs from phase 2 trials were divided by the RR from phase 3 trial to quantify the relationship of effect sizes between phases. Twenty-two studies (9 phase 2 trials, 13 phase 3 trials) were included for CD and 30 studies (12 phase 2 trials, 18 phase 3 trials) for UC. In UC (pooled RR 0.72; 95% confidence interval: 0.58-0.86; RR <1 indicates smaller treatment effect sizes in phase 2 trials), but not CD (pooled RR 1.01; 95% confidence interval: 0.84-1.18), phase 2 trials systematically underestimated treatment effect sizes for the primary endpoint compared with phase 3 trials. The underestimation was observed for clinical, but not endoscopic, endpoints in UC. Treatment effect sizes for the primary and clinical endpoints were similar across clinical trial phases in CD, but not UC, where only endoscopic endpoints were comparable. This will help inform clinical development plans and future trial design.

Obefazimod: A First-in-class Drug for the Treatment of Ulcerative Colitis.

Biologic agents and oral small molecules are the mainstays of inflammatory bowel disease [IBD] management. However, an unmet clinical need remains for additional agents with novel mechanism of action which are effective, safe, and disease-modifying; this is due to the substantial proportion of patients who do not respond, lose response, or develop intolerance to currently marketed products. microRNAs [miRNAs] that play a role in the modulation of signal transduction pathways implicated in the development of IBD hold the potential to be used as therapeutic targets. Recently, a novel first-in-class compound, obefazimod, originally conceived as a human immunodeficiency virus [HIV] infection drug, has shown great promise in phase II induction trials for ulcerative colitis [UC] patients. Findings from the maintenance phases of trials showed that long-term obefazimod treatment provides continued improvement in clinical symptoms of disease, with a substantial proportion of patients in clinical remission, and an overall good safety profile. With a novel mechanism of action, obefazimod is an orally available small molecule with anti-inflammatory properties through the specific and selective upregulation of miR-124 expression. The aim of this paper is to critically review the available evidence related to pharmacokinetics and pharmacodynamics, and to discuss the potential clinical implications of this first-in-class oral small molecule.

A167 HISTOLOGICAL REMISSION PLACEBO RATES IN ULCERATIVE COLITIS TRIALS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background High histologic remission rates have been reported with placebos in randomized controlled trials (RCTs) evaluating ulcerative colitis (UC) therapies and have varied based on trial designs. We performed a systematic review and meta-analysis to quantify placebo histological remission rates and identify factors influencing those rates. Purpose This systematic review aims to improve future trials design and minimize placebo rates in UC trials. Method MEDLINE, EMBASE, and the Cochrane library were searched from inception of the databases until December 2021. We included placebo-controlled RCTs of adult patients with UC treated with aminosalicylates, corticosteroids, immunosuppressives, biologics, and small molecules. We pooled estimates using a random-effects model and performed subgroup analysis as well as meta-regression to evaluate the effect of different covariates on placebo rates. Result(s) Thirty-three studies (30 induction and 3 maintenance) were included. The overall placebo histological remission rate was 15.7% [95% CI 12.9-19%] across all 33 studies (Figure). High heterogeneity was observed among studies with I2 = 62.10%. In induction studies, the pooled estimate of histological remission was 15.8% [95% CI 12.7-19.5%], while in maintenance studies the pooled estimate was 14.5% [95% CI 8.4-24%]. Subgroup analysis revealed statistically significant differences in placebo rates when accounting for background medications, the intervention drug class, and disease severity [p= 0.041, 0.025, and 0.025, respectively]. There was no statistical difference between induction vs. maintenance studies or between different histological scales [p= 0.771, and 0.075, respectively]. Meta-regression showed similar results except that the therapy used was not statistically significant [p-value= 0.059]. Image Conclusion(s) Placebo histological remission rates range from 13-19% in UC RCTs, but studies are highly heterogeneous. Factors found to influence placebo rates include presence of background medications, the drug used and the disease severity in UC patients. These observations have important implications in informing future trial designs to minimize placebo rates and reduce heterogeneity. Disclosure of Interest M. Youssef: None Declared, K. Dong: None Declared, S. J. Lee: None Declared, N. Narula Speakers bureau of: received honoraria from Janssen, Abbvie, Takeda, Pfizer, Merck, Sandoz, Novartis, and Ferring

Ulcerative Colitis-Symptom Questionnaire: Valid for Use in Adults with Moderately to Severely Active Ulcerative Colitis

BackgroundDue to wide-ranging impacts of Ulcerative Colitis (UC), regulatory authorities emphasize the importance of including validated patient-reported symptom severity measures in clinical trials.AimTo describe the development and validation of the Ulcerative Colitis-Symptom Questionnaire (UC-SQ).MethodsThe UC-SQ was developed in a qualitative study involving a targeted literature review, semi-structured concept elicitation interviews, and combined concept elicitation/cognitive interviews. Measurement properties, including item-level analyses, factor structure, reliability, validity, responsiveness, and clinically meaningful change were evaluated using data from a phase 2b, randomized trial in adults with UC (N = 113).ResultsFourteen symptom concepts were elicited across 22 interviews, with saturation at the fifth interview. Twenty-two items were unmodified as cognitive interview participants interpreted underlying concepts correctly. Instructions were clear and items were relevant, with appropriate response options and recall periods. Reduction to 17 items was completed prior to psychometric testing. Two items (joint pain/constipation) did not contribute to reliability in initial testing and were included as non-scored items. The 15-item UC-SQ showed evidence of internal consistency (α = 0.86) and test–retest reliability (intraclass correlation coefficient = 0.88). The UC-SQ discriminated by disease severity as defined by Mayo and Inflammatory Bowel Disease Questionnaire scores (p < 0.0001). Convergent validity was supported by strong correlations with criterion measures. The UC-SQ was responsive in patients indicating change in other measures. A 10-point decrease from baseline indicated within-patient meaningful improvement.ConclusionsThe UC-SQ is reliable, valid and responsive, with a 10-point improvement estimating within-patient clinically meaningful improvement. The tool is fit-for-purpose as a key endpoint in pivotal UC trials.

Histological Remission Placebo Rates in Ulcerative Colitis Trials: A Systematic Review and Meta-analysis.

High histologic remission rates have been reported with placebos in randomized controlled trials (RCTs) evaluating ulcerative colitis (UC) therapies and have varied based on trial designs. We performed a systematic review and meta-analysis to quantify placebo histological remission rates and identify factors influencing those rates. MEDLINE, EMBASE, and the Cochrane library were searched from inception of the databases until December 2021. We included placebo-controlled RCTs of adult patients with UC treated with aminosalicylates, corticosteroids, immunosuppressives, biologics, and small molecules. We pooled estimates using a random-effects model and performed subgroup analysis and meta-regression to evaluate the effect of different covariates on placebo rates. Thirty-three studies (30 induction and 3 maintenance) were included. The overall placebo histological remission rate was 15.7% (95% confidence interval, 12.9%-19%) across all 33 studies. High heterogeneity was observed among studies with I2 = 62.10%. The pooled estimate of histological remission was 15.8% in induction studies and 14.5% in maintenance studies. Subgroup analysis revealed statistically significant differences in placebo rates when accounting for background medications, the intervention drug class, and disease severity (P = .041, .025, and .025, respectively). There was no statistical difference between induction vs maintenance studies or between different histological scales (P = .771, and .075, respectively). Placebo histological remission rates range from 13% to 19% in UC RCTs, but studies are highly heterogeneous. Factors found to influence placebo rates include presence of background medications, the drug used, and the disease severity. These observations inform future trial designs to minimize placebo rates and reduce heterogeneity.

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.

P814 Clinical trial design in Crohn’s disease: interpreting future endpoints based on post hoc analyses of the vedolizumab phase 3 trials GEMINI 2 and VISIBLE 2

Abstract Background Crohn’s disease (CD) is a chronic, relapsing–remitting disease characterized by inflammation of the gastrointestinal tract. Historically, the Crohn’s Disease Activity Index (CDAI) has been used to assess outcomes in clinical trials involving patients with CD. However, in contrast to the alignment of regulatory standards for trials in ulcerative colitis, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) differ regarding the most appropriate endpoint definitions for trials in CD. We examined how clinical remission endpoints in CD trials have evolved and conducted post hoc analyses of two vedolizumab trials, GEMINI 2 and VISIBLE 2, to understand how endpoint definitions influence clinical trial outcome measures of treatment efficacy. Methods Endpoint definitions of clinical remission in completed and ongoing phase 3 trials of advanced therapies in CD were extracted from published literature and ClinicalTrials.gov. Post hoc analyses of data from GEMINI 2 and VISIBLE 2 were conducted by measuring the difference (%Δ) between the proportions of patients achieving clinical remission with vedolizumab versus placebo at week 52 as assessed by six endpoint definitions (A: stool frequency score [SFS] ≤ 2.8 and not worse than baseline score; B: SFS ≤ 3 and not worse than baseline score; C: abdominal pain score (APS) ≤ 1 and not worse than baseline score; D: SFS ≤ 2.8 and APS ≤ 1; E: SFS ≤ 3 and APS ≤ 1; F: CDAI ≤ 150) (Figure 1). Results Most phase 3 trials of advanced therapies in CD included a clinical remission endpoint that was defined by CDAI score: typically, CDAI &amp;lt; 150 or ≤ 150. However, several recent trials have also included a primary or secondary clinical remission endpoint defined using components of the CDAI score such as SFS and APS (Table 1). Post hoc analyses of GEMINI 2 and VISIBLE 2 revealed minimal change in %Δ for each of the new endpoint definitions tested compared with the primary analysis for each trial (Figure 1). Conclusion Objective measures, including patient-reported outcomes and components of the CDAI score such as SFS and APS, have been used to define clinical remission in recent CD trials. Despite differences in regulatory guidance for defining clinical remission, our post hoc analyses of GEMINI 2 and VISIBLE 2 reveal that the efficacy of vedolizumab, measured using a variety of endpoint definitions from recent CD trials, was similar to that previously reported using CDAI ≤ 150.

P111 Efficacy of a novel long-acting lipidated interleukin-22, alone and in combination with anti-TNF treatment, in a murine chronic DSS colitis model

Abstract Background Most current treatments and new agents in clinical development for Inflammatory Bowel Disease focus on inhibition of excessive inflammation. However, to break the ceiling on current clinical remission rates, new approaches, for example targeting mucosal healing, are needed. The cytokine interleukin-22 (IL-22) plays a key role in epithelial healing and has early proof-of-concept as a potential drug class in a phase 1 trial in Ulcerative Colitis. Here we present results from a mouse model of colitis demonstrating the efficacy of IL-22 agonism and complementarity with existing immunomodulatory treatment options. Methods Eight-week-old female C57Bl/6N mice (n=56) were subjected to a DSS-induced model of colitis; mice were given 2% (weight/volume) DSS in the drinking water for three 7-day cycles followed by 7 days of regular drinking water. Mice were treated from day 18 until the end of study with either vehicle, lipidated IL-22, an anti-murine TNF antibody at a suboptimal dose, a combination of the lipidated IL-22 and anti-TNF, and, as positive control, anti-murine TNF at an optimal dose. Colitis severity was monitored during the study and at study end endoscopic scoring was performed. Colon length and weight were measured, and histological analysis on formalin-fixed paraffin sections performed by a blinded pathologist. Results At termination, all treatment groups showed reduced body weight loss and improved DAI scores compared to vehicle treated animals, which was significant for all but the suboptimal anti-TNF group. Combination treatment resulted in an additive treatment effect compared to single treatment alone, with mean DAI improving by 13% and 48% for the anti-TNF and IL-22 groups alone versus 68% in combination. Similar effects were observed for the endoscopic and histological scores. The compositive endoscopic score improved by 21% (anti-TNF) and 55% (IL-22) versus 66% for the combination, and histological scores 22% and 52% versus 66%. These combination results likely represent the maximum response that can be achieved in the model, since the improvements obtained are the same as those for the treatment positive control for the model (68% and 62% improvements in endoscopic and histological scores, respectively). Conclusion A novel long-acting lipidated IL-22, which acts on epithelial repair mechanisms, demonstrated strong and significant improvements on all measured parameters in a chronic DSS model of colitis. Combining the IL-22 mode-of-action with an immunomodulatory agent, exemplified by a murine anti-TNF antibody, demonstrated the complementarity of IL-22 agonism to existing treatment options. Clinical trials to assess safety and tolerability of lipidated IL-22 are expected to commence at the start of 2023.

P314 Microscopic appendicitis in ulcerative colitis: Feasibility of ultrasonographic diagnosis

Abstract Background Increasing evidence suggests appendectomy as potential alternative treatment in patients with ulcerative colitis (UC), especially in those with histological appendiceal inflammation (AI). Intestinal ultrasound (IUS) is a non-invasive diagnostic modality that detects differences in the appendix between UC patients and healthy controls1. This study aimed to correlate appendiceal IUS and endoscopic findings to histopathological inflammation in resection specimens of UC patients undergoing appendectomy. Methods In this prospective cohort study, appendiceal IUS was performed in UC patients undergoing endoscopy and subsequent appendectomy between 2020 and 2022 in a trial for UC (NCT03912714). Primary outcome was the correlation between an increased maximal cross-sectional diameter (MCD, ≥ 6 mm) and AI in patients with a visible appendix on IUS. Presence of AI was assessed in pathology reports. Patients with fibrosis (F) were excluded from IUS analyses. Secondary outcomes included bowel wall thickness (BWT) on IUS and presence of endoscopic peri-appendiceal red patch (PARP) before appendectomy. Results In total, 32 UC patients who underwent laparoscopic appendectomy in study setting were included (84% female, median age 40 [IQR 27-50] years). The majority of patients demonstrated left sided disease (38%) and a mayo score ≥ 2 (88%) on baseline endoscopy. A median window between ultrasound and appendectomy of 1.2 (0.1-2.1) months was found. A total of eighteen (56%) patients were demonstrated to have AI in the resection specimen, and five (16%) patients demonstrated F. The appendix was visualised on IUS in 25 (78%) UC patients, with no difference in patients with AI (AI: 78%, no AI: 78%, p= 1.0). The overall median MCD and BWT were 5.6 [IQR 4.4-6.6] and 2.2 [1.6-2.5] mm, respectively. Patients with AI demonstrated a numerically higher median MCD (AI: [6.0 [4.2-6.8], no AI: 4.9 [4.4-5.8] mm, p= 0.3). Patients with an increased MCD were more likely to demonstrate pathologic AI, although not significant (OR: 6.0, CI 95%: 0.6-63.7, p=0.1). A minority of patients with AI demonstrated to have an endoscopic PARP: 5/18 (28%). The median MCD of patients with PARP was numerically higher (PARP: 6.0 [IQR 4.4-7.8] vs no PARP: 5.5 [4.0-6.6], p=0.5). Conclusion IUS is a feasible modality for assessment of the appendix. Although significance was not reached, patients with an increased MCD were more likely to demonstrate AI. 1Reijntjes MA, de Voogd FAE, et al. Intestinal ultrasound detects an increased diameter and submucosal layer thickness in the appendix of patients with ulcerative colitis compared to healthy controls - a prospective cohort study. Aliment Pharmacol Ther. 2022 Nov 1.

DOP73 Predicting endoscopic improvement in Ulcerative Colitis using the Ulcerative Colitis Severity Index (UCSI)

Abstract Background Scoring indices used in clinical trials for moderate-severe ulcerative colitis (UC) may lack specificity as a prognostic tool. We developed and internally validated a prognostic scoring index for UC patients on therapy that considers baseline patient-reported outcomes, biomarkers, endoscopy, and histology for achieving one-year endoscopic improvement (EI). Methods This post-hoc analysis of the UNIFI clinical trial (ClinicalTrials.gov identifier: NCT02407236) included 644 patients treated with ustekinumab induction therapy. Data were randomly split into 70% training and 30% testing cohorts. Baseline variables were assessed in multivariate analyses and variables with p &amp;lt;0.05 were assigned weights according to their relative prognostic value for predicting one-year EI (Mayo endoscopic score (MES) ≤1). A cut-off was obtained by calculating the maximum Youden index and validated in the testing cohort. Results Prior biologic failure, albumin &amp;lt; 40 g/L, CRP &amp;gt; 5mg/L, Mayo stool frequency (SF) subscore, endoscopic erosions/ulcerations based on the UC Endoscopic Index of Severity, and histologic structural/architectural changes demonstrated significant associations with one-year EI and included in the final model. The Ulcerative Colitis Severity Index (UCSI) was generated (Table 1) and the median UCSI score among all participants was 10.4 (IQR 7-14.4, range: 2.2-20), which had acceptable discriminative ability for one-year EI in the training [AUC: 0.78 (95% CI: 0.70-0.86)] and testing cohort [AUC: 0.76 (95% CI: 0.68-0.85)] (Table 2). Compared to the UCSI, the Mayo score demonstrated poor accuracy [AUC: 0.49 (95% CI: 0.40-0.58)] for predicting one-year EI (p=0.0006). The UCSI also predicted one-year endoscopic healing (MES of 0), clinical remission (total Mayo score ≤2 and no subscore &amp;gt;1), partial Mayo score (PMS) remission (PMS &amp;lt; 2), and PRO-2 remission (SF and rectal bleeding subscore of 0) with significantly greater accuracy compared to the Mayo score. Similar findings were observed when the UCSI was compared with the adapted Mayo score. The maximum Youden index corresponded to a cut-off of 10. Participants with a UCSI ≥10 had a lower probability of one-year EI [27/104 (26%) vs. 40/76 (52.6%)]. Performance characteristics are detailed in Tables 3 and 4. Conclusion The UCSI is an internally validated prognostic scoring tool that accurately predicts one-year EI at baseline among patients with moderate-to-severe UC on active therapy. The UCSI demonstrated greater accuracy for one-year EI, EH, and clinical remission compared to the total and adapted Mayo score. The UCSI could improve disease management in UC by stratifying patients based on their predicted likelihood of long-term outcomes.

P696 Design and rationale for the multicentre, randomised, controlled VERDICT trial to determine the optimal treatment target in patients with ulcerative colitis

Abstract Background Symptoms, endoscopy, histology, and biomarkers are used to evaluate disease activity and response to therapy in ulcerative colitis (UC). Histologic disease activity may persist in ~25% of patients with normal-appearing endoscopic mucosa, and observational studies demonstrate an association between the achievement of histologic remission (vs endoscopic remission alone) and a lower risk of complications. These findings suggest that histologic remission may be a distinct treatment target. The aim of the VERDICT trial is to determine the optimal treatment target in UC to inform clinical practice and future drug development. Methods The primary objective of the multicentre, randomised, controlled VERDICT trial (Figure 1) is to determine whether a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone in moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score &amp;lt;2B.0) + endoscopic remission + symptomatic remission (Group 3). Therapy is administered according to a treatment algorithm that is dependent on each patient’s existing UC treatment regimen at study entry (Figures 2-4). Early introduction of vedolizumab and dose escalation to a maximum of 300 mg every 4 weeks until the assigned treatment target is reached are central to each algorithm. There are 3 opportunities, 16 weeks apart (weeks 16, 32, or 48), to achieve the treatment target. Urine, stool, mucosa, and serum samples are collected at these follow-up time points and at baseline for subsequent biomarker and prediction model development. Results The primary efficacy outcome is the time from treatment target achievement to a UC-related complication, defined as a UC-related hospitalisation, colectomy, need for rescue therapy, or treatment-related or other complication. This composite outcome will be compared among treatment target Groups 1 and 3 using the Cox proportional hazard model analysis. The trial was initiated in September 2020, and 660 patients are planned for enrolment. Of these, ~50% are currently enrolled at 55 sites across 10 North American and European countries. Prespecified interim analyses will be conducted when the first 50 patients in each group reach weeks 16, 32, and 48. Conclusion The VERDICT trial in active UC is designed to determine the optimal treatment target to inform clinical practice, drug trials, and future evidence-based recommendations.

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.

The IL7R-Antagonist OSE-127 Blocks Acute Lymphoblastic Leukemia Development Via a Dual Mode of Action

Acute lymphoblastic leukemia (ALL) may arise from precursor B or T cells (BCP- and T-ALL, respectively) and treatment is based on polychemotherapy. There is an urgent need for novel immunotherapy targets to reduce therapy toxicity and to target relapsed/refractory (r/r) disease, especially in T-ALL where immunotherapy approaches are scarce. The Interleukin-7-receptor (IL7R) has been shown to play a pivotal role in the development of both BCP-ALL and T-ALL (Geron et al. 2022; Silva et al. 2022). The IL7Rα-chain (CD127)-targeting antibody OSE-127 has a good safety profile in healthy volunteers (NCT03980080) and has entered phase 2 trials in Ulcerative Colitis (NCT04882007) and Sjögren's syndrome (NCT04605978). We previously reported high preclinical efficacy of OSE-127 in BCP-ALL patient derived xenograft (PDX) models of different cytogenetic backgrounds (Lenk and Baccelli et al. ASH, 2021). However, the preclinical efficacy of OSE-127 in T-ALL had not yet been investigated and the mechanism of action underlying its anti-leukemic efficacy remained unclear. First, we investigated the in vivo efficacy of OSE-127 treatment on BCP-ALL and T-ALL cells by conducting a preclinical phase 2-like PDX study. Two NSG mice per patient were injected with BCP-ALL (n=13) or T-ALL (n=9) PDX cells (including 7 r/r ALL samples), randomly assigned into treatment groups and OSE-127 therapy was initiated when 1% leukemic blasts were detected in the peripheral blood (PB). OSE-127 treated mice showed a reduction of PB blasts in 21/22 (95%) PDX samples in vivo when the corresponding control mice showed clinical signs of overt leukemia (Figure 1A). This translated into a 1.6-fold prolongation of median survival (MS) of OSE-127 treated PDX mice (P<0.0001, Figure 1B). Of note, blast reduction strongly correlated with CD127 expression levels in the samples (Pearson r=0.5372, P=0.0099). Next, we characterized the mode of action of OSE-127. As expected, OSE-127 blocked STAT5 phosphorylation in IL7-dependent ALL cell lines and PDX samples. As OSE-127 is not internalized by CD127 expressing cells (Belarif et al. 2018), we investigated whether OSE-127 might also exert immune-mediated effects. We found that OSE-127 did not promote antibody-dependent cellular cytotoxicity (ADCC), but efficiently induced macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) in BCP- and T-ALL cell lines and PDX cells in vitro, in a manner dependent on CD127 expression levels (Pearson r=0.5000, P=0.0352, Figure 1C-D). In line with these observations, inactivating mutations of the Fc fraction of OSE-127 (OSE-127-LALAPG) prevented ADCP of ALL cells in vitro, while conserving its antagonistic properties on IL7R signaling. To further evaluate the contribution of ADCP to the anti-leukemic activity of OSE-127, we compared the in vivo efficacy of OSE-127 and OSE-127-LALAPG in ALL samples with dysfunctional IL7R signaling (e. g., DND41 cells showing constitutive pathway activation due to IL7Rα mutations or NALM6 cells being absent of P-STAT5 induction upon IL7 stimulation). In this context, OSE-127-LALAPG did not impact leukemic engraftment as compared to control treatment, while OSE-127 significantly reduced leukemic burden, thereby substantiating that ADCP contributes to the anti-leukemic efficacy of OSE-127 (Figure 1E). Finally, we conducted a phase2-like PDX overt leukemia study testing OSE-127 alone or in combination with Dexamethasone/Vincristine/PEG-Asparaginase chemotherapy employing PDX samples with high CD127 expression (6 BCP-ALL and 3 T-ALL-PDX samples with >50% CD127+ cells in flow cytometry analysis). OSE-127 alone significantly prolonged the survival of PDX mice in comparison to control treatment (MS 106d vs 79d, P=0.0071), which was comparable to the effect of chemotherapy (MS 106d vs 79d, P=0.0037). Importantly, the strongest effects were observed when combining OSE-127 with chemotherapy (MS 79d vs undefined, P=0.0003, Figure 1F). Overall, we propose OSE-127 as a novel potential immunotherapeutic agent for the treatment of BCP-ALL and T-ALL, particularly in r/r disease and in combination with chemotherapy. Due to its dual mode of action comprising ADCP induction and IL7R-pathway blockade, OSE-127 could be efficacious in CD127+ ALL with and without IL7R pathway alterations. L.L. and I.B. contributed equally to this work. N.P. and D.M.S. share senior authorship Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S812 Hepatic Safety of Ozanimod in Ulcerative Colitis and Relapsing Multiple Sclerosis Phase 3 Trials

Introduction: Ozanimod (OZA) is a sphingosine 1-phosphate (S1P) receptor modulator approved for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing forms of multiple sclerosis (MS) in the United States and European Union. Other S1P receptor modulators have shown substantial elevations in hepatic enzymes. Methods: The impact of OZA on liver function tests was assessed in this safety analysis from phase 3 UC and MS trials. In the 52-week (10-week induction period and 42-week maintenance period), randomized True North (TN) trial, patients (pts) with moderately to severely active UC were treated with placebo (n=216) or OZA 0.92 mg (equivalent to OZA HCl 1 mg) (n=796). In the randomized MS trials (SUNBEAM and RADIANCE), MS pts were treated with interferon beta-1a 30 µg (n=885) or OZA (n=882) for 12 and 24 months, respectively. Hepatic enzymes were assessed at baseline and Weeks 5, 10, 18, 28, 40, and 52 in TN, and at baseline and every 3 months for the MS trials. In the UC and MS trials, enzyme elevations were confirmed with a repeated test within 14 days. Results: Percentages of pts on OZA 0.92 mg with elevations in alanine transaminase (ALT), aspartate aminotransferase (AST), and bilirubin are shown in the Table; < 6% and < 2% of pts had ALT and AST elevations ≥3 x upper limit of normal (ULN), respectively, and < 2% had bilirubin elevations >2 x ULN. Of those with ALT ≥3 x ULN, 86.4% (19/22) of UC pts and 85.4% (41/48) of MS pts recovered to ALT < 3 x ULN within 3 months. Most hepatic treatment-emergent adverse events (TEAEs) were mild to moderate in UC and MS pts. In TN, 3 (0.4%) pts on OZA reported a hepatobiliary disorder TEAE, 1 (0.1%) of whom had hyperbilirubinemia. In the MS trials, 15 (1.7%) pts on OZA 0.92 mg reported a hepatobiliary disorder TEAE, 3 (0.3%) of whom had hyperbilirubinemia. Hepatic-related events leading to discontinuation, which were generally asymptomatic laboratory abnormalities, were reported in 4 (0.5%) UC pts and in 11 (1.2%) MS pts on OZA 0.92 mg. No serious hepatic TEAEs, Hy’s law cases, or severe drug-induced hepatocellular injuries occurred with OZA 0.92 mg in any of the trials. Conclusion: In this analysis of phase 3 UC and MS trials with OZA, elevations of aminotransferases and bilirubin occurring with OZA were infrequent, generally asymptomatic, and transient. These elevations, which generally resolved without study drug discontinuation, did not meet the criteria for Hy’s law or protocol-defined serious AEs. Table 1. - Maximum postbaseline ALT, AST, and bilirubin levels with OZA 0.92 mg Parameter TN (UC)(n=783) Sunbeam/Radiance (MS) (n=878) ALT >1 × ULN 215 (27.5) 373 (42.5) ≥3 × ULN 22 (2.8) 48 (5.5) ≥5 × ULN 8 (1.0) 14 (1.6) AST >1 × ULN 136 (17.4) 185 (21.1) ≥3 × ULN 14 (1.8) 9 (1.0) ≥5 × ULN 5 (0.6) 5 (0.6) Bilirubin >1 × ULN 32 (4.1) 122 (13.9) >2 × ULN 3 (0.4) 14 (1.6) >3 × ULN 1 (0.1) 3 (0.3)