Management of complications in patients with an ileostomy: an umbrella review of systematic reviews for the EndOTrial Consortium.

BACKGROUND: Standardized clinical care processes for patients with Crohn's disease (CD) and a permanent ileostomy (PI) are lacking. The EndOTrial consortium aims to address this gap by developing pathways for care. METHODS: In this umbrella review, we searched major databases for relevant systematic reviews (SRs) or scoping reviews (ScR) published until January 5, 2024. Screening, data extraction, and quality appraisal (AMSTAR 2) were performed by two independent reviewers. RESULTS: Of 1349 screened papers, 22 reviews met our inclusion criteria, including 20 SRs (eight with meta-analysis) and 2 ScRs. None exclusively focused on PI. Furthermore, nine reviews did not mention patients with inflammatory bowel disease (IBD), and only two reviews included patients with high-output ileostomy, highlighting a large evidence gap. The identified reviews covered six categories with nine types of interventions, including ostomy care pathways, peristomal skin care, patient education, clinical management of high-output stoma, management and prevention of postoperative ileus, dietary and nutritional support, nursing and supporting care, telemedicine, and self-management interventions. Most SRs including nursing interventions for stoma care highlighted nurses' role in a variety of standard and specialized treatments. Notably, none of the reviews exclusively examined disease recurrence, stoma pouching systems or adhesives, behavioral interventions, or mental health in patients living with ileostomy. CONCLUSIONS: Evidence for best practice interventions to treat complications and improve quality of life in patients living with an ileostomy for CD is limited and heterogeneous. These results outline the need for standardized clinical care processes and pathways tailored to the unique needs of this patient population.

Performance of bowel preparation quality scales in patients with Crohn's disease.

BACKGROUND: The performance of bowel preparation (BP) in patients with Crohn's disease (CD) is unknown. AIMS: To evaluate the operating properties of instruments used to assess BP quality in patients with CD. METHODS: We used the Boston Bowel Preparation Scale, modified Boston Bowel Preparation Scale, Harefield Cleansing Scale, Food and Drug Administration Bowel Cleansing Assessment Scale (BCAS), and a 100-mm visual analogue scale of bowel cleanliness to assess BP quality in 50 videos from 40 patients with CD. We assessed endoscopic activity with the Simple Endoscopic Score for CD (SES-CD). Assessments were on endoscope insertion and withdrawal. Reliability was quantified using the intraclass correlation coefficient (ICC). We assessed validity by within-patient correlation between instruments and the visual analogue scale using mixed-effect models. The correlation between BP quality and SES-SD scores was assessed using Spearman's rho. RESULTS: Inter- and intra-rater reliability for all BP quality instruments was substantial (ICC ≥0.61) except for the Food and Drug Administration BCAS on insertion (inter-rater reliability ICC ≥0.41). The visual analogue scale had substantial inter- and almost perfect (ICC ≥0.81) intra-rater reliability. Correlation coefficients for the validity of the instruments exceeded 0.58. BP quality and endoscopic disease activity scores in the colon were negatively correlated. CONCLUSION: Most existing instruments reliably assess BP quality in patients with CD. These results support the use of these instruments in clinical practice, provide a framework for scoring BP quality in CD clinical trials, and support evaluation of novel BP agents in patients with CD.

US National Estimates of Contemporary Mortality Rates in Patients With Ulcerative Colitis Undergoing Colectomy.

INTRODUCTION: Despite a growing armamentarium of medical therapies for ulcerative colitis, colectomy remains an important therapeutic option. To better inform shared decision-making about surgery, we estimated the contemporary risk of mortality after colectomy. METHODS: Mortality rates were estimated using the National Inpatient Sample (2016-2020). Factors associated with postcolectomy death were evaluated in multivariable regression. RESULTS: Postcolectomy mortality occurred in 1.2% (95% CI: 0.8%, 1.9%) of hospitalizations. Comorbidity burden, emergent laparotomy, and delays to surgery >5 days after admission were associated with mortality. DISCUSSION: Colectomy may be associated with mortality; however, this risk is heterogeneous based on patient- and procedural-related factors.

Endoscopic Skipping, Stricturing, and Penetrating Complications in Crohn's Disease on Tandem Ileo-colonoscopy and Cross-sectional Imaging: A Retrospective Cohort Study.

BACKGROUND: Crohn's disease (CD) is characterized by discontinuous inflammation. Failure to identify skipping lesions of the terminal ileum (TI) or transmural changes can lead to incorrect management. METHODS: Eligible adult patients with CD undergoing ileo-colonoscopy and computed tomography enterography or magnetic resonance enterography within 6 months. We determined the prevalence of endoscopic skipping (normal ileum on colonoscopy but proximal small bowel inflammation on cross-sectional imaging), skip lesions (discontinuous inflammation along the gastrointestinal tract identified on cross-sectional imaging), structuring, and penetrating complications. RESULTS: Among 202 patients, 45 (22.3%) had endoscopic skipping proximal to TI intubation. Fifty patients (24.5%) had small bowel skip lesions, primarily in the ileum. Strictures were identified in 34 patients (16.8%) through both imaging and ileo-colonoscopy, in 21 patients (10.4%) solely through cross-sectional imaging, and in 3 patients (1.5%) solely through ileo-colonoscopy. Approximately 36.2% of stricturing cases would be missed without cross-sectional imaging. Penetrating complications, including abscesses (2.5%) and various fistula types (4.9%), were detected in 15 (7.4%) patients. CONCLUSIONS: Ileo-colonoscopy missed detection of active CD in approximately one-fifth of cases due to more proximal disease location. Stricturing disease might be missed in more than a third of cases if cross-sectional imaging is not performed.

Crohn's disease often presents with discontinuous inflammation, with endoscopic evaluation sometimes missing proximal lesions. This study highlights the importance of cross-sectional imaging, which identifies skip lesions and strictures missed by endoscopy, crucial for accurate management.

Prevalence of stricturing, penetrating complications and extraintestinal manifestations in inflammatory bowel disease detected on cross-sectional imaging in a tertiary care setting.

BACKGROUND: Stricturing, penetrating complications and extraintestinal manifestations (EIMs) are frequent in patients with inflammatory bowel disease (IBD). There is limited data on the prevalence of these complications in patients with IBD. Therefore, we aimed to assess the burden of these complications detected incidentally on cross-sectional imaging. METHODS: A retrospective study conducted at two tertiary care centers in London, Ontario. Patients (≥18 years) with a confirmed diagnosis of IBD who underwent CT enterography (CTE) or MR enterography (MRE) between 1 Jan 2010 and 31 Dec 2018 were included. Categorical variables were reported as proportions and the mean and standard deviations were reported for continuous variables. RESULTS: A total of 615 imaging tests (MRE: 67.3% [414/615]) were performed in 557 IBD patients (CD: 91.4% [509/557], UC: 8.6% [48/557]). 38.2% (213/557) of patients were male, with mean age of 45.6 years (±15.8), and median disease duration of 11.0 years (±12.5). Among patients with CD, 33.2% (169/509) had strictures, with 7.8% having two or more strictures and 66.3% considered inflammatory. A fistula was reported in 10.6% (54/509), the most common being perianal fistula (27.8% [15/54]), followed by enterocutaneous fistula (16.8% [9/54]), and enteroenteric fistula (16.8% [9/54]). Additionally, 7.4% (41/557) of patients with IBD were found to have an EIM on cross-sectional imaging, with the most prevalent EIM being cholelithiasis (63.4% [26/41]), followed by sacroiliitis (24.4% [10/41]), primary sclerosing cholangitis (4.8% [2/41]) and nephrolithiasis (4.8% [2/41]). CONCLUSIONS: Approximately 40% of patients with CD undergoing cross-sectional imaging had evidence of a stricture or fistulizing disease, with 7% of patients with IBD having a detectable EIM. These results highlight the burden of disease and the need for specific therapies for these disease phenotypes.

The Future of Clinical Trials in Inflammatory Bowel Disease.

The medical management of inflammatory bowel disease (IBD) has been transformed over the past few decades by the approval of multiple classes of advanced therapies and the integration of more targeted treatment strategies for Crohn's disease and ulcerative colitis. These changes have been driven by an increasing number of pivotal randomized controlled trials, which have grown in size and complexity over time. Several landmark studies that are anticipated to change current IBD management paradigms have recently been completed or are on-going, including the first head-to-head biologic trials, advanced combination treatment trials, therapeutic strategy and treatment target trials, and multiple phase 3 registrational programs of novel compounds. Despite these advances, the future of IBD trials also faces major challenges with respect to cost, feasibility, and recruitment. Accordingly, innovative methods for early and late phase randomized controlled trials must be adopted. In this review, we provide a comprehensive overview of the evolution of modern IBD trials, discuss methods for improving trial efficiency in early and late phase development, and provide insights into the interpretation and implications of these data for clinical care.

TL1A inhibition for inflammatory bowel disease treatment: From inflammation to fibrosis.

The pivotal role of TL1A in modulating immune pathways crucial for inflammatory bowel disease (IBD) and intestinal fibrosis offers a promising therapeutic target. Phase 2 trials (TUSCANY and ARTEMIS-UC) evaluating an anti-TL1A antibody show progress in expanding IBD therapeutic options. First-in-human data reveal reduced expression of genes associated with extracellular matrix remodeling and fibrosis post-anti-TL1A treatment. Investigational drug TEV-48574, potentially exerting dual antifibrotic and anti-inflammatory effects, is undergoing a phase 2 basket study in both ulcerative colitis (UC) and Crohn disease (CD). Results are eagerly awaited, marking advancements in IBD therapeutics. This critical review comprehensively examines the existing literature, illuminating TL1A and the intricate role of DR3 in IBD, emphasizing the evolving therapeutic landscape and ongoing clinical trials, with potential implications for more effective IBD management.

Toward Patient Centricity: Why Do Patients With Inflammatory Bowel Disease Participate in Pharmaceutical Clinical Trials? A Mixed-Methods Exploration of Study Participants.

Background: A better understanding of motivations to participate as well as recommendations to reduce barriers to enrollment may assist in design of future clinical trials. Methods: We developed a 32-item electronic questionnaire to explore motivations, experiences, and recommendations of inflammatory bowel disease patients, who had participated in pharmaceutical clinical trials in a tertiary center in Canada over the last decade. We employed a mixed-methods approach that integrates both quantitative and qualitative research methods. Results: We distributed a total of 69 e-mails with surveys and received 46 responses (66.6% response rate). Study participants were mostly male (27/46, 58.7%), non-Hispanic White (43/46, 93.5%), with a mean age of 45.5 years (SD 10.9). Most decided to participate in a clinical trial to benefit future patients (29/46, 63.0%). Half of the participants (23/46, 50.0%) reported they were worried about the possibility of receiving placebo, although the majority (29/46, 63.0%) understood they could improve on placebo. The most challenging aspect reported was the number and length of questionnaires (15/46, 32.6%), as well as the number of colonoscopies (14/46, 30.4%). Strategies recommended to increase enrollment were reduction of the chance of receiving placebo (20/46, 43.5%), facilitating inclusion of patients who have failed multiple therapies (20/46, 43.5%), allowing virtual visits (18/46, 39.1%), including subtypes of disease traditionally excluded from trials (16/46, 34.8%) and improving outreach to underrepresented populations (13/46, 28.3%). The vast majority (37/46, 80.4%) reported their experience of participation to be better than expected. Conclusions: These results should help inform the design of future clinical trials with a focus on patient-centricity.

Operating Properties of Disease Activity Indices in Pediatric Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND: Accurate, reliable, and responsive disease activity indices are important to streamline drug approval and treatment modalities for pediatric inflammatory bowel disease (pIBD). We aimed to identify all scoring indices used in pIBD randomized controlled trials (RCTs) and to evaluate their operating properties. METHODS: MEDLINE, EMBASE, and CENTRAL were searched on December 6, 2022, to identify studies evaluating clinical, endoscopic, imaging, or patient-reported outcome measures (PROMs) in pIBD including Crohn's disease (CD) and ulcerative colitis (UC). Validity, reliability, responsiveness, and feasibility were summarized. RESULTS: Seventy RCTs evaluating pIBD indices were identified. Forty-one studies reported on the operating properties of 14 eligible indices (n = 9 CD, n = 5 UC). The Pediatric Crohn's Disease Activity Index (PCDAI) varied widely in terms of validity and reliability and was less feasible overall. In contrast, the Mucosal Inflammation Noninvasive Index, which includes fecal calprotectin, had better operating properties than the PCDAI. The Simplified Endoscopic Mucosal Assessment of Crohn's Disease appears more feasible and had similar operating properties than the longer Simple Endoscopic Score for Crohn's Disease. The Pediatric Ulcerative Colitis Activity Index was feasible, valid, and reliable, but responsiveness needs to be evaluated further. The Endoscopic Mayo score and the Ulcerative Colitis Endoscopic Index of Severity were reliable, but validity and responsiveness need to be evaluated further. Imaging and PROMs/quality of life indices need further evaluation. CONCLUSIONS: The operating properties of pIBD clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices.

The operating properties of pediatric inflammatory bowel disease clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices in this population.

Withdrawal of Immunomodulators or TNF Antagonists in Patients With Inflammatory Bowel Diseases in Remission on Combination Therapy: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Withdrawal of immunomodulators (IMMs) or tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel diseases (IBDs) in remission on combination therapy is attractive. We evaluated the efficacy and safety of (1) IMM, or (2) TNF antagonist withdrawal in patients with IBD in sustained remission on combination therapy. METHODS: Through a systematic review till March 31, 2023, we identified randomized controlled trials (RCTs) that compared the efficacy and safety of IMM or TNF antagonist withdrawal vs continued combination therapy, in patients with IBD in sustained corticosteroid-free clinical remission for >6 months on combination therapy. Primary outcome was risk of relapse and serious adverse events at 12 months. We conducted meta-analysis to calculate relative risk (RR) and 95% confidence interval (CI) and used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to appraise certainty of evidence. RESULTS: We identified 8 RCTs with 733 patients (77% with Crohn's disease, 91% on infliximab-based combination therapy). On meta-analysis of 5 RCTs, there was no difference in the risk of relapse between patients with IMM withdrawal (continued TNF antagonist monotherapy) vs continued combination therapy (16.8% vs 14.9%; RR, 1.15; 95% CI, 0.75-1.76) without heterogeneity (low certainty of evidence). TNF antagonist withdrawal (continued IMM monotherapy) was associated with 2.4-times higher risk of relapse compared with continuing combination therapy (31.5% vs 11.2%; RR, 2.35; 95% CI, 1.38-4.01), with minimal heterogeneity (low certainty of evidence). There was no difference in the risk of serious adverse events with IMM or TNF antagonist withdrawal vs continued combination therapy. CONCLUSIONS: In patients with IBD in sustained corticosteroid-free clinical remission for >6 months on combination therapy, de-escalation with TNF antagonist withdrawal, but not IMM withdrawal, was associated with an increased risk of relapse.

Scoring Indices for Perianal Fistulising Crohn's Disease: A Systematic Review.

BACKGROUND AND AIMS: In this systematic review we summarise existing scoring indices for assessing disease activity and quality of life in perianal fistulising Crohn's disease [PFCD], and highlight gaps in the literature. METHODS: MEDLINE, EMBASE, and CENTRAL were searched from August 24, 2022, to identify studies evaluating clinical, radiological, or patient-reported outcome measures [PROMS] in PFCD. The primary objective was to identify all available scoring indices and describe the operating properties of these indices. RESULTS: A total of 53 studies reported on the use of one clinical index [Perianal Disease Activity Index: PDAI], three PROMs, and 10 radiological indices; 25 studies evaluated the operating properties of these indices. The PDAI demonstrated content validity, construct validity, and responsiveness but criterion validity or reliability were not assessed. The Van Assche Index [VAI], modified VAI, and the Magnetic Resonance Index for Assessing Fistulas in Patients with CD [MAGNIFI-CD] were the most studied radiological indices. These indices demonstrated responsiveness and reliability. The VAI and MAGNIFI-CD demonstrated construct validity; criterion and content validity and feasibility have not been assessed. Among the three PROMs, the Crohn's Anal Fistula Quality of Life index demonstrated content and construct validity, inter-observer reliability, and responsiveness; criterion validity, intra-observer reliability, and feasibility have not been assessed for this index. CONCLUSIONS: There are no fully valid, reliable, and responsive clinical disease or radiological indices for PFCD. Although the radiological indices demonstrated responsiveness and reliability, well-defined cut-offs for response and remission are lacking. Future research should focus on establishing standardised definitions and thresholds for outcomes.

Implementation of regulatory guidance for JAK inhibitors use in patients with immune-mediated inflammatory diseases: An international appropriateness study.

BACKGROUND AND AIMS: The Pharmacovigilance Risk Assessment Committee (PRAC) proposed measures to address severe side effects linked to Janus kinase inhibitors (JAKi) in immune-mediated inflammatory diseases (IMID). Use of these medications in individuals aged 65 and older, those at high cardiovascular risk, active or former long-term smokers, and those with increased cancer risk should be considered only if no alternatives exist. Caution is advised when administering JAKi to patients at risk of venous thromboembolism. We aim to implement recommendations from regulatory guidelines based on areas of uncertainty identified. METHODS: A two-round modified Research and Development/University of California Los Angeles appropriateness methodology study was conducted. A panel of 21 gastroenterologists, dermatologists and rheumatologists used a 9-point Likert scale to rate the appropriateness of administering a JAKi for each proposed clinical scenario. Scores for appropriateness were categorized as appropriate, uncertain, or inappropriate. Two rounds were performed, each with online surveys and a virtual meeting to enable discussion and rating of each best practice. RESULTS: Round 1 involved participants rating JAKi appropriateness and suggesting descriptors to reduce uncertainty. Survey results were discussed in a virtual meeting, identifying areas of disagreement. In round 2, participants rated their agreement with descriptors from round 1, and the level of uncertainty and disagreement reduced. Age flexibility is recommended in the absence of other risk factors. Active counseling on modifiable risks (e.g., overweight, mild hyperlipidemia and hypertension) and smoking cessation is advised. Uncertainty persists regarding cancer risk due to various factors. CONCLUSIONS: We outlined regulatory guidance without a personalized evaluation of the patient's risk profile might lead to uncertainty and become an arid technicality. Therefore, we identified gaps and implemented PRAC recommendations to help health professionals in clinical practice.

Reliability and Responsiveness of Histologic Indices for the Assessment of Crohn's Disease Activity.

BACKGROUND & AIMS: The operating properties of histologic indices for evaluating Crohn's disease (CD) activity are poorly characterized. We assessed the reliability and responsiveness of existing histologic indices/items used in CD and ulcerative colitis (UC), in addition to 3 novel items, and developed exploratory ileal, colonic, and colonic-ileal CD instruments. METHODS: Blinded central readers independently reviewed paired baseline and week 12 image sets from the EXTEND trial. Disease activity was scored using 4 indices (the Global Histologic Activity Score, Geboes Score, Nancy Histological Index, and Robarts Histopathology Index) and 3 items identified by an expert panel (mucin depletion, basal plasmacytosis, and ileal pyloric gland metaplasia). Reliability and responsiveness were quantified using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an inter-rater ICC ≥0.40 and AUC ≥0.56. The dependent variable was histologic disease activity measured by a 100-mm visual analogue scale. RESULTS: Paired image sets were available from 55 patients. Substantial to almost perfect inter-rater reliability (ICC, 0.63-0.87) and some responsiveness (AUC, 0.57-0.94) were observed for all existing indices regardless of whether individual colonic and ileal segments, combined colonic segments, or combined colonic and ileal segments were assessed and the calculation method used. Five items were tested as candidate items, and exploratory colonic, ileal, and colonic-ileal indices were developed. CONCLUSIONS: CD and UC indices were similarly reliable and responsive in measuring histologic CD activity. Exploratory index development did not offer benefit over current histologic instruments.

Pharmacological therapies for the management of fistulising Crohn's disease: A systematic review and meta-analysis.

BACKGROUND: Fistulas are a debilitating complication of Crohn's disease (CD). We conducted a systematic review to assess the efficacy of medical therapies for fistulising CD. METHODS: MEDLINE, Embase, and CENTRAL were searched on May 26, 2022, for randomised controlled trials (RCTs) of pharmacologic therapy in adults with fistulising CD. The primary outcome was induction and maintenance of fistula response. Pooled risk ratios (RRs) and 95% confidence intervals (CI) were calculated. GRADE was used to assess certainty of evidence. RESULTS: Thirty-eight RCTs were included. Nineteen trials (50%) exclusively involved perianal fistula. The remaining studies included some participants with non-perianal fistula. Pooled RRs for anti-tumor necrosis factor (TNF) agents were not statistically significant for induction (RR 1.36, 95% CI 0.97-1.91) or maintenance of fistula response (RR 1.48, 95% CI 0.97-2.27). However, in a sensitivity analysis of studies with fistula response as the primary outcome, anti-TNFs were superior to placebo for induction (RR 1.94, 95% CI 1.10-3.41) and maintenance (RR 1.88, 95% CI 1.23-2.88) of fistula response. Oral small molecules (RR 2.56, 95% CI 1.18-5.53) and mesenchymal stem cell (MSC) therapy (RR 1.26, 95% CI 1.01-1.57) were effective for induction of fistula response. Ustekinumab was associated with maintenance of fistula response (RR 1.80, 95% CI1.04-3.11). Vedolizumab was not superior to placebo. The certainty of evidence ranged from very low to moderate. CONCLUSION: Very low-to-moderate certainty evidence suggests that anti-TNF therapy, oral small molecules, ustekinumab, and MSCs are effective for perianal fistulising CD. Dedicated fistula studies evaluating biologics and small molecules are needed.

Practical Management of Biosimilar Use in Inflammatory Bowel Disease (IBD): A Global Survey and an International Delphi Consensus.

As the patents for biologic originator drugs expire, biosimilars are emerging as cost-effective alternatives within healthcare systems. Addressing various challenges in the clinical management of inflammatory bowel disease (IBD) remains crucial. To shed light on physicians' current knowledge, beliefs, practical approaches, and concerns related to biosimilar adoption-whether initiating a biosimilar, transitioning from an originator to a biosimilar, or switching between biosimilars (including multiple switches and reverse switching)-a global survey was conducted. Fifteen physicians with expertise in the field of IBD from 13 countries attended a virtual international consensus meeting to develop practical guidance regarding biosimilar adoption worldwide, considering the survey results. This consensus centered on 10 key statements covering biosimilar effectiveness, safety, indications, rationale, multiple switches, therapeutic drug monitoring of biosimilars, non-medical switching, and future perspectives. Ultimately, the consensus affirmed that biosimilars are equally effective and safe when compared to originator drugs. They are considered suitable for both biologic-naïve patients and those who have previously been treated with originator drugs, with cost reduction being the primary motivation for transitioning from an originator drug to a biosimilar.

Advanced Combination Treatment With Biologic Agents and Novel Small Molecule Drugs for Inflammatory Bowel Disease.

The use of combination therapy with a biologic agent and immunosuppressant has well-established efficacy and safety and is common practice in the management of inflammatory bowel disease (IBD). Current research has shifted focus toward the use of advanced combination treatment (ACT). This term was coined to describe combination therapy using 2 or more advanced treatments (biologic agents and/or oral small molecule drugs) with the aim of achieving optimal disease control in selected patients. An ACT approach may be particularly beneficial in patients with documented medically refractory IBD and in patients with a poor prognosis, extraintestinal manifestations, or concomitant immune-mediated inflammatory diseases. To date, the body of evidence for ACT strategies in IBD is largely comprised of uncontrolled retrospective case series and cohort studies in highly refractory patients. Recently, results from the VEGA trial have suggested that combination induction therapy with guselkumab and golimumab was more effective in ulcerative colitis than either agent alone. However, questions remain about issues such as related costs, ACT duration, and optimal combinations to adopt. Future randomized controlled trials are likely to evaluate rationally selected combinations of agents. This article summarizes the available literature on ACT, including comparisons with traditional combination therapy and the rheumatology field, and discusses practical recommendations, profiles of IBD patients who should be considered for combination approaches in clinical practice, and remaining knowledge gaps.

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.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Disease Clearance as a New Outcome in Ulcerative Colitis: a Systematic Review and Expert Consensus.

The concept of disease clearance has been proposed as a potential target in ulcerative colitis (UC). We conducted a systematic review to investigate the role of disease clearance, defined as a composite outcome including simultaneous clinical, endoscopic, and histologic remission of disease in the management of patients with UC. Based on the literature data, statements regarding disease clearance were developed and voted on by the members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) according to a Delphi methodology. A definition of disease clearance was proposed to standardize its use in clinical practice and clinical trials and to provide practical recommendations for its implementation as a therapeutic target in UC.