Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial.

INTRODUCTION: Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC. METHODS AND ANALYSIS: In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score <2B.0), endoscopic remission and symptomatic remission (group 3). Treatment is escalated using vedolizumab according to a treatment algorithm that is dependent on the patient's baseline UC therapy until the target is achieved at weeks 16, 32 or 48. The primary outcome, the time from target achievement to a UC-related complication, will be compared between groups 1 and 3 using a Cox proportional hazards model. ETHICS AND DISSEMINATION: The study was approved by ethics committees at the country level or at individual sites as per individual country requirements. A full list of ethics committees is available on request. Study results will be disseminated in peer-reviewed journals and at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT: 2019-002485-12; NCT04259138.

Clinical, Endoscopic, and Radiological Effectiveness of Ustekinumab in Bio-naïve Versus Bio-experienced Patients With Crohn's Disease: Real-world Experience From a Large Canadian Center.

INTRODUCTION: With the expanding therapeutic armamentarium for inflammatory bowel disease (IBD), real-world data may help inform drug positioning. We assessed clinical, endoscopic, imaging, and biochemical response/remission outcomes in patients with Crohn's disease (CD) treated with ustekinumab in a large Canadian IBD center. METHODS: A retrospective cohort study of CD patients was treated with ustekinumab. Clinical, endoscopic, radiological, and biochemical response and remission outcomes were stratified by prior biologic exposure status. Hazard ratios for biologic exposure status were estimated using Cox proportional hazard models and subgroup-specific incidence rates for healing. RESULTS: A total of 231 patients (55.9% female, median 45.8 years) were identified as receiving ustekinumab during the study period, with 2 patients subsequently excluded (N = 229). Of these patients, 79.0% (181 of 229) were bio-experienced, with 38.7% (70 of 181) having failed 1 biologic and 61.3% (111 of 181) having failed ≥2 biologics. At 3 months of follow-up after induction, clinical remission (Harvey-Bradshaw Index ≤4) was achieved by 59.1% (62 of 105) of bio-experienced patients and 79.4% (27 of 34) of bio-naïve patients (relative risk [RR], 1.34; 95% CI, 1.06-1.70; P = .013). Endoscopic remission (absence of mucosal ulcers) was achieved in 37.9% (33 of 87) cases. Rate of endoscopic healing (either endoscopic response or remission) per 1000 person-months was 72.7 (95% CI, 42.4-125.1) and 50.2 (37.9-66.4); and the median time to endoscopic response was 8.4 months (95% CI, 6.4-9.8) and 15.4 months (95% CI, 10.3-17.9) in bio-naïve vs bio-experienced patients, respectively. Imaging response/remission and steroid-free remission rates were higher in bio-naïve patients. CONCLUSION: In this large real-world cohort of CD patients with complex phenotypes and high rates of prior biologic exposure, we observed that ustekinumab was effective and safe with higher rates of improvement in bio-naïve subjects across a range of end points.

In this large real-world study of patients with Crohn's Disease treated with ustekinumab, we observed high rates of clinical, endoscopic, radiological, and biochemical response and remission rates. Effectiveness was greater in bio-naïve compared with bio-experienced patients.

Placebo Response Rates in Randomized Controlled Trials for Perianal Crohn's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Perianal fistulizing disease is a common complication of Crohn's disease [CD], for which new therapies are urgently needed. To assist the design of clinical trials for novel therapeutics, we conducted a systematic review and meta-analysis of randomised controlled trials [RCTs] to quantify placebo rates and identify factors influencing them in perianal CD [pCD]. METHODS: We searched MEDLINE, Embase and CENTRAL from inception to June 2021. Eligible studies were placebo-controlled trials of pharmacological interventions for pCD. Placebo fistula response and remission rates for induction and maintenance trials were extracted and pooled using a random-effects model. Mixed-effects meta-regression was used to evaluate the impact of patient and study-level characteristics on point estimates. RESULTS: In 17 RCTs [13 induction, five maintenance] the pooled placebo fistula response and remission rate for induction trials was 25% (95% confidence interval [CI] 17-36%) and 17% [95% CI 11-25%], respectively. For maintenance trials, the pooled placebo fistula response and remission rate was 23% [95% CI 17-32%] and 19% [95% CI 14-25%], respectively. Trials enrolling patients with less disease activity and a higher proportion with ileal predominant disease were associated with significantly higher placebo response rates. Trials originating in Europe [compared to North America], therapies requiring perianal injection and a longer timepoint to measure remission were associated with higher placebo remission rates. CONCLUSIONS: Placebo response and remission rates in pCD trials are influenced by patient and disease-related factors, as well as the type of intervention being studied. These contemporary rates will inform trial design for novel therapeutics.

An Expert Consensus to Standardize Assessment of Bowel Cleansing for Clinical Trials of Bowel Preparations for Crohn's Disease.

BACKGROUND: Despite regular need for colonoscopy in patients with Crohn's disease (CD), the efficacy and tolerability of bowel preparation (BP) agents is rarely assessed in this population. Assessing BP quality with existing scales may be challenging in CD due to presence of inflammation, bowel resection, and strictures. AIMS: To provide recommendations for assessing BP quality in clinical trials for CD using a modified Research and Development/University of California, Los Angeles appropriateness process. METHODS: Based on systematic reviews and a literature search, 110 statements relating to BP quality assessment in CD were developed. A panel of 15 gastroenterologists rated the statements as appropriate, uncertain, or inappropriate using a 9-point Likert scale. RESULTS: Panelists considered it appropriate that central readers, either alone or with local assessment, score BP quality in clinical trials. Central readers should be trained on scoring BP quality and local endoscopists on performing high-quality video recording. Both endoscope insertion and withdrawal phases should be reviewed to score BP quality in each colonic segment and segments should align with endoscopic disease activity indices. The Harefield Cleansing Scale and the Boston Bowel Preparation Scale were considered appropriate. The final score should be calculated as the average of all visualized segments. Both total and worst segment scores should also be assessed. CONCLUSIONS: We developed a framework for assessing BP quality in patients with CD based on expert feedback. This framework could support the development or refinement of BP quality scales and the integration of BP quality assessment in future CD studies.

Immunotherapy for Cancer: Common Gastrointestinal, Liver, and Pancreatic Side Effects and Their Management.

Cancer cells can block the activation of T lymphocytes by deploying inhibitory signals to cell surface receptors that downregulate the immune response. Immune checkpoint inhibitors (ICI) are monoclonal antibodies that regulate the immune response by acting on these receptors. The use of ICI has been successful for cancer types that do not respond well to conventional chemotherapy, showing clinical benefit in various advanced and metastatic cancers and supporting the promise of cancer immunotherapy. However, in some cases, these treatments are associated with immune-related adverse events, many of which affect the digestive system. The treatment of immune-related adverse events depends on the affected organ and the severity of symptoms. Here, we review the commonly used US FDA-approved ICI and briefly outline their mechanism of action. We also describe the resulting collateral effects on the gastrointestinal tract, liver, and pancreas and discuss their management and prognosis.

Janus Kinase Inhibitors for the Management of Patients With Inflammatory Bowel Disease.

In recent years, knowledge about the pathophysiology of inflammatory bowel disease (IBD) has led to the development of novel therapies and biologics with differing mechanisms of action. A major innovation has been the development of small molecules. Tofacitinib was the first pan-Janus kinase (Jak) inhibitor approved for the treatment of IBD, targeting the 4 isoforms of cytokine-associated Jaks (Jak1, Jak2, Jak3, and tyrosine-protein kinase 2). Compared with biologic agents, novel small molecules have a short half-life, a rapid onset of action, and no immunogenicity, but they are associated with a potentially increased risk of off-target side effects. These differences in properties between biologic and oral small molecule therapies may be important when considering their relative treatment positioning and role in clinical practice. Although tofacitinib has been demonstrated to be highly effective as both first- and second-line therapy for ulcerative colitis, concerns about safety, including the risk of infection, venous thromboembolism, major adverse cardiovascular events, and malignancy, have dampened enthusiasm for its widespread use. Subsequently, several Jak inhibitors with more selective profiles, and potentially improved safety while maintaining treatment efficacy, are currently in late-stage clinical trials for use in patients with IBD. This article summarizes the current data regarding the use, safety, and efficacy of Jak inhibitors in patients with IBD.

Similar Clinical Improvement Rates Among Biologic Drug Classes in Crohn's Disease: Systematic Review and Meta-Regression.

We conducted a systematic review and metaregression of pivotal Crohn's disease trials to evaluate the rates of change in Crohn's Disease Activity Index scores in patients receiving biologic treatments. The speed of clinical improvement was similar among biologic drug classes.

Underrepresentation of Minorities and Lack of Race Reporting in Ulcerative Colitis Drug Development Clinical Trials.

Historically, inflammatory bowel disease trials report high rates of White patients enrollment. To promote initiatives toward diversifying the enrolled population, we assessed the reporting of race and ethnicity of patients enrolled in pharmaceutical clinical trials for ulcerative colitis.

Clinical, Endoscopic, and Safety Placebo Rates in Induction and Maintenance Trials of Crohn's Disease: Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Precision in estimating placebo rates is important for clinical trial design. AIM: To quantify placebo rates across relevant endpoints in Crohn's disease [CD] trials and identify the factors influencing these rates in a contemporary meta-analysis. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from inception to March 2021. Eligible studies were placebo-controlled trials of pharmacological interventions for CD. Placebo response and remission rates for induction and maintenance trials were extracted and pooled by random-effects to quantify placebo rates across studies. Mixed-effects meta-regression was used to evaluate the effects of study-level characteristics on placebo rates. RESULTS: In 125 studies [91 induction, 46 maintenance], placebo clinical remission and response rates for induction studies were 18% (95% confidence interval [CI] 16, 21%], and 32% [95% CI 29, 35%], respectively, and for maintenance studies were 28% [95% CI 23, 34%] and 30% [95% CI 24, 37%], respectively. Endoscopic remission and response rates in induction studies were 8% [95% CI 4, 18%] and 16% [95% CI 11, 23%], respectively. Trials enrolling patients with prior biologic exposure, longer disease duration, and higher CD activity index scores were associated with lower placebo clinical remission rates. Increased duration of follow-up, more follow-up visits, and a greater proportion of patients with colonic disease distribution were associated with higher clinical placebo rates. CONCLUSIONS: Placebo remission and response rates in CD trials vary according to the phase of the trial, endpoint assessed, and induction or maintenance design. These contemporary estimates will help to inform future CD trial design.

Treatment of pouchitis, Crohn's disease, cuffitis, and other inflammatory disorders of the pouch: consensus guidelines from the International Ileal Pouch Consortium.

Pouchitis, Crohn's disease of the pouch, cuffitis, polyps, and extraintestinal manifestations of inflammatory bowel disease are common inflammatory disorders of the ileal pouch. Acute pouchitis is treated with oral antibiotics and chronic pouchitis often requires anti-inflammatory therapy, including the use of biologics. Aetiological factors for secondary pouchitis should be evaluated and managed accordingly. Crohn's disease of the pouch is usually treated with biologics and its stricturing and fistulising complications can be treated with endoscopy or surgery. The underlying cause of cuffitis determines treatment strategies. Endoscopic polypectomy is recommended for large, symptomatic inflammatory polyps and polyps in the cuff. The management principles of extraintestinal manifestations of inflammatory bowel disease in patients with pouches are similar to those in patients without pouches.

The Relationship Between Endoscopic and Clinical Recurrence in Postoperative Crohn's Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: We aimed to quantify the magnitude of the association between endoscopic recurrence and clinical recurrence [symptom relapse] in patients with postoperative Crohn's disease. METHODS: Databases were searched to October 2, 2020, for randomised controlled trials [RCTs] and cohort studies of adult patients with Crohn's disease with ileocolonic resection and anastomosis. Summary effect estimates for the association between clinical recurrence and endoscopic recurrence were quantified by risk ratios [RR] and 95% confidence intervals [95% CI]. Mixed-effects meta-regression evaluated the role of confounders. Spearman correlation coefficients were calculated to assess the relationship between these outcomes as endpoints in RCTs. An exploratory mixed-effects meta-regression model with the logit of the rate of clinical recurrence as the outcome and the rate of endoscopic recurrence as a predictor was also evaluated. RESULTS: In all, 37 studies [N = 4053] were included. For eight RCTs with available data, the RR for clinical recurrence for patients who experienced endoscopic recurrence was 10.77 [95% CI 4.08 to 28.40; GRADE moderate certainty evidence]; the corresponding estimate from 11 cohort studies was 21.33 [95% CI 9.55 to 47.66; GRADE low certainty evidence]. A single cohort study showed a linear relationship between Rutgeerts score and clinical recurrence risk. There was a strong correlation between endoscopic recurrence and clinical recurrence treatment effect estimates as trial outcomes [weighted Spearman correlation coefficient 0.51]. CONCLUSIONS: The associations between endoscopic recurrence and subsequent clinical recurrence lend support to the choice of endoscopic recurrence to monitor postoperative disease activity and as a primary endpoint in clinical trials of postoperative Crohn's disease.

Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn's disease: a systematic review and network meta-analysis.

BACKGROUND: Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic exposure. We aimed to assess the comparative efficacy and safety of biologics in patients with Crohn's disease. METHODS: We did a systematic review and network meta-analysis of phase 2 and phase 3 randomised controlled trials done in adults (≥18 years) with moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450) treated with tumour necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12 and IL-23p40, or anti-IL23p19 agents, either alone or in combination with immunosuppressants, as their first-line biologic or after previous biologic exposure, compared with placebo or an active comparator. The minimum duration of therapy was 14 days for trials reporting induction of remission in active disease and 22 weeks in trials reporting maintenance of remission. We searched Medline, EMBASE, the Cochrane CENTRAL Register of Controlled Trials, conference proceedings, trial registries, and unpublished data from inception to June 3, 2021, without any language restrictions. Summary estimates of the primary and secondary outcomes were extracted from the published reports; individual patient-level data were not sought. The primary endpoint was induction of clinical remission in patients with active disease (CDAI <150) and maintenance of remission in patients with response to induction therapy, with data extracted from published reports. A network meta-analysis with multivariate consistency model random-effects meta-regression was done, with rankings based on surface under the cumulative ranking curve (SUCRA) values. FINDINGS: The search strategy yielded 18 382 citations, of which 31 trials were eligible for inclusion. On the basis of 15 randomised controlled trials including 2931 biologic-naive patients, infliximab monotherapy (odds ratio [OR] 4·53 [95% CI 1·49-13·79]), infliximab combined with azathioprine (7·49 [2·04-27·49]), adalimumab (3·01 [1·25-7·27]), and ustekinumab (2·63 [1·10-6·28]) were associated with significantly higher odds of inducing remission compared to certolizumab pegol (all moderate confidence); infliximab and azathioprine combination therapy was also associated with significantly higher odds of inducing remission than vedolizumab (3·76 [1·01-14·03]; low confidence). On the basis of ten randomised controlled trials including 2479 patients with previous biologic exposure, adalimumab after loss of response to infliximab (OR 2·82 [95% CI 1·20-6·62]; low confidence), and risankizumab (2·10 [1·12-3·92]; moderate confidence), were associated with higher odds of inducing remission than vedolizumab. No differences between active interventions were observed in maintenance trials. Most trials were at low or uncertain risk of bias. INTERPRETATION: Although biologic treatment choices in patients with moderate-to-severe Crohn's disease must be individualised for each patient, this analysis suggests that either infliximab with azathioprine or adalimumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission. FUNDING: None.

Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium.

Restorative proctocolectomy with ileal pouch-anal anastomosis is an option for most patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although the construction of an ileal pouch substantially improves patients' health-related quality of life, the surgery is, directly or indirectly, associated with various structural, inflammatory, and functional adverse sequelae. Furthermore, the surgical procedure does not completely abolish the risk for neoplasia. Patients with ileal pouches often present with extraintestinal, systemic inflammatory conditions. The International Ileal Pouch Consortium was established to create this consensus document on the diagnosis and classification of ileal pouch disorders using available evidence and the panellists' expertise. In a given individual, the condition of the pouch can change over time. Therefore, close monitoring of the activity and progression of the disease is essential to make accurate modifications in the diagnosis and classification in a timely manner.

An expert consensus to standardise clinical, endoscopic and histologic items and inclusion and outcome criteria for evaluation of pouchitis disease activity in clinical trials.

BACKGROUND: Pouchitis is a condition with large unmet medical needs and no approved therapies. Lack of validated instruments to measure disease activity and treatment response is a major barrier to drug development. AIM: To conduct a modified RAND/University of California Los Angeles appropriateness process to produce a standardised assessment of pouchitis disease activity in clinical trials. METHODS: A list of 164 items generated upon a systematic review and expert opinion were rated based on a 9-point scale (appropriate, uncertain and inappropriate), by a panel including 16 gastroenterologists, surgeons and histopathologists. RESULTS: Items rated as appropriate to evaluate in pouchitis clinical trials were: (a) clinical: stool frequency and faecal urgency; (b) endoscopic: primary assessment in the pouch body according to the percentage of affected area (<50%, 50%-75% and >75%), evaluation of the presence of ulcers/erosions according to size (erosions <5 mm, ulcers ≥5 mm to 2 cm and large ulcers >2 cm) and ulcerated area (<10%, 10%-30% and >30%); (c) histologic: two biopsies from each segment, from the ulcer's edge when present, or endoscopically normal areas, assessment of lamina propria chronic inflammation, epithelial and lamina propria neutrophils, epithelial damage, erosions and ulcers; and (d) clinical trial inclusion/outcome criteria: minimum histologic disease activity for inclusion, a primary endpoint based on stool frequency and assessment of clinical, endoscopic and histologic response and remission. The overall majority of items surveyed (100/164) were rated 'uncertain'. CONCLUSION: We conducted a RAND/UCLA appropriateness process to help inform measurement of pouchitis disease activity within clinical trials and foster the development of novel therapies.

An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials.

BACKGROUND & AIMS: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment. METHODS: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting. RESULTS: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations. CONCLUSIONS: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty.

Intravenous Ustekinumab Reinduction Is Effective in Prior Biologic Failure Crohn's Disease Patients Already on Every-4-Week Dosing.

Ustekinumab (UST) targets the common subunit (p40) of interleukins-12/23,1,2 approved for intravenous (IV) induction of remission in moderate-to-severe Crohn's disease (CD), followed by subcutaneous (SC) doses for maintenance of remission.3,4 The role of IV reinduction of UST in patients already on every-4-week (Q4) maintenance with partial response or loss of response (LOR) is unclear.5 The aim was to assess response and remission rates for UST IV reinduction in patients with CD with partial response or LOR who already were on Q4 SC dosing and had failed prior biological therapies.