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Epithelial barrier dysfunction contributes to a dysregulated intestinal immune response in ulcerative colitis (UC). GB004 is an orally administered, small molecule, gut-targeted stabiliser of hypoxia-inducible factor-1α, a transcription factor with protective roles at the epithelial layer of the inflamed gut.To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of GB004 in patients with active UC.This double-blind, placebo-controlled study randomised patients 2:1 to receive an oral solution of GB004 120 mg or placebo once daily for 28 days. Eligible patients had a Robarts Histopathology Index score ≥4 with neutrophils in the epithelium, total Mayo Clinic score 3-12, Mayo Clinic endoscopic subscore ≥1, and blood in the stool, despite treatment with 5-aminosalicylates, corticosteroids or immunosuppressants.Thirty-four patients were randomised. GB004 120 mg for 28 days was generally well-tolerated. Adverse events occurred in 27.3% (3/11) and 39.1% (9/23) of patients in the placebo and GB004 groups respectively. Nausea and dysgeusia were most commonly reported in the GB004 group (0% for placebo and 21.7% [5/23] and 13.0% [3/23] respectively for GB004). There were no treatment-related serious adverse events or deaths. GB004 exhibited minimal accumulation, with higher colonic concentrations relative to plasma. Exploratory pharmacodynamic and efficacy analyses demonstrated GB004 target engagement and numerically higher proportions of patients achieving improvement in multiple measures of disease activity, respectively, at day 28 for GB004 compared to placebo.Results from this phase 1b trial support evaluation of the full therapeutic potential of GB004 for the treatment of UC. A phase 2 study (NCT04556383) is ongoing. Clinicaltrials.gov NCT03860896.

Background GB004 is a small molecule that stabilizes hypoxia inducible factor (HIF-1α), a key transcription factor involved in the cellular responses at the intersection of hypoxia and inflammation. GB004 induction of HIF-1a target genes improves barrier integrity and reduces barrier permeability in rodent models of colitis. Here we investigated gene expression and secretion of soluble factors elicited by GB004 treatment on immune cells and epithelial cells, human monolayer assays and immune co-culture studies to further explore its protective mechanism. Methods In the BioMAP human co-culture assay, cells were treated with GB004 one hour prior to stimulation and incubated for 24–168 hours. Biomarkers, cell viability and proliferation were assessed. Repligut human stem-cell-derived monolayer platforms were used to assess GB004 effects under unstimulated or TNFa stimulation conditions. Barrier integrity was assessed by Transepithelial Endothelial Electric Resistance (TEER), HIF-1a target genes were assessed in cell lysates, and tight junction formation and epithelial monolayer viability were investigated by immunofluorescence staining. Results GB004 demonstrated activity in 11 of 12 systems in the BioMAP human co-culture assay, which covers a range of disease-relevant immune and non-immune mechanisms under stimulation conditions. Collectively, GB004 treatment led to changes in biomarkers associated with inflammation (sTNFa, IL-8, MCP-1, CXCL11), immunomodulation (sIL-17F, sIL-17A), and tissue remodeling (collagen I, collagen IV). GB004 treatment also reduced the proliferative activity in the in vitro lymphocyte assay systems. In the human Repligut intestinal epithelium assay, GB004 significantly reduced cell death and improved barrier integrity in response to pro-inflammatory cytokines. The protective role of GB004 on barrier integrity was further supported by immunostaining experiments demonstrating that GB004 treatment protected epithelial cells from TNFa-induced cell apoptosis, improving both epithelial cell number and tight junction protein ZO-1 staining. Conclusion GB004 modulates key anti-inflammatory and immunomodulatory activities in human co-culture systems. Furthermore, GB004 demonstrates protective effects on human derived monolayer cultures by reducing cell death, promoting tight junction formation, and improving barrier integrity. Targeting both barrier function and local colonic inflammation represents a multi-faceted approach to treatment of inflammatory bowel disease. A phase 2 clinical study of GB004 is ongoing in patients with ulcerative colitis (NCT04556383). Sponsored by GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.

With the early success of their trials for the treatment of ulcerative colitis, corticosteroids gained popularity as a treatment for inflammatory bowel disease (IBD). However, when used chronically, corticosteroids are not effective in maintaining remission and associated with toxic effects. Steroid-free remission has become a major treatment goal. Prolonged corticosteroid use is currently a sign of suboptimal quality of care. Trends over the past 2 decades, spanning the emergence of biologic therapies for IBD, are explored here in the University of Manitoba IBD Epidemiologic Database.

Background and Aims Although several endoscopic and histopathologic indices are available for evaluating the severity of inflammation in mouse models of colitis, the reliability of these scoring instruments is unknown. Our aim was to evaluate the reliability of the individual items in the existing indices and develop new scoring systems by selection of the most reliable index items. Methods Two observers scored the histological slides [n = 224] and endoscopy videos [n = 201] from treated and untreated Interleukin[IL]-10 knock-out and T-cell transferred SCID mice. Intra-rater and inter-rater reliability for endoscopy and histology scores, and each individual item, were measured using intraclass correlation coefficients [ICCs]. The Mouse Colitis Histology Index [MCHI] and Mouse Colitis Endoscopy Index [MCEI] were developed using the most reliable items. Both were correlated to the colon density and to each other and were evaluated for their ability to detect changes in pathobiology. Results The intraclass correlation coefficients (ICCs) for inter-rater agreement (95% CIs) for the total histology and endoscopy scores were 0.90 [0.87–0.92] and 0.80 [0.76–0.84], respectively. The MCHI and MCEI were highly correlated with colon density, with a Spearman Rho = 0.81[0.75–0.85] and 0.73 [0.66–0.79], respectively, and with each other, Spearman Rho = 0.71 [0.63–0.77]. The MCHI and MCEI were able to distinguish between the experimental groups within the models, with pairwise differences between the treated and untreated groups being statistically significant [p < 0.001]. Conclusions These histological and endoscopic indices are valid and reliable measures of intestinal inflammation in mice, and they are responsive to treatment effects in pre-clinical studies.

SummaryBackground Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. Aims To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. Methods A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. Results Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. Conclusions Although “almost perfect” intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument.

Background Ulcerative colitis (UC) is characterized by the loss of epithelial barrier function and chronic mucosal inflammation. GB004 is an oral, gut-targeted, small molecule stabilizer of hypoxia inducible factor (HIF-1α) that promotes epithelial repair and function. A phase 1b study was conducted in patients with active UC where trends in clinical efficacy favoring GB004 were observed. Here we report the target engagement (TE) and pharmacodynamic (PD) biomarker analysis of colon biopsies and stool samples from the phase 1b study. Methods Subjects with active UC despite 5-ASA treatment were randomized 2:1 to GB004 120 mg solution or placebo (PBO) once daily for 28 days. Colon biopsies (sigmoid and rectum) and stool samples were collected at baseline and Day 28. HIF-1a and myeloperoxidase (MPO) immunohistochemistry was performed on formalin-fixed paraffin-embedded colon biopsies. Gene expression profiling (Affymetrix HTA 2.0) was performed on mRNA extracted from colon biopsies. Fecal calprotectin (FC) and secretory IgA (sIgA) were measured from stool samples. Results presented are overall means for baseline characteristics and differences in mean (HIF-1a, MPO) and median (FC, sIgA) percent change from baseline to Day 28 for GB004 vs PBO. Results Thirty-four subjects (age 45.4 years, Mayo score 7.5, sigmoid colon Mayo endoscopic subscore 2.2, sigmoid colon Robarts Histopathology Index 14.1) were randomized to a GB004 120 mg solution (n=23) or PBO (n=11) group. GB004 demonstrated evidence of TE, with an increase in the percent of HIF-1α positive cells (+11.4%) in sigmoid colon segment sections. Tissue and stool-based PD biomarkers of intestinal inflammation associated with lamina propria neutrophil infiltration and cytotoxicity measured by the MPO+ cell count per mm2 (-7.3%) and FC (-30.4%) levels decreased. Lastly, GB004 resulted in an increase in sIgA levels (+87.16%) and transcriptional changes consistent with enhanced epithelial integrity, such as increases in ITGA6 and TJP1. Conclusion In this phase 1b study, GB004, an oral gut-targeted HIF-1α stabilizer, demonstrated TE in the sigmoid colon and histologic, fecal biomarker, and transcriptional PD effects consistent with a reduction in inflammation and mucosal healing. These observations are consistent with the role of HIF-1α stabilization in improving barrier function in UC patients and support the trends in clinical effects observed, including histologic endpoints. A Phase 2 study of GB004 in patients with mild-to-moderate UC (SHIFT-UC, NCT04556383) is currently ongoing. Sponsored by GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.

SummaryBackground Minimising placebo response is essential for drug development. Aim To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates. Methods MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates. Results In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16–21%] and 28% (95% CI 24–32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25–39%) and 26% (95% CI 19–35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics. Conclusions Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease.

Endoscopic assessment of the presence and severity of endoscopic lesions has become an essential part of clinical trials in ulcerative colitis and Crohn's disease, for both patient eligibility and outcome measures. Variability in lesion interpretation between and within observers and the potential bias of local investigators in patient assessment have long been recognized. This variability can be reduced, although not completely removed, by independent evaluation of the examinations by experienced off-site (central) readers, properly trained in regard to lesion definition and identification, that should be removed from direct patient contact and blinded to any other clinical or study data. Adding endoscopic demonstration of active disease to eligibility criteria has the potential to reduce placebo response rates, whereas in outcome assessment it has the potential to provide a more precise estimation of the treatment effect, increasing the efficiency of the study. Central endoscopy reading is still at the beginning of its development, and the paradigms of central reading need refinement in terms of the number of readers, the process by which a final score is assigned, the selection and sequence of central readers, and the endoscopic indices of choice.

Background and Aims: The Crohn’s Disease Endoscopic Index of Severity [CDEIS] and Simplified Endoscopic Score for Crohn’s Disease [SES-CD] demonstrate consistent overall intra- and inter-rater reliability. However, the reliability of some index items is relatively poor. We evaluated scoring conventions to improve the reliability of these items. Methods: Five gastroenterologists with no previous experience scoring the CDEIS or SES-CD were trained on their use. A total of 65 video recordings of colonoscopies were scored blindly by each gastroenterologist before and after additional training on index scoring conventions. Intra-class correlation coefficients [ICCs] assessed the effect of application of these conventions on the reliability of the CDEIS, SES-CD, and a Global Evaluation of Lesion Severity [GELS] score. Results: Following training on scoring conventions, inter-rater ICCs (95% confidence interval [CI]) for the total SES-CD score increased from 0.78 [0.71, 0.85] to 0.85 [0.79, 0.89]. The ICCs for the total CDEIS and GELS scores were not affected: corresponding inter-rater ICCs were 0.74 [0.65, 0.81] and 0.49, [0.38, 0.61] before and 0.73 [0.65, 0.81] and 0.53 [0.42, 0.64] following application of scoring conventions. Estimations of ulcer depth, surface area, anatomical location, and stenosis were important sources of variability. Conclusions: Use of scoring conventions previously developed by expert central readers enhanced the reliability of the SES-CD but did not similarly affect the CDEIS or GELS. As the SES-CD is more likely to be reliable than the CDEIS and can be optimised with targeted training, it is the preferred instrument for use in clinical trials.

Summary Background Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. Aim To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. Methods We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. Results Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. Conclusion This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis.

Background GB004 is a small molecule prolyl hydroxylase inhibitor (PHDi) that stabilizes hypoxia inducible factors (HIF1-α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF1-α stabilization. Consistent with this, orally administered GB004 in a healthy non-human primate model engaged HIF-related genes in the gut, and, in animal models of colitis, demonstrated a significant reduction in disease activity, improvements in histologic measures, and greater exposure in GI tissue relative to plasma. GB004 is in clinical development for treatment of inflammatory bowel disease (IBD) and was shown to be safe in a single ascending dose study. The study described here evaluates the safety, tolerability, and pharmacokinetics (PK) of multiple daily doses of GB004 in plasma and colon biopsies. Methods This was a randomized, double-blind, placebo-controlled, multiple dose, Phase 1a study conducted in healthy subjects at a single site in Canada. Three dose levels of GB004 formulated as a solution or placebo solution were administered orally once a day for 8 days; safety and PK were evaluated. Plasma levels of HIF target genes EPO and VEGF were determined by immunoassays from samples collected at pre-dose, 4, 8, and 12 hours post dose on Day 1 and Day 7. Colon biopsies were obtained one day prior to first dose and at Day 8. Results 42 subjects (20 male and 22 female) were dosed. No serious adverse events or deaths were recorded. The most commonly observed adverse event in GB004-treated subjects was dizziness (31%;10/22); all events were mild and did not result in study drug discontinuation. There were no identified risks of GB004. Following oral dosing, GB004 was rapidly absorbed and eliminated from the systemic circulation, with a median time to maximum concentration of 0.5 hour for all doses. Both Cmax and AUC of GB004 increased in a dose-dependent manner on Day 1 and 7. Concentrations of GB004 measured in colon biopsies were greater than concentrations in the plasma at the time of biopsy. Changes in plasma EPO or VEGF levels were similar for GB004 and placebo with no dose-related effects observed. Conclusions This study demonstrated that multiple daily doses of GB004 solution were safe and tolerable. The PK profile was consistent with its intended preferential exposure in the gut. In support of the gut-targeted exposure, HIF target genes EPO and VEGF were not modulated in plasma. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, PK, and pharmacodynamics both systemically and within colonic tissue (NCT03860896). A tablet formulation is also being developed.

Background GB004 is a small-molecule prolyl hydroxylase inhibitor that stabilises hypoxia-inducible factors (HIF-1α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF-1α stabilisation. GB004 is in clinical development for the treatment of inflammatory bowel disease and was shown to be safe in a single ascending dose study. The study described here evaluates the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple daily doses of GB004 in plasma and colon biopsies. Methods This was a randomised, double-blind, placebo-controlled, multiple-dose, Phase 1a study conducted in healthy subjects at a single site in Canada. Three dose levels of GB004 or placebo formulated as a solution were administered orally once a day for 8 days; safety and PK were evaluated. Colon biopsies were obtained one day prior to the first dose and on Day 8. Colonic tissue concentrations of GB004 and HIF pathway target genes were determined. Results Forty-two subjects (20 male and 22 female) were dosed. No serious adverse events or deaths were recorded. The most commonly observed adverse event in GB004-treated subjects was dizziness (31%,10/32); all events were mild and did not result in study drug discontinuation. There were no identified risks of GB004. Following oral dosing, GB004 was rapidly absorbed and eliminated from the systemic circulation, with a median time to maximum concentration of 0.5 h for all dose levels. Concentrations of GB004 measured in colon biopsies were greater than in plasma at the time of the biopsy. Dose-related HIF pathway target gene engagement and PD were confirmed. Conclusion This study demonstrated that multiple daily doses of GB004 solution were safe and tolerable. The PK profile was consistent with its intended preferential exposure in the gut. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, tolerability, PK and PD both systemically and within colonic tissue (NCT03860896). A tablet formulation is also being developed.

Crohn’s disease (CD) is frequently complicated by intestinal strictures, which are commonly treated by endoscopic balloon dilation (EBD). However, available data on this area of treatment is limited. The aim of this study was to depict the heterogeneity of endoscopic management of CD-associated strictures among international CD specialists to identify common treatment standards. IBD experts of the International Organization for the Study of Inflammatory Bowel Disease (IOIBD), the European Crohn’s and Colitis Organization (ECCO), and from the Prospective Value In IBD trials (PROVIT) completed a web-based questionnaire to evaluate their endoscopic experience, practice setting, and number of EBDs performed annually. Additionally, two case scenarios and technical practice parameters were investigated. A total of 126 subjects from 15 countries completed the survey. The maximal length of dilated stricture was 4.5 ± 1.7 cm. The most commonly used maximal balloon size was graded as 15–18 mm. While 87.2 % of the participants favored EBD for anastomotic strictures, only 58.6 % did so in the case of naive strictures. Only 35.7 % of physicians dilated actively inflamed strictures. Interventional endoscopists were more likely to dilate only clinically symptomatic strictures (p = 0.046). Surgeons favored surgical treatment of de novo ileocecal strictures compared to gastroenterologists (p = 0.026), reported a shorter stricture length being amendable by EBD (p = 0.045), and more frequently used concomitant therapies (p = 0.001). Operator experience increased the likelihood of EBD use in actively inflamed strictures (p = 0.002), maximum length of stricture, and maximum balloon size (p = 0.001). EBD is a widely used treatment approach for stricturing CD. Individual approaches differ significantly based on background of the operator, experience level, and practice setting.

BACKGROUND AN AIM: Minimization of the placebo responses in randomized controlled trials (RCTs) is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis (UC) clinical trials and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception through April 2014 for placebo controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. RESULTS: Fifty-one trials (48 induction and 10 maintenance phases) were identified. Placebo response and remission rates were pooled according to random-effects models and mixed effects meta-regression models used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7%–13%) and 33% (95% CI 29%–37%) respectively. Corresponding values for maintenance trials were 19% (95% CI 11%–30%) and 22% (95% CI 17%–28%). Trials enrolling patients with more active disease confirmed by endoscopy (endoscopy subscore ≥2) were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. CONCLUSIONS: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.

Summary Background Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease. Methods In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. Findings This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI −5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. Interpretation Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. Funding AbbVie Pharmaceuticals.

SummaryBackground Patient-reported outcomes (PROs) have an increasingly important role in the evaluation of new therapies for inflammatory bowel disease. The US Food and Drug Administration has issued formal guidance to describe the role of PRO instruments in evaluation of claims for product labelling. However, no validated PRO exists for ulcerative colitis. Aim To investigate whether the PROs from the Mayo Clinic Score (MCS) for UC can be modified, to develop an interim PRO for use in clinical trials, alone or in combination with endoscopy. Methods Data from an induction trial of a mesalazine (mesalamine) formulation were used to compare effect sizes between mesalazine and placebo for PRO items (stool frequency and rectal bleeding) alone and in combination with endoscopy. The operating properties of the PRO were validated using data from a phase 2 trial of MLN02, a humanised antibody to the α4β7 integrin in patients with UC. Results A two-item PRO (PRO2) consisting of rectal bleeding = 0 and stool frequency ≤1 or ≤2, combined with an endoscopy subscore ≤1 yielded statistically significant differences between active drug and placebo. This combination yielded the most similar effect sizes and placebo rates for remission, compared to the primary trials. Use of PRO items alone yielded high placebo remission rates in both data sets, although rates were lower when the items were combined and remission defined as PRO2 = 0. Conclusion Patient-reported outcomes items derived from the Mayo Clinic Score combined with endoscopy as a co-primary endpoint may be an appropriate interim outcome measure for ulcerative colitis trials.

Ulcerative colitis is a chronic, idiopathic, inflammatory bowel disease characterized by a relapsing and remitting course. A substantial proportion of patients fail conventional therapies despite therapy with immunosuppressives and tumor necrosis factor antagonists. Accordingly, newer therapeutic agents that target disease-specific inflammation and minimize adverse events are required. Central to the pathogenesis of ulcerative colitis is an aberrant host response to commensal microorganisms with a resultant dysregulation of gut immune homeostasis and lymphocyte trafficking. Recently, a newer biologic, vedolizumab, which blocks lymphocyte trafficking, has been developed for use in moderate to severe ulcerative colitis. The efficacy of this agent has been demonstrated to be similar to that of other currently available biologics, and the selectivity of this agent in blocking lymphocyte migration to the gut has substantially reduced treatment-related adverse events. The drug has now been approved for use in the United States and Europe, and, although the exact positioning of this biologic in clinical practice is yet to be defined, it represents an important new chapter in our armamentarium of treatment options for this population. In this review, we will highlight key considerations to be made by providers when using this agent in clinical practice.

Background: Magnetic resonance enterography is increasingly utilized for assessment of luminal Crohn's disease activity. The Magnetic Resonance Index of Activity and the London Index are the most commonly used outcome measures in clinical trials. We assessed the reliability of these indices and several additional items. Methods: A consensus process clarified scoring conventions and identified additional items based on face validity. Four experienced radiologists evaluated 50 images in triplicate, in random order, at least 1 month apart, using a central image management system. Intra- and interrater reliability were assessed by calculating and comparing intraclass correlation coefficients. Results: Intrarater intraclass correlation coefficients (95% confidence intervals) for the Magnetic Resonance Index of Activity, London, and London "extended" indices and a visual analogue scale were 0.89 (0.84 to 0.91), 0.87 (0.83 to 0.90), 0.89 (0.85 to 0.92), and 0.86 (0.81 to 0.90). Corresponding interrater intraclass correlation coefficients were 0.71 (0.61 to 0.77), 0.67 (0.55 to 0.75), 0.70 (0.61 to 0.76), and 0.71 (0.62 to 0.77). Reliability for each index was greatest in the terminal ileum and poorest in the rectum. All 3 indices were highly correlated with the visual analogue scale; 0.79 (0.71 to 0.85), 0.78 (0.71 to 0.84), and 0.79 (0.72 to 0.85) for the Magnetic Resonance Index of Activity, London, and the London "extended" indices, respectively. Conclusions: "Substantial" interrater reliability was observed for all 3 indices. Future studies should assess responsiveness to treatment in order to confirm their utility as evaluative indices in clinical trials and clinical practice.

Primary nonresponse and primary nonremission are important limitations of tumor necrosis factor (TNF) antagonists, occurring in 10% to 40% and 50% to 80% of patients with inflammatory bowel disease, respectively. The magnitude of primary nonresponse differs between phase III clinical trials and cohort studies, indicating differences, e.g., in definition, patient population or blinding. The causes of nonresponse can be attributed to the drug (pharmacokinetics, immunogenicity), the patient (genetics, disease activity), the disease (type, location, severity), and/or the treatment strategy (dosing regimen, combination therapy). Primary nonresponse has been attributed to "non-TNF-driven disease" which is an overly simplified and potentially misleading approach to the problem. Many patients with primary nonresponse could successfully be treated with dose optimization during the induction phase or switching to another TNF antagonist. Therefore, primary nonresponse is frequently not a non-TNF-driven disease. Recent studies from rheumatoid arthritis and preliminary data from inflammatory bowel disease evaluating therapeutic drug monitoring have suggested that early measurement of drug and anti-drug antibody concentrations could help to define primary nonresponse and rationalize patient management of this problem. Moreover, a modeling approach including pharmacological parameters and patient-related covariants could potentially be predictive for response to the treatment. We describe an overview of this evolution in thinking, underpinned by previous findings, and assess the potential role of early measurement of drug and antidrug antibody concentrations in the definition and management of primary nonresponse.

Objective Histopathology is potentially an important outcome measure in UC. Multiple histological disease activity (HA) indices, including the Geboes score (GS) and modified Riley score (MRS), have been developed; however, the operating properties of these instruments are not clearly defined. We assessed the reproducibility of existing measures of HA. Design Five experienced pathologists with GI pathology fellowship training and expertise in IBD evaluated, on three separate occasions at least two weeks apart, 49 UC colon biopsies and scored the GS, MRS and a global rating of histological severity using a 100 mm visual analogue scale (VAS). The reproducibility of each grading system and for individual instrument items was quantified by estimates of intraclass correlation coefficients (ICCs) based on two-way random effects models. Uncertainty of estimates was quantified by 95% two-sided CIs obtained using the non-parametric cluster bootstrap method. Biopsies responsible for the greatest disagreement based on the ICC estimates were identified. A consensus process was used to determine the most common sources of measurement disagreement. Recommendations for minimising disagreement were subsequently generated. Results Intrarater ICCs (95% CIs) for the total GS, MRS and VAS scores were 0.82 (0.73 to 0.88), 0.71 (0.63 to 0.80) and 0.79 (0.72 to 0.85), respectively. Corresponding inter-rater ICCs were substantially lower: 0.56 (0.39 to 0.67), 0.48 (0.35 to 0.66) and 0.61 (0.47 to 0.72). Correlation between the GS and VAS was 0.62 and between the MRS and VAS was 0.61. Conclusions Although ‘substantial’ to ‘almost perfect’ ICCs for intrarater agreement were found in the assessment of HA in UC, ICCs for inter-rater agreement were considerably lower. According to the consensus process results, standardisation of item definitions and modification of the existing indices is required to create an optimal UC histological instrument.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The primary objective will be to determine the efficacy and safety of vedolizumab used for induction and maintenance of remission in CD.

Although tumor necrosis factor (TNF)-α antagonists play a critical role in the treatment of moderate-to-severe inflammatory bowel disease (IBD), several factors can impact treatment response. The degree of systemic inflammation, serum albumin concentration, disease type, body mass index, gender, concomitant therapy with immunosuppressive agents, and especially development of antidrug antibodies (ADAs) are key determinants of TNF antagonist pharmacokinetics and clinical outcomes. Therefore, measurement of serum drug and antibody concentrations in patients with IBD who are on TNF antagonists has the potential to guide clinical decision-making, optimize treatment, improve outcomes, and reduce healthcare costs. Multiple strategies to prevent ADA formation exist, including multiple clinical algorithms that employ therapeutic drug monitoring to optimize treatment following a secondary loss of therapeutic response. An individualized approach is needed, however, to identify early predictors of ADA development and other confounders of TNF antagonist therapy.

Clinical trial endpoints for Crohn's disease (CD) activity correlate poorly with mucosal inflammation; to assess treatment efficacy, patient-reported outcomes and endoscopic assessments are preferred. This study assessed the impact on treatment efficacy estimations of using different definitions of clinical and endoscopic remission and endoscopic response, and of using site- or central-based endoscopy evaluation.This post hoc analysis of data fromEXTEND (extend the safety and efficacy of adalimumab through endoscopic healing), a placebo (PBO)-controlled, randomized trial of adalimumab (ADA) for mucosal healing, included adults with moderate-to-severe CD. Subsets of patients meeting specified Simplified Endoscopic Score for CD (SES-CD) inclusion criteria, according to site or central reading, and baseline stool frequency (SF) and/or abdominal pain score (AP) thresholds were evaluated. Various endpoint definitions based on the Crohn's Disease Activity Index (CDAI), its SF and AP components, SES-CD, and composite endpoints were compared between treatment groups.Increased stringency of Week 12 clinical endpoints compared to CDAI150 to SF≤3.0/1.5AP≤1.0 reduced PBO response rates by ≥12% and increased treatment effects by ≤10%. Amending the SES-CD endpoint from ≤4 to ≤2 reduced the treatment effect from 24% to 8%. Composite endpoints further diminished response rates and effect sizes. Site-based evaluation was associated with lower remission rates versus central reading in the PBO group and, thus, greater ADA-related treatment effects.This analysis is the first to demonstrate that increasing the stringency of clinical and endoscopic endpoint definitions in CD trials, especially lowering SF or SES-CD definitions, reduces the ability to detect treatment-related change in CD activity; focus on endpoints that reflect clinical change is warranted.

Objectives There is no clear consensus regarding the most appropriate measure(s) of eosinophilic esophagitis (EoE) disease activity. We aimed to identify all scoring indices used for the measurement of disease activity in EoE, appraise their operating properties, and discuss their value as outcome measures. Methods MEDLINE, EMBASE, and CENTRAL (The Cochrane library) were searched from inception to 11 May 2016. Randomized controlled trials (RCTs), cohort, case-control, and cross-sectional studies that reported outcomes to measure EoE disease activity or response to treatment were eligible. Operating properties of histologic, endoscopic, and patient reported/symptomatic and health-related quality of life measures were critically appraised according to guidelines proposed by the United States Food and Drug Administration. Results Of 4,373 citations, 130 studies were eligible, of which 20 were RCTs. Although no index met all evaluative criteria, we found that: (1) the EoE histologic scoring system (EoEHSS) is the most valid histologic measure; (2) the Endoscopic Reference Score (EREFS) is the most reliable and responsive endoscopy measure; and (3) the Eosinophilic Esophagitis Activity Index (EEsAI) or the Dysphagia Symptoms Questionnaire (DSQ) had superior construct validity and responsiveness in adults. The Pediatric Quality of Life Inventory EoE was the most valid pediatric symptomatic measure. Conclusions Current evidence supports the use of the EoEHSS and EREFS as measures of histologic and endoscopic EoE disease activity, respectively, and the EEsAI, DSQ, or Pediatric Quality of Life Inventory EoE as measures of adult and pediatric symptoms. Additional research is needed to optimize endpoint configuration to facilitate development of new therapies.

Introduction Crohn’s disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel disease (IBD), are chronic, progressive and disabling disorders of the gastrointestinal tract. Although data from randomised controlled trials (RCTs) provide the foundation of evidence that validates medical therapy for IBD, considerable heterogeneity exists in the measured outcomes used in these studies. Furthermore, in recent years, there has been a paradigm shift in IBD treatment targets, moving from symptom-based scoring to improvement or normalisation of objective measures of inflammation such as endoscopic appearance, inflammatory biomarkers and histological and radiographic end points. The abundance of new treatment options and evolving end points poses opportunities and challenges for all stakeholders involved in drug development. Accordingly, there exists a need to harmonise measures used in clinical trials through the development of a core outcome set (COS). Methods and analysis The development of an IBD-specific COS includes four steps. First, a systematic literature review is performed to identify outcomes previously used in IBD RCTs. Second, semistructured qualitative interviews are conducted with key stakeholders, including patients, clinicians, researchers, pharmaceutical industry representatives, healthcare payers and regulators to identify additional outcomes of importance. Using the outcomes generated from literature review and stakeholder interviews, an international two-round Delphi survey is conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting is held to ratify the COS and disseminate findings for application in future IBD trials. Ethics and dissemination Given that over 30 novel therapeutic compounds are in development for IBD treatment, the design of robust clinical trials measuring relevant and standardised outcomes is crucial. Standardising outcomes through a COS will reduce heterogeneity in trial reporting, facilitate valid comparisons of new therapies and improve clinical trial quality.

BACKGROUND: Disease activity can be determined using clinical, endoscopic or histologic criteria in patients with ulcerative colitis (UC). Persistent disease activity is associated with poor outcomes. Histologic disease activity has been shown to be associated with relapse, colectomy and colorectal cancer. The ability to objectively evaluate microscopic disease activity using histology is important for both clinical practice and clinical trials. However, the operating properties of the currently available histologic indices remain unclear. OBJECTIVES: A systematic review was undertaken to identify and evaluate the development and operating characteristics of histologic disease activity indices used to assess disease activity in people with ulcerative colitis. SEARCH METHODS: We searched MEDLINE, EMBASE, PubMed, CENTRAL and the Cochrane IBD Review Group Specialized Trials Register from inception to 2 December 2016 for applicable studies. There were no language or document type restrictions. SELECTION CRITERIA: Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated a histologic index in patients with UC were considered for inclusion. Eligible patients were adults (> 18 years), diagnosed with UC using conventional clinical, radiographic, endoscopic and histologic criteria. DATA COLLECTION AND ANALYSIS: Two authors (MHM and CEP) independently reviewed the titles and abstracts of the studies identified from the literature search. A standardized form was used to assess eligibility of trials for inclusion and for data extraction. Two authors (MHM and CEP) independently extracted and recorded data, which included the number of patients enrolled, number of patients per treatment arm, patient characteristics including age and gender distribution, and the name of the histologic index. Outcomes (i.e. intra‐rater reliability, inter‐rater reliability, internal consistency, content validity, criterion validity, construct validity, responsiveness, and feasibility) were recorded for each trial. MAIN RESULTS: In total, 126 reports describing 30 scoring indices were identified through the screening process. Eleven of the 30 scoring indices have undergone some form of index validation. Intra‐rater reliability was assessed for eight scoring indices. Inter‐rater reliability was evaluated for all 11 of the scoring indices. Three of the indices underwent content validation. Two of the included scoring indices assessed criterion validity. Six of the included scoring indices explored content validity. Two of the included scoring indices were tested for responsiveness. AUTHORS' CONCLUSIONS: The Nancy Index and the Robarts Histopathology Index have undergone the most validation in that four operating properties including reliability, content validity, construct validity (hypothesis testing) and criterion validity have been tested. However, none of the currently available histologic scoring indices have been fully validated. In order to determine the optimal endpoint for histologic healing in UC, more research is required. The optimal index would need to be fully validated.

Background Crohn's disease (CD) is an idiopathic, chronic, transmural inflammatory disorder of the gastrointestinal tract. Because mucosal involvement is near-universal, endoscopic healing has emerged as an important aspect in improving outcome. However, resolution of histologic disease activity has potential to convey additional benefit beyond that attained with endoscopic healing alone. Validated scoring systems of histologic disease activity are required to further assess this possibility. The aim of this study was to systematically review the existing histologic disease activity indices (HDAI) for CD and to assess their operating properties and potential use as outcome measures in clinical trials. Methods MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and Digestive Disease Week (DDW) abstracts were searched from 1981 to April 2013 for applicable studies to identify relevant studies for review and analysis. Results In total, 3732 citations were screened to obtain 89 articles for inclusion. Sixty-six HDAIs were characterized as either stepwise or numerical instruments. These HDAIs were used for either assessment of response to medical therapy or for comparison with biomarkers or imaging tests. None of the HDAIs identified was developed according to currently accepted methods for developing evaluative instruments, and none have been formally validated. Conclusions Measurement of histologic disease activity has potential value in CD; however, no validated measures are available. Additional research is needed to develop a methodologically rigorous instrument for use in clinical investigation and potentially for clinical practice.

Background: Assessment of endoscopic disease activity, as measured by various endoscopic evaluative instruments, is an essential part of quantifying disease activity in clinical trials in patients with ulcerative colitis (UC). Evaluative instruments have specifi cd efinitions and operating properties that influence the interpretation of clinical trial results. Our objective was to systematically review all endoscopic evaluative instruments that measure endoscopic disease activity in UC and to describe their definitions and operating characteristics (reliability, responsiveness, and predictive validity). Methods: We performed a systematic review of evaluative instruments assessing endoscopic disease activity in UC. MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and Digestive Disease Week abstracts of clinical trials were searched from inception to January 2013. Results: In total, 5885 studies were identified and screened for inclusion criteria. Four hundred twenty-two studies involving 31 evaluative instruments were identified. Two types of indices were found, numerical scoring systems and stepwise grading scales. Conclusions: Both the endoscopic evaluative instrument selected and the definition chosen for mucosal healing affect the validity of assessing endoscopic disease activity during a clinical trial for UC. Currently, the sigmoidoscopic component of the Mayo Score and the ulcerative colitis endoscopic index of severity show the most promise as reliable evaluative instruments of endoscopic disease activity. However, further validation is required. (Inflamm Bowel Dis 2014;0:1–7)

International audience; BACKGROUND & AIMS: Mucosal healing has been proposed as a goal for treatment because it is associated with improved clinical outcomes of patients with Crohn's disease (CD). However, little is known about the feasibility or probability of achieving mucosal healing in clinical practice. We evaluated the feasibility of treating patients to achieve mucosal healing based on endoscopic evaluation (treating to target). METHODS: We reviewed the endoscopic outcomes of 67 patients with CD who had lesions detected by endoscopy. Patients underwent 2 to 4 subsequent endoscopic evaluations at the University of California San Diego and were followed up from 2011 through 2012; data were collected on therapies and patient management. The cumulative incidences of mucosal healing and endoscopic improvement were estimated using the Kaplan-Meier method. Factors independently associated with mucosal healing were identified using a Cox proportional hazards model. RESULTS: After a median follow-up period of 62 weeks, 34 patients (50.7%) had mucosal healing and 41 patients (61.1%) had endoscopic improvement. The cumulative probabilities of mucosal healing were 12.7% and 45.0% at 24 and 52 weeks of treatment, respectively. Factors associated with mucosal healing were as follows: fewer than 26 weeks between endoscopic procedures (hazard ratio, 2.35; 95% confidence interval, 1.15-4.97; P = .035) and adjustment to medical therapy when mucosal healing was not observed (hazard ratio, 4.28; 95% confidence interval, 1.9-11.5; P = .0003). CONCLUSIONS: In an endoscopic study of patients with CD, we found that assessment of endoscopic disease activity and adjustments to medical therapy (treat to target) increase the likelihood of mucosal healing.

Summary Background Patients with Crohn's disease (CD) may experience disease relapse on maintenance infliximab. Anti-drug antibodies likely contribute to loss of response, and serum infliximab levels likely correlate with efficacy. Aim To prospectively evaluate the relationship between trough serum infliximab concentration and disease activity. Methods Adult patients (N = 327) with a diagnosis of CD who had received at least five consecutive infliximab infusions and who planned to receive at least two additional infusions were enrolled. The Crohn's Disease Activity Index (CDAI), serum infliximab, C-reactive protein (CRP) and antibodies-to-infliximab (ATI) were assessed at baseline, week 4 and week 8. Receiver operating characteristic (ROC) analysis examined the relationship between infliximab concentrations and disease activity. Results The mean CDAI score, which decreased 1.05 points between infusions, did not correlate with the mean change in trough infliximab concentration (+0.39 μg/mL; r = 0.099, P = 0.083), but was associated with the mean change in CRP concentration (r = 0.19, P 5 mg/mL at the second infusion. ATI at either visit decreased the proportion of patients with therapeutic infliximab trough levels compared with patients who were ATI negative (17.5% vs. 77.3% at visit 1 and 13.8% vs. 75.6% at visit 3; P

BACKGROUND Ulcerative colitis (UC) is an idiopathic inflammatory disorder. Currently, the main goals of treatment are to induce and maintain clinical and/or endoscopic remission. However, evidence indicates that persistent disease activity on colonic biopsies in the setting of clinical or endoscopic remission is an independent predictor of poor outcomes. A number of previous studies have proposed histologic indices for use in specific trials of UC. The aim of this study was to systematically review the existing histological indices for UC and assess their potential use in both patient management and clinical trials. METHODS We performed a systematic review of histological indices evaluating disease activity in UC. MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and Digestive Diseases Week (DDW) abstracts of randomized and/or controlled trials clinical trials were searched from inception to February 2013 for applicable studies. Data from these studies were reviewed and analyzed. RESULTS After systematically applying inclusion criteria, we identified 108 scientific articles including 88 clinical studies and 21 related clinical reviews. Eighteen indices of histological activity in UC were identified and reviewed. CONCLUSIONS Although multiple histological scoring indices for assessment of UC disease activity currently exist, none of these instruments were developed using a formal validation process and their operating properties remain poorly understood. Future studies are needed to address this deficiency.

BACKGROUND:GB004 is a small molecule prolyl hydroxylase inhibitor (PHDi) that stabilizes hypoxia inducible factors (HIF-α), key transcription factors involved in the adaptive and protective cellular responses at the intersection of hypoxia and inflammation. GB004 is being developed as a therapy for

Objective To develop a consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn’s disease (pCD), based on best available evidence. Methods Based on a systematic literature review, statements were formed, discussed and approved in multiple rounds by the 20 working group participants. Consensus was defined as at least 80% agreement among voters. Evidence was assessed using the modified GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Results Highest diagnostic accuracy can only be established if a combination of modalities is used. Drainage of sepsis is always first line therapy before initiating immunosuppressive treatment. Mucosal healing is the goal in the presence of proctitis. Whereas antibiotics and thiopurines have a role as adjunctive treatments in pCD, anti-tumour necrosis factor (anti-TNF) is the current gold standard. The efficacy of infliximab is best documented although adalimumab and certolizumab pegol are moderately effective. Oral tacrolimus could be used in patients failing anti-TNF therapy. Definite surgical repair is only of consideration in the absence of luminal inflammation. Conclusions Based on a multidisciplinary approach, items relevant for fistula management were identified and algorithms on diagnosis and treatment of pCD were developed.

Anti-tumor necrosis factor-α agents are key therapeutic options for the treatment of ulcerative colitis. Their efficacy and safety have been shown in large randomized controlled trials. The key evidence gained from these trials of infliximab, adalimumab, and golimumab is reviewed along with their effect on mucosal healing and long-term outcomes. Also reviewed are methods for optimizing their effectiveness, including therapeutic drug monitoring and treat-to-target strategies. Finally, remaining unresolved questions regarding their role and effectiveness are considered including how these may be addressed in future clinical trials.

This is the protocol for a review and there is no abstract. The objectives are as follows: The objective of this review is to determine the factors that influence placebo response and remission rates in induction and maintenance trials of CD in which patients with active or quiescent disease were enrolled using the CDAI or Harvey-Bradshaw Index (HBI).

SummaryBackground Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. Aim To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. Methods We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case–controlled studies. Results Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case–controlled studies indicate that an intensified infliximab dosing regimen with 1–2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. Conclusions Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority.

OBJECTIVES: Flow cytometry (FC) aids in characterization of cellular and molecular factors involved in pathologic immune responses. Although FC has potential to facilitate early drug development in inflammatory bowel disease, interlaboratory variability limits its use in multicenter trials. Standardization of methods may address this limitation. We compared variability in FC-aided quantitation of T-cell responses across international laboratories using three analytical strategies. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from three healthy donors, stimulated with phorbol 12-myristate 13-acetate and ionomycin at a central laboratory, fixed, frozen, and shipped to seven international laboratories. Permeabilization and staining was performed in triplicate at each laboratory using a common protocol and centrally provided reagents. Gating was performed using local gating with a local strategy (LGLS), local gating with a central strategy (LGCS), and central gating (CG). Median cell percentages were calculated across triplicates and donors, and reported for each condition and strategy. The coefficient of variation (CV) was calculated across laboratories. Between-strategy comparisons were made using a two-way analysis of variance adjusting for donor. RESULTS: Mean interlaboratory CV ranged from 1.8 to 102.1% depending on cell population and gating strategy (LGLS, 4.4-102.1%; LGCS, 10.9-65.6%; CG, 1.8-20.9%). Mean interlaboratory CV differed significantly across strategies and was consistently lower with CG. CONCLUSIONS: Central gating was the only strategy with mean CVs consistently lower than 25%, which is a proposed standard for pharmacodynamic and exploratory biomarker assays

Objective Although the Geboes score (GS) and modified Riley score (MRS) are commonly used to evaluate histological disease activity in UC, their operating properties are unknown. Accordingly, we developed an alternative instrument. Design Four pathologists scored 48 UC colon biopsies using the GS, MRS and a visual analogue scale global rating. Intra-rater and inter-rater reliability for each index and individual index items were measured using intraclass correlation coefficients (ICCs). Items with high reliability were used to develop the Robarts histopathology index (RHI). The responsiveness/validity of the RHI and multiple histological, endoscopic and clinical outcome measures were evaluated by analyses of change scores, standardised effect size (SES) and Guyatt9s responsiveness statistic (GRS) using data from a clinical trial of an effective therapy. Results Inter-rater ICCs (95% CIs) for the total GS and MRS scores were 0.79 (0.63 to 0.87) and 0.80 (0.69 to 0.87). The correlation estimates between change scores in RHI and change score in GS and MRS were 0.75 (0.67 to 0.82) and 0.84 (0.79 to 0.88), respectively. The SES and GRS estimates for GS, MRS and RHI were: 1.87 (1.54 to 2.20) and 1.23 (0.97 to 1.50), 1.29 (1.02 to 1.56) and 0.88 (0.65 to 1.12), and 1.05 (0.79 to 1.30) and 0.88 (0.64 to 1.12), respectively. Conclusions The RHI is a new histopathological index with favourable operating properties.

This is the protocol for a review and there is no abstract. The objectives are as follows: The primary objective is to systematically review the current literature describing the development and operating characteristics of available histologic disease activity indices in Crohn’s disease.

BACKGROUND: Endoscopic assessment of mucosal disease activity is widely used to determine eligibility and response to therapy in clinical trials of treatment for Crohn’s disease. However, the operating properties of the currently available endoscopic indices remain unclear. OBJECTIVES: A systematic review was undertaken to evaluate the development and operating characteristics of the Crohn’s Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Scale for Crohn’s Disease (SES‐CD). SEARCH METHODS: Electronic searches of the MEDLINE (1966 to December 2015), EMBASE (1980 to December 2015), and Cochrane CENTRAL Register of Controlled Trials (Issue 12, 2015) databases were supplemented by manual reviews of reference listings and conference proceedings (Digestive Disease Week, United European Gastroenterology Week, European Crohn’s and Colitis Organization). SELECTION CRITERIA: Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated either or both the CDEIS or SES‐CD in patients with Crohn’s disease was considered for inclusion. Eligible participants were adult patients (> 16 years), diagnosed with Crohn’s disease using conventional clinical, radiographic, and endoscopic criteria. DATA COLLECTION AND ANALYSIS: Two authors (RK, JKM) independently reviewed the titles and abstracts of the studies identified from the literature search. The full texts of potentially relevant citations were reviewed for inclusion and the study investigators were contacted to clarify any unclear data. Any disagreements were resolved by discussion and consensus with a third author. A standardized form was used to assess eligibility of trials for inclusion in the study and for data extraction. Two authors independently extracted and recorded data (RK, SAN). The number of patients enrolled; number of patients per treatment arm; patient characteristics including age and gender distribution; endoscopic index; and outcomes such as intra‐rater reliability, inter‐rater reliability responsiveness, validity, feasibility, construct validity, and criterion validity were recorded for each trial. MAIN RESULTS: Forty‐three reports of 30 studies fulfilled the inclusion criteria. For the SES‐CD, inter‐rater reliability was assessed in four studies. In the development study for the SES‐CD (Daperno 2004), the overall ICC (0.9815, 95% CI 0.9705 to 0.9884) and the kappa for the regions is high; however the paired raters were in the same room which introduces the potential for bias. For the CDEIS, inter‐rater reliability was assessed in six studies. Daperno 2014 reported that the ICC for the CDEIS was 0.985 (95% CI 0.939‐1.000) for average measures of video score and was 0.835 (95% CI 0.540‐0.995) for single measures of video score. With respect to validity, correlation between the CDEIS and clinical measures, including C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR), was also reported. The estimates of correlation with CRP were r = 0.521 (Sipponen 2010b), r = 0.553 (Sipponen 2008a) and r = 0.608 (Sipponen 2008c). For the SES‐CD, the corresponding values for correlation with CRP ranged from r = 0.46 (Jones 2008) to r = 0.68 (Green 2011). Responsiveness data for the CDEIS were available in nine studies. Seven studies demonstrated statistically significant decreases in the CDEIS score after administration of a treatment of known efficacy. Minimal responsiveness data were available for the SES‐CD. Sipponen 2010a and Sipponen 2010b demonstrated statistically significant changes in the SES‐CD score after subjects were administered a treatment of known efficacy. No studies were identified that explicitly evaluated the feasibility for either the SES‐CD or the CDEIS. The SES‐CD requires fewer calculations and may therefore be easier to use than the CDEIS. AUTHORS' CONCLUSIONS: Although they are used in clinical trials, the CDEIS and SES‐CD remain incompletely validated. Future research is required to determine the operating properties and to define the optimal index.

ObjectiveAlthough several pharmacological agents have emerged as potential adjunctive therapies to a gluten-free diet for coeliac disease, there is currently no widely accepted measure of disease activity used in clinical trials. We conducted a systematic review of coeliac disease activity indices to evaluate their operating properties and potential as outcome measures in registration trials.DesignMEDLINE, EMBASE and the Cochrane central library were searched from 1966 to 2015 for eligible studies in adult and/or paediatric patients with coeliac disease that included coeliac disease activity markers in their outcome measures. The operating characteristics of histological indices, patient-reported outcomes (PROs) and endoscopic indices were evaluated for content and construct validity, reliability, responsiveness and feasibility using guidelines proposed by the US Food and Drug Administration (FDA).ResultsOf 19 123 citations, 286 studies were eligible, including 24 randomised-controlled trials. Three of five PROs identified met most key evaluative criteria but only the Celiac Disease Symptom Diary (CDSD) and the Celiac Disease Patient-Reported Outcome (CeD PRO) have been approved by the FDA. All histological and endoscopic scores identified lacked content validity. Quantitative morphometric histological analysis had better reliability and responsiveness compared with qualitative scales. Endoscopic indices were infrequently used, and only one index demonstrated responsiveness to effective therapy.ConclusionsCurrent best evidence suggests that the CDSD and the CeD PRO are appropriate for use in the definition of primary end points in coeliac disease registration trials. Morphometric histology should be included as a key secondary or co-primary end point. Further work is needed to optimise end point configuration to inform efficient drug development.

Crohn's disease and ulcerative colitis are heterogeneous inflammatory bowel diseases, and therapeutic requirements vary among patients. We have a limited capacity to predict disease progression for individual patients, therefore it is important that they are evaluated for the presence of active disease when symptoms are mild or even absent, when patients are more likely to respond to new treatment interventions. It then is important to monitor responses to treatment, to quickly identify those therapies that are ineffective, modify or change therapy, and avoid disease complications. Studies are underway to assess the effects of different monitoring strategies. Because of the heavy burden of severe inflammatory bowel disease on patients' health and quality of life, and the association between intestinal healing and disease progression in high-risk patients, a treat-to-target strategy (based on tissue healing) is likely to be optimal.

The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however neither instrument is fully validated. We evaluated the responsiveness to change of the SES-CD and CDEIS using data from a trial of adalimumab, a drug therapy of known efficacy. Paired video recordings (N=112) of colonoscopies (baseline and week 8-12) obtained from patients with CD who participated in a trial of adalimumab therapy were reviewed in random order, in duplicate, by four central readers (56 pairs of videos by 2 groups of readers). Responsiveness of the SES-CD and the CDEIS was evaluated by comparing correlations between the observed and pre-specified predictions of change scores for these endoscopic indices with a global endoscopic evaluation of severity (GELS), a patient reported outcome (PRO2), and the Crohn's disease activity index (CDAI), and by calculation of the standardized effect size, and Guyatt's Responsiveness statistic (GRS) using 2 definitions of change; (1) treatment assignment and (2) an absolute change in total PRO2 of 50. The potential application of effect size estimates was demonstrated by calculating hypothetical sample sizes for comparing two independent groups. The impact of removing stenosis as an index item and adjusting for the number of segments observed was also assessed. Changes in both endoscopic instruments and the GELS were highly correlated. The SES-CD displayed numerically higher effect sizes for both definitions of change. The standardized effect size and GRS estimates (95% confidence interval) for the SES-CD based on treatment assignment were 0.84 (0.53, 1.15) and 0.79 (0.48, 1.09). Corresponding values for the CDEIS were 0.72 (0.42, 1.02) and 0.75 (0.45, 1.06). The standardized effect size and GRS estimates for the SES-CD based on an absolute change in total PRO2 of 50 points or greater were 0.76 (0.49, 1.02) and 0.93 (0.64, 1.21). Corresponding values for CDEIS were 0.70 (0.44, 0.97), 0.83 (0.55, 1.10). Removal of stenosis as an index item and adjusting for observed segments did not improve responsiveness estimates. Although both the SES-CD and CDEIS are valid measures of endoscopic disease activity that are moderately responsive to changes in endoscopic disease activity, the SES-CD displayed numerically greater responsiveness in this data set

This is the protocol for a review and there is no abstract. The objectives are as follows: The primary objectives are to systematically review the prevalence of immunogenicity to biologics with the use of different test assays, the impact of ADA formation on the efficacy and safety of biologics and the influence of combination therapy on immunogenicity in patients with IBD.