Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial.

BACKGROUND: The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis. METHODS: This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries. Eligible patients were aged 18-75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522. FINDINGS: Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1-19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6-12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0-35·9; p<0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0-20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment. INTERPRETATION: Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. FUNDING: Gilead Sciences.

British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults.

Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss.Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel.IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease- with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.

Leptin activates Akt in oesophageal cancer cells via multiple atorvastatin-sensitive small GTPases.

Obesity is a risk factor for Barrett's oesophagus and oesophageal adenocarcinoma. Adipose tissue secretes the hormone leptin. Leptin is a growth factor for several cell types, including Barrett's cells and oesophageal adenocarcinoma cells. Statins are associated with reduced rates of Barrett's oesophagus and oesophageal cancer and exhibit anti-cancer effects in vitro. The mechanisms of these effects are not fully established. We have examined the effects of leptin and the lipid-soluble statin, atorvastatin, on signalling via monomeric GTP-binding proteins and Akt. Proliferation and apoptosis were assessed in OE33 cells. Akt activity was quantified by cell-based ELISA and in vitro kinase assay. Specific small-molecule inhibitors and a dominant-negative construct were used to reduce Akt activity. Small GTPases were inhibited using transfection of dominant-negative plasmids, prenylation inhibitors and pretreatment with atorvastatin. Leptin stimulated Akt activity and cell proliferation and inhibited camptothecin-induced apoptosis in an Akt-sensitive manner. Leptin induced phosphorylation of Bad and FOXO1 in an Akt-sensitive manner. Leptin activated Ras, Rac, RhoA and cdc42. Transfection of dominant-negative plasmids confirmed that leptin-induced Akt activation required Ras, RhoA cdc42 but not Rac. Atorvastatin inhibited leptin-induced activation of Ras, RhoA, cdc42 and Akt. Co-treatment with mevalonate prevented these effects of atorvastatin. The protein kinase Akt is essential to the growth-promoting and anti-apoptotic effects of leptin in oesophageal adenocarcinoma cells. Akt is activated via Ras-, Rho- and cdc42-dependant pathways. Atorvastatin reduces leptin-induced Akt activation by inhibiting prenylation of small GTPases. This may explain the reduced incidence of oesophageal adenocarcinoma in statin-users.

Correction to: Direct observation of procedural skills (DOPS) assessment in diagnostic gastroscopy: nationwide evidence of validity and competency development during training.

The citation for Reference 22 should be replaced with: Kumar NL, Kugener G, Perencevich ML, et al (2018) The SAFE-T assessment tool: derivation and validation of a web-based application for point-of-care evaluation of gastroenterology fellow performance in colonoscopy. Gastrointest Endosc 87(1):262-269.

Direct observation of procedural skills (DOPS) assessment in diagnostic gastroscopy: nationwide evidence of validity and competency development during training.

BACKGROUND: Validated competency assessment tools and the data supporting milestone development during gastroscopy training are lacking. We aimed to assess the validity of the formative direct observation of procedural skills (DOPS) assessment tool in diagnostic gastroscopy and study competency development using DOPS. METHODS: This was a prospective multicentre (N = 275) analysis of formative gastroscopy DOPS assessments. Internal structure validity was tested using exploratory factor analysis and reliability estimated using generalisability theory. Item and global DOPS scores were stratified by lifetime procedure count to define learning curves, using a threshold determined from receiver operator characteristics (ROC) analysis. Multivariable binary logistic regression analysis was performed to identify independent predictors of DOPS competence. RESULTS: In total, 10086 DOPS were submitted for 987 trainees. Exploratory factor analysis identified three distinct item groupings, representing 'pre-procedure', 'technical', and 'post-procedure non-technical' skills. From generalisability analyses, sources of variance in overall DOPS scores included trainee ability (31%), assessor stringency (8%), assessor subjectivity (18%), and trainee case-to-case variation (43%). The combination of three assessments from three assessors was sufficient to achieve the reliability threshold of 0.70. On ROC analysis, a mean score of 3.9 provided optimal sensitivity and specificity for determining competency. This threshold was attained in the order of 'pre-procedure' (100-124 procedures), 'technical' (150-174 procedures), 'post-procedure non-technical' skills (200-224 procedures), and global competency (225-249 procedures). Higher lifetime procedure count, DOPS count, surgical trainees and assessors, higher trainee seniority, and lower case difficulty were significant multivariable predictors of DOPS competence. CONCLUSION: This study establishes milestones for competency acquisition during gastroscopy training and provides validity and reliability evidence to support gastroscopy DOPS as a competency assessment tool.

Changes in scoring of Direct Observation of Procedural Skills (DOPS) forms and the impact on competence assessment.

BACKGROUND: Direct Observation of Procedural Skills (DOPS) is an established competence assessment tool in endoscopy. In July 2016, the DOPS scoring format changed from a performance-based scale to a supervision-based scale. We aimed to evaluate the impact of changes to the DOPS scale format on the distribution of scores in novice trainees and on competence assessment. METHODS: We performed a prospective, multicenter (n = 276), observational study of formative DOPS assessments in endoscopy trainees with ≤ 100 lifetime procedures. DOPS were submitted in the 6-months before July 2016 (old scale) and after (new scale) for gastroscopy (n = 2998), sigmoidoscopy (n = 1310), colonoscopy (n = 3280), and polypectomy (n = 631). Scores for old and new DOPS were aligned to a 4-point scale and compared. RESULTS: 8219 DOPS (43 % new and 57 % old) submitted for 1300 trainees were analyzed. Compared with old DOPS, the use of the new DOPS was associated with greater utilization of the lowest score (2.4 % vs. 0.9 %; P < 0.001), broader range of scores, and a reduction in competent scores (60.8 % vs. 86.9 %; P < 0.001). The reduction in competent scores was evident on subgroup analysis across all procedure types (P < 0.001) and for each quartile of endoscopy experience. The new DOPS was superior in characterizing the endoscopy learning curve by demonstrating progression of competent scores across quartiles of procedural experience. CONCLUSIONS: Endoscopy assessors applied a greater range of scores using the new DOPS scale based on degree of supervision in two cohorts of trainees matched for experience. Our study provides construct validity evidence in support of the new scale format.

Validity Evidence for Direct Observation of Procedural Skills in Paediatric Gastroscopy.

OBJECTIVES: Direct observation of procedural skills (DOPS) are competence-assessment tools in endoscopy. Formative paediatric gastroscopy DOPS were implemented into the UK curriculum in 2016 but lack validity evidence; we aimed to assess validity evidence using a recognised contemporary validity framework. METHODS: We performed a prospective UK-wide analysis of formative paediatric gastroscopy DOPS submitted to the e-Portfolio over 1 year. Internal structure validity was assessed using interitem correlations between DOPS items, average domain, and skillset scores and with the overall competency rating. Overall competence scores and mean DOPS scores were compared by trainee seniority and procedure count (discriminative validity). Receiver operating characteristic curve analysis was performed to explore if DOPS scores could be used to delineate procedural competency (consequential validity). RESULTS: A total of 157 DOPS assessments were completed by 20 trainers for 17 trainees. Strengths of correlations varied between DOPS components, with overall competency correlating most with technical-predominant items, domains and skillsets. Both the overall assessor's rating and mean DOPS scores increased with trainee seniority (P < 0.001) and lifetime procedure count (P < 0.001). Overall competency could be delineated using mean DOPS scores (area under receiver operating characteristic curve 0.95, P < 0.001), with a threshold of 3.9 providing optimal sensitivity (94.4%) and specificity (89.7%). CONCLUSIONS: Competencies in paediatric gastroscopy, as assessed using DOPS, vary in their correlation with overall competence and increase with trainee experience. Formative DOPS thresholds could be used to indicate readiness for summative assessment. Our study therefore provides evidence of internal structure, discriminative, and consequential validity in support of formative paediatric gastroscopy DOPS.

Reduced Risk of Barrett's Esophagus in Statin Users: Case-Control Study and Meta-Analysis.

BACKGROUND: Use of statins has been associated with a reduced incidence of esophageal adenocarcinoma in population-based studies. However there are few studies examining statin use and the development of Barrett's esophagus. AIM: The purpose of this study was to examine the association between statin use and the presence of Barrett's esophagus in patients having their first gastroscopy. METHODS: We have performed a case-control study comparing statin use between patients with, and without, an incident diagnosis of non-dysplastic Barrett's esophagus. Male Barrett's cases (134) were compared to 268 male age-matched controls in each of two control groups (erosive gastro-esophageal reflux and dyspepsia without significant upper gastrointestinal disease). Risk factor and drug exposure were established using standardised interviews. Logistic regression was used to compare statin exposure and correct for confounding factors. We performed a meta-analysis pooling our results with three other case-control studies. RESULTS: Regular statin use was associated with a significantly lower incidence of Barrett's esophagus compared to the combined control groups [adjusted OR 0.62 (95 % confidence intervals 0.37-0.93)]. This effect was more marked in combined statin plus aspirin users [adjusted OR 0.43 (95 % CI 0.21-0.89)]. The inverse association between statin or statin plus aspirin use and risk of Barrett's was significantly greater with longer duration of use. Meta-analysis of pooled data (1098 Barrett's, 2085 controls) showed that statin use was significantly associated with a reduced risk of Barrett's esophagus [pooled adjusted OR 0.63 (95 % CI 0.51-0.77)]. CONCLUSIONS: Statin use is associated with a reduced incidence of a new diagnosis of Barrett's esophagus.

Statin use is associated with a reduced incidence of colorectal adenomatous polyps.

BACKGROUND: Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to have potentially useful anticancer effects against colorectal cancers in experimental studies, but clinical studies have shown inconsistent results on colorectal cancer incidence. Most colorectal cancers are believed to develop through the polyp-cancer sequence. We hypothesized that statins may protect against the development of adenomatous polyps, and this may contribute to the apparent cancer-protective effects. OBJECTIVE: This study aims to compare previous statin use in patients with newly diagnosed adenomatous polyps against a control group without polyps. METHOD: A case-control study involving 264 patients attending for diagnostic colonoscopy at the Norfolk and Norwich University Hospital was used. Polyp cases were age and sex matched against controls with normal colonoscopies. Structured patient interviews and clinical notes were used to ascertain drug and risk factor. Logistic regression was used to compare statin exposure and correct for confounding factors. RESULTS: There was a significant negative association between prior statin use and a diagnosis of adenomatous polyps [odds ratio (OR) = 0.40 (0.24-0.76)]. The association was significantly stronger with higher statin doses [≥40 mg simvastatin or equivalent; OR 0.33 (0.10-0.53)] or longer duration of use [>5 years; OR 0.36 (0.10-0.67)]. Statin use was negatively associated with both high- and low-risk polyps. CONCLUSIONS: Statins may have a protective effect against the development of adenomatous polyps. The negative association between statin use and polyp incidence showed a significant dose and duration relationship.

JAG consensus statements for training and certification in colonoscopy.

Introduction: In the UK, endoscopy certification is awarded when trainees attain minimum competency standards for independent practice. A national evidence-based review was undertaken to update and develop standards and recommendations for colonoscopy training and certification. Methods: Under the oversight of the Joint Advisory Group (JAG), a modified Delphi process was conducted between 2019 and 2020 with multisociety expert representation. Following literature review and Grading of Recommendations, Assessment, Development and Evaluations appraisal, recommendation statements on colonoscopy training and certification were formulated and subjected to anonymous voting to obtain consensus. Accepted statements were peer reviewed by JAG and relevant stakeholders for incorporation into the updated colonoscopy certification pathway. Results: In total, 45 recommendation statements were generated under the domains of: definition of competence (13), acquisition of competence (20), assessment of competence (8) and postcertification support (4). The consensus process led to revised criteria for colonoscopy certification, comprising: (1) achieving key performance indicators defined within British Society of Gastroenterology standards (ie, unassisted caecal intubation rate >90%, rectal retroversion >90%, polyp detection rate >15%+, polyp retrieval rate >90%, patient comfort <10% with moderate-severe discomfort); (2) minimum procedure count 280+; (3) performing 15+ procedures over the preceding 3 months; (4) attendance of the JAG Basic Skills in Colonoscopy course; (5) terminal ileal intubation rates of 60%+ in inflammatory bowel disease; (6) satisfying requirements for formative direct observation of procedure skills (DOPS) and direct observation of polypectomy skills (Size, Morphology, Site, Access (SMSA) level 2); (7) evidence of reflective practice as documented on the JAG Endoscopy Training System reflection tool; (8) successful performance in summative DOPS. Conclusion: The UK standards for training and certification in colonoscopy have been updated, culminating in a single-stage certification process with emphasis on polypectomy competency (SMSA Level 2+). These standards are intended to support training, improve standards of colonoscopy and polypectomy, and provide support to the newly independent practitioner.

JAG consensus statements for training and certification in flexible sigmoidoscopy.

Introduction: Joint Advisory Group (JAG) certification in endoscopy is awarded when trainees attain minimum competency standards for independent practice. A national evidence-based review was undertaken to update standards for training and certification in flexible sigmoidoscopy (FS). Methods: A modified Delphi process was conducted between 2019 and 2020 with multisociety representation from experts and trainees. Following literature review and Grading of Recommendations, Assessment, Development and Evaluations appraisal, recommendation statements on FS training and certification were formulated and subjected to anonymous voting to obtain consensus. Accepted statements were peer-reviewed by national stakeholders for incorporation into the JAG FS certification pathway. Results: In total, 41 recommendation statements were generated under the domains of: definition of competence (13), acquisition of competence (17), assessment of competence (7) and postcertification support (4). The consensus process led to revised criteria for colonoscopy certification, comprising: (A) achieving key performance indicators defined within British Society of Gastroenterology standards (ie, rectal retroversion >90%, polyp retrieval rate >90%, patient comfort <10% with moderate-severe discomfort); (B) minimum procedure count ≥175; (C) performing 15+ procedures over the preceding 3 months; (D) attendance of the JAG Basic Skills in Lower gastrointestinal Endoscopy course; (E) satisfying requirements for formative direct observation of procedural skill (DOPS) and direct observation of polypectomy skill (SMSA level 1); (F) evidence of reflective practice as documented on the JAG Endoscopy Training System reflection tool and (G) successful performance in summative DOPS. Conclusion: The UK standards for training and certification in FS have been updated to support training, uphold standards in FS and polypectomy, and provide support to the newly independent practitioner.

Statin use is associated with a reduced incidence of colorectal cancer: a colonoscopy-controlled case-control study.

BACKGROUND: The aetiology of colorectal cancer (CRC) remains elusive in the majority of cases. There is experimental evidence to show that HMG-CoA reductase inhibitors (statins) may inhibit proliferation and induce cause apoptosis in CRC cells and although some clinical studies have suggested that statins may protect against the development of CRC, this has not been a consistent finding. Therefore we have examined any potential protective effects of statins by comparing statin use in patients with colorectal cancer against a control group. METHODS: This was a case-control study examining statin use in symptomatic patients attending for diagnostic colonoscopy. Statin use was compared between patients with CRC and a control group, who had all had normal colonoscopy. Structured interviews and clinical records notes were used to determine drug exposure. Logistic regression was used to compare statin exposure and correct for confounding factors. RESULTS: There was a significant inverse association between previous statin use and a diagnosis of CRC (OR = 0.43 (95% confidence interval 0.25 - 0.80), p<0.01). This inverse association was stronger with higher statin doses (OR = 0.19 (0.07 - 0.47), p<0.01) and greater duration of statin use (statin use >years: OR = 0.18 (0.06 - 0.55), p<0.01). CONCLUSIONS: Statins use was associated with a protective effect against the development of CRC. This effect is associated with a significant dose and duration response. These findings need to be repeated in other observational studies before an interventional study can be considered.

Endoscopy training in the UK pre-COVID-19 environment: a multidisciplinary survey of endoscopy training and the experience of reciprocal feedback.

OBJECTIVE: Training in gastrointestinal endoscopy in the UK occurs predominantly in a real world one-to-one trainer to trainee interaction. Previous surveys have shown surgical and gastroenterology trainees have had mixed experiences of supervision and training, and no surveys have explored specifically the role of trainee to trainer feedback. This study aimed to explore the experience of training and of providing trainer feedback for all disciplines of endoscopy trainees. DESIGN/METHOD: An online survey designed in collaboration with Joint Advisory Committee training committee and trainee representatives was distributed from January 2020 but was interrupted by the COVID-19 pandemic and hence terminated early. RESULTS: There were 129 responses, including trainees from all disciplines and regions, of which 86/129 (66.7%) rated the culture in their endoscopy units favourably-either good or excellent. 65/129 (50.4%) trainees reported having one or more training lists allocated per week, with 41/129 (31.8%) reporting only ad hoc lists. 100/129 (77.5%) respondents were given feedback and 97/129 (75.2%) were provided with learning points from the list. 65/129 (50.4%) respondents reported their trainer completed a direct observation of procedure or direct observation of polypectomies. 73/129 (56.6%) respondents reported that they felt able to give feedback to their trainer, with 88/129 (68.2%) feeling they could do this accurately. Barriers to trainer feedback cited included time constraints, lack of anonymity and concerns about affecting the trainer-trainee relationship. CONCLUSION: Overall, the training environment has improved since previous surveys. There are still issues around interdisciplinary differences with some surgical trainees finding the training environment less welcoming, and trainee perceptions of hierarchical barriers and trainer responsiveness to feedback limiting the accuracy of their feedback.

JAG consensus statements for training and certification in oesophagogastroduodenoscopy.

Introduction: Training and quality assurance in oesophagogastroduodenoscopy (OGD) is important to ensure competent practice. A national evidence-based review was undertaken to update and develop standards and recommendations for OGD training and certification. Methods: Under the oversight of the Joint Advisory Group (JAG), a modified Delphi process was conducted with stakeholder representation from British Society of Gastroenterology, Association of Upper Gastrointestinal Surgeons, trainees and trainers. Recommendations on OGD training and certification were formulated following literature review and appraised using Grading of Recommendations Assessment, Development and Evaluation. These were subjected to electronic voting to achieve consensus. Accepted statements were incorporated into the updated certification pathway. Results: In total, 32 recommendation statements were generated for the following domains: definition of competence (4 statements), acquisition of competence (12 statements), assessment of competence (10 statements) and post-certification support (6 statements). The consensus process led to following certification criteria: (1) performing ≥250 hands-on procedures; (2) attending a JAG-accredited basic skills course; (3) attainment of relevant minimal performance standards defined by British Society of Gastroenterology/Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, (4) achieving physically unassisted D2 intubation and J-manoeuvre in ≥95% of recent procedures, (5) satisfactory performance in formative and summative direct observation of procedural skills assessments. Conclusion: The JAG standards for diagnostic OGD have been updated following evidence-based consensus. These standards are intended to support training, improve competency assessment to uphold standards of practice and provide support to the newly-independent practitioner.