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This is a plain language summary (PLS) of an article published in a peer-reviewed scientific journal. This PLS is not peer-reviewed. The publisher of the orignial manuscript was not involved in the preparation of this PLS and has neither reviewed not approved its content.

In the 1990s, tumour necrosis factor-alpha inhibitor therapy ushered in the biologic therapy era for inflammatory bowel disease, leading to marked improvements in treatment options and patient outcomes. There are currently four tumour necrosis factor-alpha inhibitors approved as treatments for ulcerative colitis and/or Crohn's disease: infliximab, adalimumab, golimumab and certolizumab pegol. Despite the clear benefits of tumour necrosis factor-alpha inhibitors, a subset of patients with inflammatory bowel disease either do not respond, experience a loss of response after initial clinical improvement or report intolerance to anti-tumour necrosis factor-alpha therapy. Optimizing outcomes of these agents may be achieved through earlier intervention, the use of therapeutic drug monitoring and thoughtful switching within class. To complement these approaches, evolving predictive biomarkers may help inform and optimize clinical decision making by identifying patients who might potentially benefit from an alternative treatment strategy. This review will focus on the current use of tumour necrosis factor-alpha inhibitors in inflammatory bowel disease and the application of personalized medicine to improve future outcomes for all patients.

BACKGROUND: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P

Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis.We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups.Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

Background For patients with UC, flexible maintenance dosing therapy may confer advantages for safety, efficacy, costs and patient preference. Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Aim To assess the efficacy and safety of tofacitinib dose de-escalation and escalation in patients with UC. Methods We evaluated data (November 2017 data cut-off) from OCTAVE Open, an ongoing, open-label, long-term extension study. The dose de-escalation group comprised 66 tofacitinib induction responders in remission following 52 weeks' tofacitinib 10 mg b.d. maintenance therapy, subsequently de-escalated to 5 mg b.d. in OCTAVE Open. The dose escalation group comprised 57 tofacitinib induction responders who experienced treatment failure while receiving 5 mg b.d. maintenance therapy, subsequently escalated to 10 mg b.d. in OCTAVE Open. Results After tofacitinib de-escalation, 92.4% (61/66) and 84.1% (53/63) of patients maintained clinical response and 80.3% (53/66) and 74.6% (47/63) maintained remission, at months 2 and 12, respectively. After dose escalation, 57.9% (33/57) and 64.9% (37/57) of patients recaptured clinical response and 35.1% (20/57) and 49.1% (28/57) were in remission, at months 2 and 12, respectively. The incidence rate of herpes zoster with dose escalation (7.6 patients with events/100 patient-years) was numerically higher than in the overall tofacitinib UC programme. Conclusions Following tofacitinib de-escalation in patients already in remission on 10 mg b.d., most maintained remission, although 25.4% lost remission, at month 12. For induction responders who dose-escalated following treatment failure on 5 mg b.d. maintenance therapy, 49.1% achieved remission by month 12. (ClinicalTrials.gov number: NCT01470612).

The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore1 [range, 0 to 3] on any of the four Mayo scale components).The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo.Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).

International audience; BACKGROUND & AIMS:There is no consensus on the best way to integrate biomarkers into inflammatory bowel disease (IBD) research and clinical practice. The International Organization for the Study of Inflammatory Bowel Disease aimed to outline biomarker definitions, categories, and operating properties required for their use in registration trials and clinical practice. Using fecal calprotectin as an example, we provide a framework for biomarker development and validation in patients with IBD.METHODS:We reviewed international society guidelines, regulatory agency guidance documents, and standardized reporting guidelines for biomarkers, in combination with publications on fecal calprotectin levels in patients with IBD. We assessed the validity of fecal calprotectin to serve as a surrogate biomarker of IBD activity and outlined a framework for further validation and development of biomarkers.RESULTS:No endpoints have been fully validated as surrogates of risk of disease complications; mucosal healing is the most valid endpoint used to determine risk of disease complications. Fecal level of calprotectin has not been validated as a biomarker for IBD activity because of lack of technical and clinical reliability, assessment of performance when used as a replacement for endoscopy, and assessment of responsiveness to changes in disease states. The level of fecal calprotectin can be used only as a prognostic factor for disease recurrence in patients in remission after medical or surgical treatment.CONCLUSIONS:We reviewed guidelines, regulatory documents, and publications to identify properties required for the development of biomarkers of IBD activity and areas in need of clarification from regulatory agencies and societies. We propose a path forward for research of biomarkers for IBD.Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

BACKGROUND & AIMS: Vedolizumab is a gut-selective monoclonal antibody for the treatment of moderately to severely active Crohn's disease (CD). We performed a prospective study of endoscopic, radiologic, and histologic healing in patients with CD who received vedolizumab therapy. METHODS: We performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220-450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline. Participants received vedolizumab (300 mg intravenously) at weeks 0, 2, and 6, and then every 8 weeks thereafter, for 26 weeks (primary study) or 52 weeks (substudy, 56 patients). The primary endpoint at week 26 was endoscopic remission (SES-CD score of 4 or less); other endpoints included endoscopic response (50% reduction in SES-CD), radiologic remission (magnetic resonance index of activity score below 7), and histologic response (modified global histologic disease activity score of 4 or less). RESULTS: At week 26, 11.9% of patients were in endoscopic remission (95% confidence interval [CI] 6.3-9.8); at week 52, 17.9% of the patients were in endoscopic remission (95% CI 8.9-30.4). Higher proportions of patients naïve to TNF antagonists achieved endoscopic remission than patients with TNF-antagonist-failure at weeks 26 and 52. Higher proportion of patients with moderate CD (SES-CD scores, 7-15) achieved endoscopic remission at weeks 26 and 52 than patients with severe CD (SES-CD scores above 15). The proportion of patients with complete mucosal healing increased over time, with greater rates of healing in the colon than in the ileum. Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3-40.0) and in 38.1% at week 52 (95% CI 18.1-61.6). At week 26, 24.4% of patients had a histologic response in the colon (95% CI 15.3-35.4) and 28.3% of patients had a histologic response in the ileum (95% CI 17.5-41.4). At week 52, 20.5% of patients had a histologic response in the colon (95% CI 9.8-35.3) and 34.3% of patients had a histologic response in the ileum (95% CI 19.1-52.2). There were no notable safety issues, including worsening of extraintestinal manifestations. CONCLUSIONS: In a phase 3b trial, we found that 26 and 52 weeks of treatment with vedolizumab (300 mg, at weeks 0, 2, and 6, and then every 8 weeks thereafter) induces endoscopic, radiologic, and histologic healing in patients with moderately to severely active CD. ClinicalTrials.gov no: NCT02425111. ispartof: GASTROENTEROLOGY vol:157 issue:4 pages:1007-+ ispartof: location:United States status: published

Summary Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Aim To report incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the tofacitinib UC programme. Methods DVT and PE were evaluated from one phase 2 and two phase 3 induction studies, one phase 3 maintenance study and an ongoing, open‐label, long‐term extension (OLE) study (September 2018 datacut). Data were analysed in induction, maintenance and overall (patients receiving ≥ 1 dose of tofacitinib 5 or 10 mg b.d. in any phase 2, 3 or OLE study) cohorts. Results 1157 patients (2404 patient‐years’ exposure; ≤ 6.1 years’ tofacitinib treatment) were evaluated in the overall cohort. In induction, one placebo‐treated patient had DVT and one had PE; no tofacitinib‐treated patients had DVT/PE. In maintenance, one placebo‐treated patient had DVT and one had PE; no tofacitinib‐treated patients had DVT/PE. In the overall cohort, one patient had DVT (incidence rate [patients with events/100 patient‐years; 95% CI]: 0.04 [0.00‐0.23]); four had PE (0.16 [0.04‐0.41]); all received predominant dose tofacitinib 10 mg b.d.; all had venous thromboembolism risk factors alongside UC. Conclusions In this post hoc analysis of patients with UC, during tofacitinib exposure, one patient had DVT and four had PE, all during the OLE study, on predominant dose 10 mg b.d. (83% of overall cohort patients received predominant dose 10 mg b.d.) with venous thromboembolism risk factors. This analysis is limited by small sample size and limited drug exposure; further studies are needed. ClinicalTrials.gov: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Background & Aims Most patients with Crohn's disease (CD) eventually require an intestinal resection. However, CD frequently recurs after resection. We performed a randomized trial to compare the ability of infliximab vs placebo to prevent CD recurrence. Methods We evaluated the efficacy of infliximab in preventing postoperative recurrence of CD in 297 patients at 104 sites worldwide from November 2010 through May 2012. All study patients had undergone ileocolonic resection within 45 days before randomization. Patients were randomly assigned (1:1) to groups given infliximab (5 mg/kg) or placebo every 8 weeks for 200 weeks. The primary end point was clinical recurrence, defined as a composite outcome consisting of a CD Activity Index score >200 and a ≥70-point increase from baseline, and endoscopic recurrence (Rutgeerts score ≥i2, determined by a central reader) or development of a new or re-draining fistula or abscess, before or at week 76. Endoscopic recurrence was a major secondary end point. Results A smaller proportion of patients in the infliximab group had a clinical recurrence before or at week 76 compared with the placebo group, but this difference was not statistically significant (12.9% vs 20.0%; absolute risk reduction [ARR] with infliximab, 7.1%; 95% confidence interval: -1.3% to 15.5%; P =.097). A significantly smaller proportion of patients in the infliximab group had endoscopic recurrence compared with the placebo group (30.6% vs 60.0%; ARR with infliximab, 29.4%; 95% confidence interval: 18.6% to 40.2%; P

Background & Aims Intestinal fibrosis is a challenge to management of patients with Crohn's disease (CD); there is an urgent need to expedite development of antifibrosis drugs for this disease. The International Organization for the Study of Inflammatory Bowel Disease (IOIBD) aimed to identify a set of endpoints that can be used to determine efficacy of antifibrosis agents tested in clinical trials of patients with CD. Methods We conducted a systematic review to identify clinical, radiologic, biochemical, endoscopic, and composite endpoints used in assessing activity of fibrostenosing CD and response to treatment, and determined their operational properties. A panel of IOIBD experts performed a consensus process to identify the best endpoints for inclusion in clinical trials, through a 2-round, Delphi-style online survey. Results A total of 36 potentially relevant endpoints for intestinal fibrosis were selected and assessed. Forty-eight physicians with expertise in inflammatory bowel disease, from 5 regions (North America, Europe, Middle East, Asia/Pacific, and Latin America), participated in the Delphi consensus process. A core set of 13 endpoints (complete clinical response, long-term efficacy, sustained clinical benefit, treatment failure, radiological remission, normal quality of life, clinical remission without steroids, therapeutic failure, deep remission, complete absence of occlusive symptoms, symptom-free survival, bowel damage progression, and no disability) were rated as critical. Agreement was high among the experts. Conclusions Members of the IOIBD reached expert consensus on a set of endpoints that can be used to assess antifibrosis agents in trials of patients with CD. Studies are needed to clarify methods for measuring these outcomes and validate measurement instruments.

The therapeutic landscape for inflammatory bowel disease [IBD] is rapidly evolving. Two new biologic drugs, vedolizumab and ustekinumab, have recently entered the marketplace, the first biosimilars have been introduced, and several other agents are at an advanced stage of clinical development. In parallel, therapeutic goals have shifted from symptom control towards mucosal healing and prevention of bowel damage. In the coming years, gastroenterologists will be faced with unprecedented choices when selecting the best treatment for their patients with IBD. In this article, we review existing data on the mechanisms of action, efficacy, and safety of recently approved and late-stage pipeline therapies, and use this information to speculate on the positioning of these drugs, alone or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis.

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

Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight ( 2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of 200; clinical management group after random assignment: CDAI decrease of

Background and Aims: The GEMINI long-term safety (LTS) study is a continuing phase 3 trial investigating the safety and efficacy of vedolizumab, an α4β7 integrin antagonist for ulcerative colitis (UC) and Crohn’s disease. We provide an interim analysis of efficacy in patients with UC. Methods: Patients from the C13004 and GEMINI 1 studies and a cohort of vedolizumab-naive patients received open-label vedolizumab every 4 weeks. Interim data were collected from 22 May 2009 to 27 June 2013. Clinical response and remission, evaluated using partial Mayo scores, and health-related quality of life (HRQL) were assessed for up to 152 weeks of cumulative treatment in the efficacy population. Results: As of 27 June 2013, 63% of the efficacy population (n=532/845) were continuing treatment. Among patients who responded to vedolizumab induction and had data available, 88% (n=120/136) were in remission after 104 weeks of exposure (96% [n=70/73] after 152 weeks). Among patients who withdrew from every-8-week vedolizumab maintenance in GEMINI 1 (n=32) before week 52, increased dosing to every 4 weeks in GEMINI LTS resulted in response and remission rates of 41% and 28%, respectively, after 52 weeks, an increase from 19% and 6%, respectively, from before the dose increase. Similar benefits were demonstrated regardless of prior tumour necrosis factor-antagonist exposure. Durable benefits on HRQL were also observed. Conclusions: Patients with UC experienced clinical and HRQL improvements with continued vedolizumab treatment. Increased dosing frequency to every 4 weeks was beneficial in patients who had loss of response to 8-weekly dosing. ClinicalTrials.gov ID [NCT00790933][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00790933&atom=%2Feccojc%2Fearly%2F2016%2F09%2F28%2Fecco-jcc.jjw177.atom

Background: Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. METHODS: We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. RESULTS: In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P

Background and Aims: Vedolizumab is a gut-selective α4β7 integrin antagonist therapy for ulcerative colitis and Crohn’s disease. The GEMINI long-term safety (LTS) trial is an ongoing open-label study investigating the safety of vedolizumab. We present interim exploratory analyses of efficacy in patients with Crohn’s disease. Methods: Patients from the C13004, GEMINI 2, and GEMINI 3 studies and vedolizumab-naive patients could enrol in GEMINI LTS and received vedolizumab every 4 weeks. Data were collected from 22 May 2009 to 27 June 2013. Outcomes of clinical response and remission, defined by the Harvey-Bradshaw Index, and health-related quality of life (HRQL) were assessed for up to 152 weeks of treatment in the efficacy population. Results: Among patients with response at week 6 in GEMINI 2 who received vedolizumab continuously, 83% (n=100/120) and 89% (n=62/70) of patients with available data were in remission after 104 and 152 weeks, respectively. Increased dosing frequency from every 8 weeks (GEMINI 2) to every 4 weeks (GEMINI LTS) improved outcomes in patients who had withdrawn early from GEMINI 2, with 47% (n=27/57) experiencing clinical response and 32% (n=18/57) in remission at week 52 of GEMINI LTS (up from 39% and 4% before the dose increase). Similar improvements were observed regardless of prior tumour necrosis factor (TNF)-antagonist exposure. Long-term benefits of HRQL were also observed. Conclusions: The clinical benefits of vedolizumab continued with long-term treatment regardless of prior TNF antagonist exposure. Increased dosing frequency might improve outcomes in patients who lose response to conventional 8-weekly dosing. ClinicalTrials.gov ID [NCT00790933][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00790933&atom=%2Feccojc%2Fearly%2F2016%2F09%2F28%2Fecco-jcc.jjw176.atom

Summary Background PF-00547659 is a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to selectively reduce lymphocyte homing to the intestinal tract. We aimed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe ulcerative colitis. Methods This phase 2, randomised, double-blind, placebo-controlled clinical trial recruited patients aged 18–65 years from 105 centres in 21 countries, with a history (≥3 months) of active ulcerative colitis extending more than 15 cm beyond the anal verge (with a total Mayo score ≥6 and a Mayo endoscopic subscore ≥2) who had failed or were intolerant to at least one conventional therapy. Patients were stratified by previous anti-TNFα treatment, and randomly assigned by a computer-generated randomisation schedule to receive a subcutaneous injection of 7·5 mg, 22·5 mg, 75 mg, or 225 mg PF-00547659 or placebo at baseline, then every 4 weeks. Patients, investigators, and sponsors were blinded to the treatment. The primary endpoint was the proportion of patients achieving remission (total Mayo score ≤2 with no individual subscore >1 and rectal bleeding subscore ≤1) at week 12. The efficacy analysis included all patients who received at least one dose of the randomised treatment; the safety analysis was done according to treatment received. All p values were one-sided and multiplicity-adjusted. This study is registered with ClinicalTrials.gov, number NCT01620255. Findings Between Nov 2, 2012, and Feb 4, 2016, we screened 587 patients; 357 were eligible and randomly assigned to receive placebo (n=73) or PF-00547659 at doses of 7·5 mg (n=71), 22·5 mg (n=72), 75 mg (n=71), or 225 mg (n=70). Remission rates at week 12 were significantly greater in three of four active-treatment groups than in the placebo group (2·7% [two of 73]): 7·5 mg (11·3% [eight of 71]), 22·5 mg (16·7% [12 of 72]), 75 mg (15·5% [11 of 71]), and 225 mg (5·7% [four of 70]). These rates corresponded to a stratum-adjusted (anti-TNFα-naive and anti-TNFα-experienced) risk difference versus placebo of 8·0% for 7·5 mg (90% CI 1·9 to 14, p=0·0425), 12·8% for 22·5 mg (5·6 to 19·9, p=0·0099), 11·8% for 75 mg (4·8 to 18·8, p=0·0119), and 2·6% for 225 mg (−1·2 to 6·4, p=0·1803). Four of 73 (5·5%) patients had a serious adverse event in the placebo group, ten of 71 (14·1%) in the 7·5 mg group, one of 70 (1·4%) in the 22·5 mg group, three of 73 (4·1%) in the 75 mg group, and three of 70 (4·3%) in the 225 mg group. No safety signal was observed for the study drug. Interpretation PF-00547659 was safe and well tolerated in this patient population, and better than placebo for induction of remission in patients with moderate to severe ulcerative colitis. The greatest clinical effects were observed with the 22·5 mg and 75 mg doses. Funding Pfizer.

International audience; BACKGROUND:Crohn's disease (CD) is a chronic disabling and progressive IBD. Only strategies looking beyond symptoms and based on tight monitoring of objective signs of inflammation such as mucosal lesions may have the potential for disease modification. Endoscopic evaluation is currently the gold standard to assess mucosal lesions and has become a major therapeutic endpoint in clinical trials. Several endoscopic indices have been proposed to evaluate disease activity; unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response and endoscopic remission in CD.METHODS:In these recommendations from the International Organization for the Study of Inflammatory Bowel Disease, we first reviewed all technical aspects of available endoscopic scoring systems in the literature. Second, in order to achieve consensus on endoscopic definitions of remission and response in trials, a two-round vote based on a Delphi method was performed among 14 specialists in the field of IBDs.RESULTS:At the end of the voting process, the investigators ranked first a >50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) or Crohn's Disease Endoscopic Index of Severity for the definition of endoscopic response, and an SES-CD 0-2 for the definition of endoscopic remission in CD. All experts agreed on a Rutgeerts' score i0-i1 for the definition of endoscopic remission after surgery.

To evaluate the efficacy and safety of oral budesonide for maintenance of remission in patients with mild to moderately active Crohn's disease (CD) of the ileum and/or ascending colon.Four double-blind, placebo-controlled trials with identical protocols were combined according to a predetermined analysis plan. Three hundred eighty patients with CD in medically induced remission (CD activity index [CDAI]or =150) were randomized to receive oral budesonide 3 mg, 6 mg, or placebo daily for 12 months. The primary outcome measure was time to relapse (increase in CDAI of 60 points above baseline and150).The median time to relapse was 268, 170, and 154 days for budesonide 6 mg, budesonide 3 mg, and placebo groups, respectively (p= 0.0072). The frequency of adverse events and glucocorticosteroid side effects were similar in all groups.Budesonide 6 mg/day is effective for prolonging time to relapse and for significantly reducing rates of relapse at 3 and 6 months but not 12 months in patients with CD in medically induced remission.

BACKGROUND & AIMS: Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through γ-chain-containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn's disease. METHODS: Patients (N = 139; age, ≥18 y) with moderate-to-severe active Crohn's disease were assigned randomly to groups given 1 mg (n = 36), 5 mg (n = 34), or 15 mg (n = 35) tofacitinib or placebo (n = 34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary end point was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn's Disease Activity Index score of ≥70 points [Response-70]). Secondary end points included clinical remission (Crohn's Disease Activity Index score of

Treatment of inflammatory bowel disease has greatly improved with the development of targeted, monoclonal antibody–based therapies. Tumor necrosis factor antagonists are frequently used to treat patients with Crohn's disease or ulcerative colitis, but they have side effects and their efficacy often decreases with use. New, more effective drugs are therefore needed and in development. However, many agents that appeared to be promising in preclinical studies have failed to show efficacy in clinical trials. We discuss possible reasons for the failures of these reagents in trials, which include the high rate of response to placebo, an inadequate range of doses, inappropriate timing of end point measurements, the changing therapeutic environment, and the competitive trial system. We also review regulatory guidelines for end points and trial design and recommend ways to improve trials.

Background & Aims Mucosal healing might alter midterm and long-term outcomes of patients with Crohn's disease (CD) and has become an important end point in clinical trials. However, the minimal degree of mucosal improvement (endoscopic response) required to alter midterm outcomes is not known. We aimed to determine the best definition of endoscopic response by evaluating data on the Simple Endoscopic Score for Crohn's Disease (SES-CD) and the Crohn's Disease Endoscopic Index of Severity (CDEIS) from the Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC trial). Methods We analyzed data from 172 patients who participated in the SONIC trial, were found to have endoscopic lesions at baseline, and underwent a second endoscopic examination at week 26 of treatment with infliximab, azathioprine, or both. Mucosal healing was defined as absence of ulcers. A central reader calculated SES-CD and CDEIS results. Different cutoff values were set for endoscopic response based on the SES-CD or CDEIS. The diagnostic ability of these different cutoff values was evaluated using receiver operating characteristic (ROC) curves, positive likelihood ratios (PLR), and negative likelihood ratios (NLR). Corticosteroid-free clinical remission (CFREM) at week 50 was used as a binary classifier. Results Based on analyses of ROC curves, PLR, and NLR, endoscopic response was defined as a decrease from baseline in SES-CD of at least 50%. At week 26, mucosal healing and endoscopic response were achieved in 48% and 65% of patients, respectively. Mucosal healing at week 26 was associated with CFREM at week 50, with 56% sensitivity, 65% specificity, a PLR of 1.60, and an NLR of 0.67. Endoscopic response at week 26 was associated with CFREM at week 50, with 74% sensitivity, 48% specificity, a PLR of 1.42, and an NLR of 0.54. Endoscopic response, defined as a decrease from baseline in CDEIS of at least 50%, yielded similar results. Conclusions In patients with CD, mucosal healing and endoscopic response (defined as a decrease from baseline in SES-CD or CDEIS of at least 50%) at week 26 of treatment identified those most likely to be in CFREM at week 50. The ability of the proposed endoscopic response cutoff value to predict midterm CFREM should be validated in an independent, prospective cohort. Its correlation with changes in long-term disease progression still needs to be demonstration. ClinicalTrials.gov, Number: NCT00094458.