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Supplemental material, sj-docx-1-tag-10.1177_17562848221090834 for Corticosteroid-free efficacy and safety outcomes in patients receiving tofacitinib in the OCTAVE Sustain maintenance study by Stephan R. Vavricka, Thomas Greuter, Benjamin L. Cohen, Walter Reinisch, Flavio Steinwurz, Marc Fellmann, Xiang Guo, Nervin Lawendy, Jerome Paulissen and Laurent Peyrin-Biroulet in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-2-tag-10.1177_17562848221090834 for Corticosteroid-free efficacy and safety outcomes in patients receiving tofacitinib in the OCTAVE Sustain maintenance study by Stephan R. Vavricka, Thomas Greuter, Benjamin L. Cohen, Walter Reinisch, Flavio Steinwurz, Marc Fellmann, Xiang Guo, Nervin Lawendy, Jerome Paulissen and Laurent Peyrin-Biroulet in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848221090834 for Corticosteroid-free efficacy and safety outcomes in patients receiving tofacitinib in the OCTAVE Sustain maintenance study by Stephan R. Vavricka, Thomas Greuter, Benjamin L. Cohen, Walter Reinisch, Flavio Steinwurz, Marc Fellmann, Xiang Guo, Nervin Lawendy, Jerome Paulissen and Laurent Peyrin-Biroulet in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-2-tag-10.1177_17562848221090834 for Corticosteroid-free efficacy and safety outcomes in patients receiving tofacitinib in the OCTAVE Sustain maintenance study by Stephan R. Vavricka, Thomas Greuter, Benjamin L. Cohen, Walter Reinisch, Flavio Steinwurz, Marc Fellmann, Xiang Guo, Nervin Lawendy, Jerome Paulissen and Laurent Peyrin-Biroulet in Therapeutic Advances in Gastroenterology

Additional file1: Table S1. Characteristics of the included studies (detailed). Table S2. Baseline characteristics of participants with CD. Table S3. Baseline characteristics of participants with UC. Figure S1. Forest plots showing the proportion of patients with Crohn’s disease achieving a CDAI-70 response during the induction phase with infliximab (upper plot) or vedolizumab (lower plot). Figure S2. Forest plots showing the proportion of with Crohn’s disease achieving a CDAI-100 response during the induction phase with infliximab (upper plot) or vedolizumab (lower plot). Figure S3. Forest plots showing the proportion of patients with Crohn’s disease achieving a CDAI-70 response during the maintenance phase with infliximab. Figure S4. Forest plots showing the proportion of patients with Crohn’s disease achieving a CDAI-100 response during the maintenance phase with infliximab (upper plot) or vedolizumab (lower plot). Figure S5. Forest plots showing the proportion of patients with Crohn’s disease experiencing any adverse event with infliximab (upper plot) or vedolizumab (lower plot). Figure S6. Forest plots showing the proportion of patients with Crohn’s disease experiencing any serious adverse event with infliximab (upper plot) or vedolizumab (lower plot). Figure S7. Forest plots showing the proportion of patients with Crohn’s disease experiencing any infection with infliximab (upper plot) or vedolizumab (lower plot). Figure S8. Forest plots showing the proportion of patients with Crohn’s disease experiencing any serious infection with infliximab (upper plot) or vedolizumab (lower plot). Figure S9. Forest plots showing the proportion of patients with Crohn’s disease who discontinued due to adverse events in the infliximab (upper plot) or vedolizumab (lower plot) treatment arms. Figure S10. Forest plots showing the proportion of patients with Crohn’s disease who discontinued due to lack of efficacy in the infliximab treatment arm. Figure S11. Forest plots showing the proportion of patients with ulcerative colitis achieving a clinical response during the induction phase with infliximab (upper plot) or vedolizumab (lower plot). Figure S12. Forest plot showing the proportion of patients with ulcerative colitis achieving mucosal healing during the induction phase with infliximab. Figure S13. Forest plots showing the proportion of patients with ulcerative colitis achieving a clinical response during the maintenance phase with infliximab (upper plot) or vedolizumab (lower plot). Figure S14. Forest plots showing the proportion of patients with ulcerative colitis achieving mucosal healing during the maintenance phase with infliximab (upper plot) or vedolizumab (lower plot). Figure S15. Forest plots showing the proportion of patients with ulcerative colitis experiencing any adverse event with infliximab (upper plot) or vedolizumab (lower plot). Figure S16. Forest plots showing the proportion of patients with ulcerative colitis experiencing any serious adverse event with infliximab (upper plot) or vedolizumab (lower plot). Figure S17. Forest plots showing the proportion of patients with ulcerative colitis experiencing any infection with infliximab (upper plot) or vedolizumab (lower plot). Figure S18. Forest plots showing the proportion of patients with ulcerative colitis experiencing any serious infection with infliximab (upper plot) or vedolizumab (lower plot). Figure S19. Forest plots showing the proportion of patients with ulcerative colitis who discontinued due to adverse events with infliximab (upper plot) or vedolizumab (lower plot). Figure S20. Forest plots showing the proportion of patients with ulcerative colitis who discontinued due to lack of efficacy with vedolizumab.

BACKGROUND Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING F Hoffmann-La Roche.

Supplemental material, sj-docx-1-tag-10.1177_17562848211005708 for Extraintestinal manifestations at baseline, and the effect of tofacitinib, in patients with moderate to severe ulcerative colitis by David T. Rubin, Walter Reinisch, Thomas Greuter, Paulo G. Kotze, Marcia Pinheiro, Rajiv Mundayat, Eric Maller, Marc Fellmann, Nervin Lawendy, Irene Modesto, Stephan R. Vavricka and Gary R. Lichtenstein in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848211005708 for Extraintestinal manifestations at baseline, and the effect of tofacitinib, in patients with moderate to severe ulcerative colitis by David T. Rubin, Walter Reinisch, Thomas Greuter, Paulo G. Kotze, Marcia Pinheiro, Rajiv Mundayat, Eric Maller, Marc Fellmann, Nervin Lawendy, Irene Modesto, Stephan R. Vavricka and Gary R. Lichtenstein in Therapeutic Advances in Gastroenterology

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.

Management of Crohn’s disease (CD) is moving towards the therapeutic goal of mucosal healing and using biomarkers of inflammation, faecal calprotectin (FC) and C-reactive protein (CRP), to monitor patient progress. CALM demonstrated superior mucosal healing in patients whose treatment was escalated based on both symptoms and biomarkers than in patients managed by symptoms alone,1 but the optimal biomarker cut-offs to predict mucosal healing have not been established yet. In this analysis, association of endoscopic outcomes with FC and CRP at cut-offs from CALM was investigated.

During two pivotal clinical trials of the infliximab biosimilar CT-P13 (PLANETAS and PLANETRA), antidrug antibodies (ADAs) and neutralising antibodies (NAbs) were detected in the sera of patients treated with CT-P13 and the reference product (RP; Remicade).

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

A protocol for the development of an instrument for the early detection of Inflammatory Bowel Diseases.

Background The efficacy of a single administration of darvadstrocel (expanded allogeneic adipose-derived mesenchymal stem cells) for treating complex perianal fistulas in patients with Crohn’s disease was demonstrated in a randomized, double-blind trial (ADMIRE-CD [Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn\'s Disease] trial). The current chart review study (INSPECT [A retrospectIve chart review study evaluatINg the longer-term effectiveneSs of darvadstrocel in PatiEnts who CompleTed ADMIRE-CD]) evaluated the longer-term effectiveness and safety of darvadstrocel. Methods Eligible patients had completed at least 52 weeks in the ADMIRE-CD trial. Data on clinical remission and fistula relapse outcomes were collected retrospectively at 104 and 156 weeks after treatment. Adverse events of special interest (tumorigenicity and ectopic tissue formation) were collected up to 208 weeks after treatment. Results Eighty-nine patients were included (43 darvadstrocel patients, 46 control subjects). At 52, 104, and 156 weeks posttreatment, clinical remission was observed in 29 (67.4%) of 43, 23 (53.5%) of 43, and 23 (53.5%) of 43 darvadstrocel-treated patients, compared with 24 (52.2%) of 46, 20 (43.5%) of 46, and 21 (45.7%) of 46 control subjects, respectively. In patients with clinical remission at week 52, this remission was sustained at 104 and 156 weeks after treatment in 19 (65.5%) of 29 and 16 (55.2%) of 29 darvadstrocel-treated patients and in 17 (70.8%) of 24 and 13 (54.2%) of 24 control subjects, respectively. Time to fistula relapse and incidence of fistula relapse or new fistula occurrence were not significantly different between groups. Tumorigenicity was reported for 1 (2.2%) patient in the control group (malignant epidermoid carcinoma). No ectopic tissue formation was reported. Conclusions Real-world follow-up of patients from the ADMIRE-CD trial indicates that clinical remission of complex perianal fistulas can be sustained in the long term irrespective of whether it is achieved through darvadstrocel administration or maintenance treatment regimens and confirms a favorable long-term safety profile of darvadstrocel.

BACKGROUND & AIMS: We investigated the effects of inducing deep remission in patients with early Crohn's disease (CD). METHODS: We collected follow-up data from 122 patients (mean age, 31.2 ± 11.3 y) with early, moderate to severe CD (median duration, 0.2 years; interquartile range, 0.1-0.5) who participated in the Effect of Tight Control Management on CD (CALM) study, at 31 sites, representing 50% of the original CALM patient population. Fifty percent of patients (n = 61) were randomly assigned to a tight control strategy (increased therapy based on fecal level of calprotectin, serum level of C-reactive protein, and symptoms), and 50% were assigned to conventional management. We categorized patients as those who were vs were not in deep remission (CD endoscopic index of severity scores below 4, with no deep ulcerations or steroid treatment, for 8 or more weeks) at the end of the follow-up period (median, 3.02 years; range, 0.05-6.26 years). The primary outcome was a composite of major adverse outcomes that indicate CD progression during the follow-up period: new internal fistulas or abscesses, strictures, perianal fistulas or abscesses, or hospitalization or surgery for CD. Kaplan-Meier and penalized Cox regression with bootstrapping were used to compare composite rates between patients who achieved or did not achieve remission at the end of the follow-up period. RESULTS: Major adverse outcomes were reported for 34 patients (27.9%) during the follow-up period. Significantly fewer patients in deep remission at the end of the CALM study had major adverse outcomes during the follow-up period (P = .01). When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07-0.31) was significantly associated with a lower risk of major adverse outcome. CONCLUSIONS: In an analysis of follow-up data from the CALM study, we associated induction of deep remission in early, moderate to severe CD with decreased risk of disease progression over a median time of 3 years, regardless of tight control or conventional management strategy. ispartof: GASTROENTEROLOGY vol:159 issue:1 pages:139-147 ispartof: location:United States status: published

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