Clinical statistical analysis plan for the ACCURE trial:the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicentre trial

Background: The primary treatment of ulcerative colitis (UC) is medical therapy using a standard step-up approach. An appendectomy might modulate the clinical course of UC, decreasing the incidence of relapses and reducing need for medication. The objective of the ACCURE trial is to assess the efficacy of laparoscopic appendectomy in addition to standard medical treatment in maintaining remission in UC patients. This article presents the statistical analysis plan to evaluate the outcomes of the ACCURE trial. Design and methods: The ACCURE trial was designed as a multicentre, randomised controlled trial. UC patients with a new diagnosis or a disease relapse within the past 12 months, treated with 5-ASA, corticosteroids, or immunomodulators until complete clinical and endoscopic remission (defined as total Mayo score < 3 with endoscopic subscore of 0 or 1), were counselled for inclusion. Also, patients previously treated with biologicals who had a washout period of at least 3 months were considered for inclusion. Patients were randomised (1:1) to laparoscopic appendectomy plus maintenance treatment or a control group (maintenance therapy only). The primary outcome is the 1-year UC relapse rate (defined as a total Mayo-score ≥ 5 with endoscopic subscore of 2 or 3, or clinically as an exacerbation of symptoms and rectal bleeding or FCP > 150 or intensified medical therapy other than 5-ASA therapy). Secondary outcomes include number of relapses per patient, time to first relapse, disease activity, number of colectomies, medication usage, and health-related quality of life. Discussion: The ACCURE trial will provide comprehensive evidence whether adding an appendectomy to maintenance treatment is superior to maintenance treatment only in maintaining remission in UC patients. Trial registration: Dutch Trial Register (NTR) NTR2883. Registered May 3, 2011. ISRCTN, ISRCTN60945764. Registered August 12, 2019

Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn’s disease

Background & Aims: We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD). Methods: We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%. Results: Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group. Conclusions: In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib's benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649

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DMPs on chromosome X. The location data: Illumina probe ID, chromosome, position, strand, UCSC gene symbol, UCSC genetic feature and regulatory feature, are shown alongside the methylation statistics: mean difference in beta, the p values and the BH-adjusted p values. DMPs associated to either PABPC5 or MIR223 are indicated in bold. (XLSX 12 kb

Anti-interleukin-23 agents for the treatment of ulcerative colitis

Introduction: Treatment of ulcerative colitis (UC) aims to control symptoms and to suppress intestinal inflammation. Despite considerable advances, a proportion of patients do not respond to currently available drugs. The interleukin (IL)-23 axis plays a significant role in the pathogenesis of UC and has thus become an important target for drug development. Areas covered: The review briefly summarizes the pathophysiology of the IL-12/23 axis and provides a synopsis of the available evidence for efficacy and safety of ustekinumab, mirikizumab (LY3074828), risankizumab (BI655066/ABBV066), brazikumab (MEDI2070; formerly AMG139) and guselkumab (CNTO1959) in UC. We also provide an overview of ongoing and anticipated trials in this field. Expert opinion: A Phase 2 trial with mirikizumab and a Phase 3 trial with ustekinumab have demonstrated the efficacy of anti-IL-23 agents in achieving clinical and endoscopic outcomes in UC with a favorable safety profile. Trials of other anti-IL-23 agents in UC are under way and designed to explore head-to-head efficacy with existing biologics, as well as the prospect of combination biological therapy. Apart from data on longer term efficacy and safety, future trials should also explore strategies to inform the positioning of IL-23 antagonists in therapeutic algorithms

Rational and clinical development of the anti-MAdCAM monoclonal antibody for the treatment of IBD

Introduction: Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression in gut-associated lymphoid tissue is upregulated in patients with inflammatory bowel disease (IBD). Blocking adhesion molecules and thereby inhibiting migration of lymphocytes into sites of inflammation in the gut is an attractive new treatment target in drug development for IBD. Areas covered: This review discusses the preclinical and clinical experience on SHP647 (previously called PF-00547659 and PF-00547,659), a fully human IgG2K monoclonal antibody that binds to MAdCAM-1 to selectively reduce lymphocyte homing to the intestinal tract. Expert opinion: Blocking endothelial adhesion molecule MAdCAM−1 could represent an attractive target for the treatment of IBD. In the next years, the results from the phase III studies as well as data to support therapeutic drug monitoring based on drug levels to guide and optimize individual therapy will become available. Furthermore, much effort is put in the development of clinical prediction models to predict which drug is optimal for an individual patient

Biologic Therapies: From Complexity to Clinical Practice in a Changing Environment

This symposium provided an opportunity for global experts to discuss the challenges posed by the introduction of biosimilars. The impact of the manufacturing process on clinical outcomes, maintaining treatment responses over the long term, and issues surrounding patient management in a changing environment were addressed. The symposium was opened by Prof Panaccione describing the evolution of inflammatory bowel disease (IBD) treatment in the last 20 years and how biologics have improved outcomes. Prof D’Haens provided an explanation of the complexity surrounding biologic drug development and the hurdles facing drug manufacturers when ensuring high quality and consistently performing products over time. Prof Panaccione discussed the clinical challenges in balancing the transition from induction to maintenance therapy in order to provide a clinically relevant and sustained response to therapy. He also discussed the evidence for long-term outcomes with adalimumab for IBD. Prof Feagan highlighted the issues faced by clinicians treating patients with biologics, including the ability to switch between biologics without loss of efficacy or impact on safety, and the need to consider interchangeability between biologic therapies and the potential risk and impact of immunogenicity