Development and Validation of a Scoring System to Predict Outcomes of Vedolizumab Treatment in Patients With Crohn's Disease.

Background & Aims: As more treatment options for inflammatory bowel diseases become available, it is important to identify patients most likely to respond to different therapies. We created and validated a scoring system to identify patients with Crohn's disease (CD) who respond to vedolizumab.

Methods: We collected data from the GEMINI 2 phase 3 trial of patients with active CD treated with vedolizumab for 26 weeks (n = 814) and performed logistic regression analysis to identify factors associated with clinical, steroid-free, and durable remission (derivation set).

The Role of Biomarkers in Clinical Trials of Inflammatory Bowel Disease.

Clinical trials require valid outcome measures to assess the therapeutic benefit of investigational agents. Recently, regulatory authorities have mandated the use of patient-reported outcomes in combination with an objective measure of disease activity as primary outcome measures in inflammatory bowel disease trials. Endoscopy has commonly fulfilled the latter role; however, due to the costs and complexity of these assessments, interest has emerged in the use of noninvasive biomarkers.

Respiratory Tract Infections in Patients With Inflammatory Bowel Disease: Safety Analyses From Vedolizumab Clinical Trials.

Background And Aims: Vedolizumab, a humanised monoclonal antibody for the treatment of inflammatory bowel disease, selectively blocks gut lymphocyte trafficking. This may reduce the risk of respiratory tract infections [RTIs] compared with systemic immunosuppressive therapies. To assess this possibility, we evaluated the rates of RTIs in clinical trials of vedolizumab.

Evolution of the Randomized Controlled Trial in Inflammatory Bowel Disease: Current Challenges and Future Solutions.

As knowledge of the pathogenesis of inflammatory bowel disease (IBD) has grown, many new medical therapies have become available. Evaluation of the efficacy and safety of new drugs has conventionally been established with placebo-controlled randomized trials. However, given that highly effective and safe biologic agents such as tumor necrosis factor (TNF) antagonists, vedolizumab, and ustekinumab are currently available, the continued use of placebo-controlled studies to evaluate new molecules should be questioned.

Evaluation of the effect of storage condition on cell extraction and flow cytometric analysis from intestinal biopsies.

Background: Flow cytometric (FC) analysis of intestinal tissue biopsies requires prompt cell isolation and processing to prevent cell death and generate valid data. We examined the effect of storage conditions prior to cell isolation and FC on viable cell yield and the proportions of immune cell phenotypes from intestinal biopsies.

Methods: Biopsies (N = 224) from inflamed or non-inflamed ileal and/or colonic tissue from three patients with Crohn's disease were processed and analyzed immediately in duplicate, or stored under different conditions.

The Effects of Ustekinumab on Health-related Quality of Life in Patients With Moderate to Severe Crohn's Disease.

Background And Aims: We assessed the effect of ustekinumab on health-related quality of life [HRQOL] in adults with Crohn's disease [CD].

Methods: Patients with moderately to severely active CD and inadequate response or intolerance to tumour necrosis factor antagonists [UNITI-1, n = 741], or conventional therapy [UNITI-2, n = 627] were randomised to placebo, ustekinumab 130 mg, or 6 mg/kg intravenous induction therapy. At Week 8, ustekinumab-treated responders (Crohn's Disease Activity Index [CDAI] reduction ≥100 or CDAI <150 points) were re-randomised to subcutaneous maintenance therapy [IM-UNITI, n = 388] with placebo, ustekinumab 90 mg every 12 weeks [q12w], or ustekinumab 90 mg every 8 weeks [q8w], for 44 additional weeks.

Performance of Crohn's disease Clinical Trial Endpoints based upon Different Cutoffs for Patient Reported Outcomes or Endoscopic Activity: Analysis of EXTEND Data.

Background: Clinical trial endpoints for Crohn's disease (CD) activity correlate poorly with mucosal inflammation; to assess treatment efficacy, patient-reported outcomes and endoscopic assessments are preferred. This study assessed the impact on treatment efficacy estimations of using different definitions of clinical and endoscopic remission and endoscopic response, and of using site- or central-based endoscopy evaluation.

Methods: This post hoc analysis of data fromEXTEND (extend the safety and efficacy of adalimumab through endoscopic healing), a placebo (PBO)-controlled, randomized trial of adalimumab (ADA) for mucosal healing, included adults with moderate-to-severe CD.

Reliability among central readers in the evaluation of endoscopic disease activity in pouchitis.

Background And Aims: Pouchitis is a common adverse event after proctocolectomy with ileal pouch anal anastomosis for ulcerative colitis. Evaluation of pouchitis disease activity and response to treatment requires use of validated indices. We assessed the reliability of items evaluating endoscopic pouchitis disease activity.

Development of Reliable, Valid and Responsive Scoring Systems for Endoscopy and Histology in Animal Models for Inflammatory Bowel Disease.

Background And Aims: Although several endoscopic and histopathologic indices are available for evaluating the severity of inflammation in mouse models of colitis, the reliability of these scoring instruments is unknown. Our aim was to evaluate the reliability of the individual items in the existing indices and develop new scoring systems by selection of the most reliable index items.

Methods: Two observers scored the histological slides [n = 224] and endoscopy videos [n = 201] from treated and untreated Interleukin[IL]-10 knock-out and T-cell transferred SCID mice.

Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease: A Systematic Review.

Background & Aims: Endpoints in randomized controlled trials (RCTs) of Crohn's disease (CD) are changing. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD.

Methods: We searched the MEDLINE, EMBASE, and the Cochrane Library through March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules.

Effects of Vedolizumab Therapy on Extraintestinal Manifestations in Inflammatory Bowel Disease.

Background: Approximately 15-20% of ulcerative colitis patients and 20-40% of those with Crohn's disease experience extraintestinal manifestations (EIMs) of their inflammatory bowel disease (IBD). Clinicians who treat IBD must manage EIMs affecting multiple organs that variably correlate with intestinal disease activity. Vedolizumab is a monoclonal antibody for the treatment of IBD with a gut-selective mechanism of action.

Efficacy of Vedolizumab in Fistulising Crohn's Disease: Exploratory Analyses of Data from GEMINI 2.

Background And Aims: Medical management of fistulising Crohn's disease [CD] is constrained by the limited number of available therapies. We evaluated the efficacy of vedolizumab, a gut-selective α4β7 integrin antagonist approved for treating moderately to severely active CD, in a subpopulation of patients with fistulising CD who participated in the GEMINI 2 trial [NCT00783692].

Methods: Exploratory analyses of data from the GEMINI 2 trial were conducted in 461 responders to 6-week vedolizumab induction therapy who received maintenance placebo [VDZ/PBO, N = 153] or vedolizumab [VDZ/VDZ, N = 308].

Infliximab for Crohn's Disease: More Than 13 Years of Real-world Experience.

Background: The purpose of this study was to compare the long-term safety of infliximab and nonbiologic agents as Crohn's disease (CD) therapy.

Methods: Patients with CD were prospectively evaluated in this large, observational registry.

Results: Patients (n = 6273) participated in this observational registry from July 1999 through March 2012; 3440 (54.

Policy Options for Infliximab Biosimilars in Inflammatory Bowel Disease Given Emerging Evidence for Switching.

Biosimilars are becoming increasingly available internationally as patents expire on the originator biologic drugs they are intended to copy. Although substitution policies seen with generic drugs are being considered as a means to reduce expenditures on biologics, some biosimilars pose particular challenges in that the act of substitution may eventually lead to increased rates of therapeutic failure. As evidence requirements from regulators do not directly address this challenge, switch trials of biosimilars have emerged that may provide further answers.

Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease.

Purpose Of Review: This article reviews current treatment options and strategies and provides an update on the status of drug development programs of new therapeutic agents for inflammatory bowel diseases (IBD).

Recent Findings: In the past two decades, tumor necrosis factor antagonist therapy has given clinicians better treatment options. However, not all patients respond to induction therapy with these agents, and of those initially responding, up to 40% ultimately lose response due to suboptimal drug exposure (e.

Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease.

Background & Aims: Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy.

Efficacy of Medical Therapies for Fistulizing Crohn's Disease: Systematic Review and Meta-analysis.

Background & Aims: Fistulas are debilitating complications of Crohn's disease (CD) that affect up to 50% of patients. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the efficacy of treatments for fistulizing CD.

Methods: We searched publication databases from inception through December 13, 2016 for trials comparing the efficacy of a therapeutic agent (single or combination) with placebo or another active therapy in adult patients with any form of fistulizing CD.

Reliability of Measuring Ileo-Colonic Disease Activity in Crohn's Disease by Magnetic Resonance Enterography.

Background: Magnetic resonance enterography is increasingly utilized for assessment of luminal Crohn's disease activity. The Magnetic Resonance Index of Activity and the London Index are the most commonly used outcome measures in clinical trials. We assessed the reliability of these indices and several additional items.

Endoscopic scoring indices for evaluation of disease activity in ulcerative colitis.

Background: Endoscopic assessment of mucosal disease activity is routinely used to determine eligibility and response to therapy in clinical trials of ulcerative colitis. The operating properties of the existing endoscopic scoring indices are unclear.

Objectives: A systematic review was undertaken to evaluate the development and operating characteristics of endoscopic scoring indices for the evaluation of ulcerative colitis.

Developing a Standard Set of Patient-Centred Outcomes for Inflammatory Bowel Disease-an International, Cross-disciplinary Consensus.

Background And Aims: Success in delivering value-based healthcare involves measuring outcomes that matter most to patients. Our aim was to develop a minimum Standard Set of patient-centred outcome measures for inflammatory bowel disease [IBD], for use in different healthcare settings.

Methods: An international working group [n = 25] representing patients, patient associations, gastroenterologists, surgeons, specialist nurses, IBD registries and patient-reported outcome measure [PROM] methodologists participated in a series of teleconferences incorporating a modified Delphi process.

Biosimilars: State of Clinical and Regulatory Science.

On May 12, 2017, various issues and challenges associated with biologics were discussed during a session of the annual joint conference of Canadian Society for Pharmaceutical Sciences and Canadian Chapter of Controlled Release Society at Hyatt Regency Hotel, Montréal, QC, Canada.  An update on the Canadian regulatory guidelines for biosimilars was given, followed by viewpoints expressed by regulatory, academic and industry scientists.  Topics of discussion included: reference biologic drug, clinical considerations, immunogenicity, extrapolation and clarification of terminology, product monograph, international collaboration, switching and interchangeability, naming conventions, clinical and non-clinical evaluation, authorization of indications, statistical equivalence, the nor-switch study and biologics marketplace.

Centrally Determined Standardization of Flow Cytometry Methods Reduces Interlaboratory Variation in a Prospective Multicenter Study.

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.