Gastroenterology

Gastroenterology

Volume 155, Issue 1, July 2018, Pages 76-87
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Identification of Endpoints for Development of Antifibrosis Drugs for Treatment of Crohn’s Disease

https://doi.org/10.1053/j.gastro.2018.03.032Get rights and content

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.

Section snippets

Systematic Review of the Literature

We systematically searched the PubMed and Embase databases from their inception to June 2017. Search algorithms included Crohn’s disease combined with fibrosis or stricture, without any language restriction. We also searched ClinicalTrials.gov and bibliographies of relevant review articles. Randomized controlled trials, clinical controlled trials, and cohort, case-control, and cross-sectional studies were considered eligible if they included adult patients (≥18 years) with

Search results and description of included studies

Figure 1 (flow diagram) summarizes the search and selection process. A total of 61 eligible studies were included24, 25, 28, 31, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111 (Supplementary Table 1). The studies were of relatively small size (mean number of participants, 75; range, 9 to 438), with the

Discussion

Intestinal fibrosis remains one of the largest clinical challenges in therapeutic management of CD. More than one-half of the patients with CD develop clinically apparent fibrostenosis throughout their disease course,16 leading to frequent hospitalizations and surgical interventions.47 However, current therapies for CD (ie, steroids, immunosuppressants, and biologics) may not be effective for this indication, and specific drug therapies aiming at intestinal fibrosis are not available.19, 20, 21

Acknowledgments

We thank all the IOIBD experts who participated in the Delphi survey.

Author contributions: Silvio Danese and Laurent Peyrin-Biroulet were involved with conception and design of the study, acquisition and analysis of data, interpretation of data, critical revision of the manuscript for important intellectual content, and approval of the final version of the manuscript. Stefanos Bonovas, Anthony Lopez, and Gionata Fiorino were involved with conception and design of the study, acquisition and

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    Conflicts of interest Silvio Danese has served as a speaker, a consultant, and an advisory board member for AbbVie, Allergan, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer, Sandoz, TiGenix, UCB Pharma, and Vifor. Stefanos Bonovas is supported by FIRMAD. Anthony Lopez has received research funding from Roche, has served as consultant for Amgen, and has received lecture fees from Vifor Pharma. Gionata Fiorino has served as a consultant and Advisory Board Member for MSD, AbbVie, Takeda, Janssen, Mundipharma, Sandoz, and Pfizer. William J. Sandborn reports grants, personal fees, and nonfinancial support from AbbVie; grants and personal fees from Prometheus Laboratories, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, and Nutrition Science Partners; and personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast Inc., Shire, Ardelyx Inc., Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc., Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx Inc., Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen, and Western University (owner of Robarts Clinical Trials). David T. Rubin has received consulting fees or research support from AbbVie, Abgenomics, Allergan, Amgen, Celgene, Forward Pharma, Genentech/Roche, Janssen, Merck, Miraca Life Sciences, Mitsubishi, Napo Pharmaceuticals, Pfizer, Prometheus Laboratories, Salix Pharmaceuticals, Shire, Takeda, Target PharmaSolutions, and UCB Pharma. Michael A. Kamm has received research funding support from AbbVie and Ferring, and has served as a consultant in the last 2 years to AbbVie, Janssen, MSD, Takeda, Pfizer, Celgene, and Ferring. Jean-Frederic Colombel has served as consultant, advisory board member, or speaker for AbbVie, Amgen, Boehringer Ingelheim, Celgene Corporation, Celltrion, Enterome, Ferring, Genentech, Janssen and Janssen, Lilly, Medimmune, Merck, Pfizer, PPM Services, Protagonist, Second Genome, Seres, Shire, Takeda, Theradiag, Theravance Biopharma, and TiGenix. Bruce E. Sands has served as a consultant for AbbVie, Akros Pharma, Allergan, Bristol-Myers Squibb, Lyndra, Lycera, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, EnGene, Gilead, Janssen, Lilly, MedImmune, Oppilan Pharma, Pfizer, Shire, Takeda, Target Pharmasolutions, Theravance Biopharma R&D, TiGenix, Immune Pharmaceuticals, Receptos, TopiVert Pharma, UCB, Vivelix Pharmaceuticals, Synergy Pharmaceuticals, and Salix Pharmaceuticals. Severine Vermeire has received grant support from AbbVie, MSD, Pfizer, and Takeda; received speaker fees from AbbVie, MSD, Takeda, Ferring, Dr. Falk Pharma, Hospira, Pfizer, and Tillots; and served as a consultant for AbbVie, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer, Galapagos, Mundipharma, Hospira, Celgene, Second Genome, and Janssen. Julian Panes has served as a speaker, a consultant, or an advisory board member for AbbVie, Biogen, Boehringer Ingelheim, Celgene, Ferring, Johnson & Johnson, MSD, Nestle, Oppilan, Pfizer, Sandoz, Takeda, Theravance, and TiGenix. Gerhard Rogler has served as a speaker, a consultant, or an advisory board member for AbbVie, Amgen, Augurix, Boehringer, Bristol-Myers Squibb, Calypso, Celgene, Falk, Ferring, Fisher, Genentech, Gilead, Index Pharmaceuticals, Janssen, MSD, Novartis, Pfizer, Phadia, Roche, UCB, Takeda, Tillots, UCB, Vifor, Vital Solutions, and Zeller. Geert D’Haens has served as advisor for AbbVie, Ablynx, Amakem, Amgen, AM Pharma, Avaxia, Biogen, Bristol Meiers Squibb, Boehringer Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronics, Ferring, Dr. Falk Pharma, Eli Lilly, Engene, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Immunic, Johnson & Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Prometheus Laboratories/Nestle, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Setpoint, Shire, Teva, TiGenix, Tillotts, Topivert, Versant, and Vifor; and received speaker fees from AbbVie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts, and Vifor. Laurent Peyrin-Biroulet has received consulting fees from AbbVie, Amgen, Biogaran, Biogen, Boerhinger-Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Ferring, Forward Pharma, Genentech, H.A.C. Pharma, Hospira, Index Pharmaceuticals, Janssen, Lycera, Merck, Lilly, Mitsubishi, Norgine, Pfizer, Pharmacosmos, Pilège, Samsung Bioepis, Sandoz, Takeda, Therakos, Tillots, UCB Pharma, and Vifor; and lecture fees from AbbVie, Ferring, H.A.C. Pharma, Janssen, Merck, Mitsubishi, Norgine, Takeda, Therakos, Tillots, and Vifor.

    Author names in bold designate shared co-first authorship.

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