Frank M Ruemmele1, Jeffrey S Hyams2, Anthony Otley3, Anne Griffiths4, Kaija-Leena Kolho5, Jorge Amil Dias6, Arie Levine7, Johanna C Escher8, Jan Taminiau9, Gabor Veres10, Jean-Frederic Colombel11, Séverine Vermeire12, David C Wilson13, Dan Turner14. 1. Université Paris Descartes, Sorbonne Paris Cité, Paris, France INSERM U989, Institut IMAGINE, Paris, France APHP, Hôpital Necker Enfants Malades, Service de Gastroentérologie pédiatrique, Paris, France. 2. Connecticut Children's Medical Center, Hartford, Connecticut, USA. 3. Division of Pediatric Gastroenterology, IWK Health Centre, Halifax, Canada. 4. The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 5. Children's Hospital, University of Helsinki, Helsinki, Finland. 6. Hospital S João, Porto, Portugal. 7. Pediatric Gastroenterology and Nutrition Unit, Wolfson Medical Center, Sackler School of Medicine, Tel Aviv University, Holon, Israel. 8. Pediatric Gastroenterology, Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands. 9. Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands. 10. Ist Dept of Pediatrics, Semmelweis University, Budapest, Hungary. 11. Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, USA. 12. Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium. 13. Department of Child Life and Health, University of Edinburgh, Scotland, UK. 14. The Juliet Keidan Institute for Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel.
Abstract
OBJECTIVE: Although paediatric-onset IBD is becoming more common, few medications have a registered paediatric indication. There are multiple hurdles to performing clinical trials in children, emphasising the importance of choosing an appropriate outcome measure, which can facilitate enrolment, and thereby also drug approval. The aim of this consensus statement is to highlight paediatric specific issues and key factors critical for the optimal conduct of paediatric IBD trials. DESIGN: The Paediatric European Crohn's and Colitis Organisation (ECCO) committee has established an international expert panel to determine the best outcome measures in paediatric IBD, following a literature search and a modified Delphi process. All recommendations were endorsed by at least 80% agreement. RESULTS: Recognising the importance of mucosal healing (MH), the panel defined steroid-free MH as primary outcome measure for all drugs of new category with one or two postintervention endoscopies per trial (at 8-12 weeks and/or 54 weeks). Since endoscopic evaluation is a barrier for recruitment in children, trials with medications already shown to induce MH in children or adults, could use paediatric-specific disease activity scores as primary outcome, including a modified Paediatric Crohn's Disease Activity Index in Crohn's disease and the Paediatric Ulcerative Colitis Activity Index in UC. Secondary outcomes should include safety issues, MR enterography-based damage and inflammatory scores (in Crohn's disease), faecal calprotectin, quality of life scales, and a patient-reported outcome. CONCLUSIONS: It is crucial to perform paediatric trials early in the development of new drugs in order to reduce off-label use of IBD medication in children. The thoughtful choice of feasible and standardised outcome measures can help move us towards this goal. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE: Although paediatric-onset IBD is becoming more common, few medications have a registered paediatric indication. There are multiple hurdles to performing clinical trials in children, emphasising the importance of choosing an appropriate outcome measure, which can facilitate enrolment, and thereby also drug approval. The aim of this consensus statement is to highlight paediatric specific issues and key factors critical for the optimal conduct of paediatric IBD trials. DESIGN: The Paediatric European Crohn's and Colitis Organisation (ECCO) committee has established an international expert panel to determine the best outcome measures in paediatric IBD, following a literature search and a modified Delphi process. All recommendations were endorsed by at least 80% agreement. RESULTS: Recognising the importance of mucosal healing (MH), the panel defined steroid-free MH as primary outcome measure for all drugs of new category with one or two postintervention endoscopies per trial (at 8-12 weeks and/or 54 weeks). Since endoscopic evaluation is a barrier for recruitment in children, trials with medications already shown to induce MH in children or adults, could use paediatric-specific disease activity scores as primary outcome, including a modified Paediatric Crohn's Disease Activity Index in Crohn's disease and the Paediatric Ulcerative Colitis Activity Index in UC. Secondary outcomes should include safety issues, MR enterography-based damage and inflammatory scores (in Crohn's disease), faecal calprotectin, quality of life scales, and a patient-reported outcome. CONCLUSIONS: It is crucial to perform paediatric trials early in the development of new drugs in order to reduce off-label use of IBD medication in children. The thoughtful choice of feasible and standardised outcome measures can help move us towards this goal. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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