¹Bicêtre Hospital - Université Paris Sud, Oncologic and Digestive Surgery, Le Kremlin-Bicêtre, France, ²Beajon Hospital, Colorectal Surgery, Clichy, France, ³CHU Lille, Digestive Surgery, Lille, France, ⁴Saint Antoine Hospital, Digestive Surgery, Paris, France, ⁵CHU Bordeaux, Digestive Surgery, Bordeaux, France, ⁶CHU Nancy, Digestive Surgery, Nancy, France, ⁷CHU Lyon-Sud, Digestive Surgery, Lyon, France, ⁸CHU Marseille, Digestive Surgery, Marseille, France, ⁹Saint Louis Hospital, Digestive Surgery, Paris, France, ¹⁰CHU Rennes, Digestive Surgery, Rennes, France, ¹¹CHU Nice, Digestive Surgery, Nice, France, ¹²CHU Toulouse, Digestive Surgery, Toulouse, France, ¹³Lariboisière Hospital, Digestive Surgery, Paris, France, ¹⁴Montsouris insitute, Digestive Surgery, Paris, France, ¹⁵CHU Rouen, Digestive Surgery, Rouen, France, ¹⁶CHU Nantes, Digestive Surgery, Nantes, France, ¹⁷CHU Grenoble, Digestive Surgery, Grenoble, France, ¹⁸Saint-Joseph Hospital, Digestive Surgery, Paris, France, ¹⁹CHU Montpellier, Digestive Surgery, Montpellier, France, ²⁰Fernand Widal Hospital, Clinical research, Paris, France

¹Janssen R & D, LLC, Spring House, Pennsylvania, United States, ²Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States, ³Robarts Clinical Trials Inc., Robarts Research Institute, University of Western Ontario, London, Ontario, Canada, ⁴UCSD, Medicine, La Jolla, California, United States

¹Academic Medical Centre, Gastroenterology, Amsterdam, Netherlands, ²University Hospitals Gasthuisberg, Gastroenterology, Leuven, Belgium, ³AZ Damiaan, Oostende, Belgium, ⁴AZ Delta, Roeselare, Belgium, ⁵Imelda GI Clinical Research Centre, Bonheiden, Belgium, ⁶Hopital Claude Hurriez, Lille, France, ⁷Hopital Estaing, Clermont-Ferrand, France, ⁸Hopital Beaujon, Clichy, France, ⁹Hospital Archet, Nice, France, ¹⁰Erasmus Medical Centre, Rotterdam, Netherlands, ¹¹St Lukas Hospital, Bruges, Belgium, ¹²Hopital Rangueil, Toulouse, France, ¹³Hopital Sart Tilman, Liège, Belgium, ¹⁴Hopital Erasme, Brussels, Belgium, ¹⁵University of Ghent, Ghent, Belgium, ¹⁶Free University of Brussels, Brussels, Belgium, ¹⁷Hopital Brabois, Nancy, France, ¹⁸Hopital Robert Debre, Reims, France, ¹⁹Hopital St Louis, Paris, France, ²⁰Ziekenhuis Oost Limburg, Genk, Belgium, ²¹Hopital Trousseau, Tours, France, ²²University of Utrecht, Utrecht, Netherlands, ²³University Hospital Maastricht, Maastricht, Netherlands, ²⁴University of Leuven, Leuven, Belgium, ²⁵Dept Biostatistique St Louis, Paris, France, ²⁶Haut-Leveque, Pessac, France

The most potent available treatment for active Crohn’s disease (CD) is a combination of infliximab (IFX) and azathioprine, leading to disappearance of ulcerations in up to 50% of patients. Because superior outcomes have been associated with serum drug concentrations within what is considered a ‘therapeutic window’, we hypothesised that prospective therapeutic drug monitoring (TDM) would lead to higher remission rates as compared with pure symptom-based dose adaptations.

This was a prospective randomised, double-blinded, multicentre controlled trial in which biologic naïve adult patients with active CD (CDAI > 220, serum CRP > 5 mg/L, and/or faecal calprotectin > 250 µg/g and endoscopic ulcerations) received induction treatment with 3 infusions of IFX 5 mg/kg in combination with azathioprine 2–2.,5 mg/kg/day or MTX in case of intolerance. At week 14, patients were randomised to 1 of 3 different maintenance strategies: 1) dose intensification of IFX in (maximally 2) steps of 2,5 mg/kg based on clinical symptoms, biomarker analysis and serum IFX concentrations drawn before the previous infusion (group 1); 2) dose intensification of IFX from 5 to 10 mg/kg based on the same criteria (group 2), and 3) IFX dose increase to 10 mg/kg based on clinical symptoms alone (group 3). The primary endpoint of the trial was sustained steroid-free clinical remission from week 22 to -54 and absence of ulceration at 1 year based on centrally read endoscopies. Target for IFX dosing was a trough concentration > 3 ug/ml. (EUDRACT NUMBER: 2011-003038-14)

At 27 sites in Belgium, France, and the Netherlands,167 patients were screened, and 122 were randomised (71 F, median age 29.8 years). The 3 groups had comparable patient characteristics. The primary endpoint based on local endoscopy reads was attained in 21/45 (47%) in group 1, 14/37 (38%) in group 2, and 16/40 (40%) in group 3 (p = NS). The proportions of patients without ulcerations at week 54 were 36%, 43%, and 48% (p = NS) and with endoscopic remission (CDEIS < 3) 49%, 51%, and 45% (p = NS). Dose intensification was done in 51%, 65%, and 40% of the patients.

In this prospective randomised exploratory trial in patients with active CD, proactive trough-level–based dose intensification was not superior to dose intensification based on symptoms alone. Results with centrally read endoscopy are being awaited, as well as detailed pharmacokinetic, immunogenicity, and biomarker analysis. More benefit from TDM may be obtained during induction and in dose reduction efforts, which was not studied in this trial.

¹Kitasato University Kitasato Institute Hospital, Centre for Advanced IBD Research and Treatment, Tokyo, Japan, ²Toho University Sakura Medical Centre, Department of Internal Medicine, Sakura, Japan, ³Sapporo-kosei General Hospital, Inflammatory Bowel Diseases Centre, Sapporo, Japan, ⁴Fukuoka University Chikushi Hospital, Department of Gastroenterology, Chikushino, Japan, ⁵Keio University School of Medicine, Centre for Diagnostic and Therapeutic Endoscopy, Tokyo, Japan, ⁶Kitano Hospital The Tazuke Kofukai Medical Research Institute, Digestive Disease Centre, Osaka, Japan, ⁷Mitsubishi Tanabe Pharma Corporation, Osaka, Japan, ⁸Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Tokyo, Japan

University of Erlangen-Nuremberg, Department of Medicine I, Erlangen, Germany

University of Parma, Department of Pharmacy, Parma, Italy

¹University of Campinas, Coloproctology Unit, Surgery Department, Campinas, Brazil, ²University of Campinas, Campinas, Brazil, ³University of Campinas, Laboratory of Cell Signalling, Internal Medicine Department, Campinas, Brazil

¹KU Leuven, Department of Human Genetics, Leuven, Belgium, ²KU Leuven, Department of Clinical and Experimental Medicine, Translational Research Centre for Gastrointestinal Disorders, Leuven, Belgium, ³KU Leuven, Department of Cellular and Molecular Medicine, Gene Expression Unit, Leuven, Belgium

¹KU Leuven, P.O. Box 820 Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium, ²KU Leuven, P.O. Box 7003, Department of Clinical and Experimental Medicine, Leuven, Belgium

¹University Hospitals Leuven - KU Leuven, Department of Clinical and Experimental Medicine, Translational Research Centre for Gastrointestinal Disorders (TARGID), Leuven, Belgium, ²KU Leuven, Department of Human Genetics, Leuven, Belgium

¹Trinity College Dublin, Dublin, Ireland, ²National Children’s Research Centre, Our Lady’s Children Hospital, Dublin, Ireland, ³University College Cork, APC Microbiome Institute, Cork, Ireland, ⁴University College Cork, Department of Pathology, Cork, Ireland, ⁵University College Dublin, Academic Centre for Paediatric Research, Dublin, Ireland

¹University of Southampton, Clinical and Experimental Sciences, Southampton, United Kingdom, ²University of Southampton, Department of Gastroenterology, Southampton, United Kingdom, ³Great Western Hospitals NHS Foundation Trust, Department of Gastroenterology, Swindon, United Kingdom

¹St Mark’s Hospital, IBD, London, United Kingdom, ²Imperial College London, Department of Surgery and Cancer, London, United Kingdom

¹Academic Medical Centre, Gastroenterology, Amsterdam, Netherlands, ²Leiden University Medical Centre, Gastroenterology, Leiden, Netherlands

¹John Radcliffe Hospital, Department of Translational Gastroenterology, Oxford, United Kingdom, ²University of Oxford, Kennedy Institute for Rheumatology, Oxford, United Kingdom

¹Juntendo University, Department of Gastroenterology, Tokyo, Japan, ²Juntendo University, Department of Immunology, Tokyo, Japan

¹Roskilde Hospital, Department of Pathology, Roskilde, Denmark, ²University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark, ³Koege Sygehus, Department of Gastroenterology, Koege, Denmark, ⁴Copenhagen University Hospital, Department of Pathology, Hvidovre, Denmark, ⁵Visiopharm, Hoersholm, Denmark

¹Academic Medical Centre (AMC), Gastroenterology & Hepatology, Amsterdam, Netherlands, ²Academic Medical Centre (AMC), Tytgat Institute for Liver and Intestinal Research, Amsterdam, Netherlands, ³GlaxoSmithKline, ImmunoInflammation Therapy Area, Stevenage, United Kingdom

KU Leuven, P.O. Box 701, Department of Clinical and Experimental Medicine, Leuven, Belgium

¹Yonsei University, Internal Medicine and Institute of Gastroenterology, Seoul, South Korea, ²Yonsei University, Brain Korea 21 PLUS Project for Medical Science, Seoul, South Korea, ³Yonsei University, Seoul, South Korea, ⁴Severance Biomedical Science Institute, Seoul, South Korea