Geert D'Haens1, Severine Vermeire2, Guy Lambrecht3, Filip Baert4, Peter Bossuyt5, Benjamin Pariente6, Anthony Buisson7, Yoram Bouhnik8, Jérôme Filippi9, Janneke Vander Woude10, Philippe Van Hootegem11, Jacques Moreau12, Edouard Louis13, Denis Franchimont14, Martine De Vos15, Fazia Mana16, Laurent Peyrin-Biroulet17, Hedia Brixi18, Matthieu Allez19, Philip Caenepeel20, Alexandre Aubourg21, Bas Oldenburg22, Marieke Pierik23, Ann Gils24, Sylvie Chevret25, David Laharie26. 1. Academic Medical Centre, Amsterdam, the Netherlands. Electronic address: g.dhaens@amc.uva.nl. 2. University Hospitals Leuven, Leuven, Belgium. 3. Damiaan Hospital, Oostende, Belgium. 4. AZ Delta, Roeselare, Belgium. 5. Imelda Hospital, Bonheiden, Belgium. 6. Hospital Claude Huriez, Lille, France. 7. Hospital Estaing, Clermont-Ferrand, France. 8. Hospital Beaujon, Clichy, France. 9. Hospital Archet, Nice, France. 10. Erasmus MC, Rotterdam, the Netherlands. 11. Sint-Lucas Hospital, Brugge, Belgium. 12. CHU Toulouse, Toulouse, France. 13. Hospital Sart-Tilman, Liège, France. 14. Hopital Universitaire Erasme, Brussels, Belgium. 15. UZ Gent, Ghent, Belgium. 16. AZ VUB, Brussels, Belgium. 17. Hospital Brabois, Nancy, France. 18. CHU Reims, Reims, France. 19. Hopital St Louis, Paris, France. 20. ZOL Genk, Genk, Belgium. 21. CHRU Tours, Tours, France. 22. UMC Utrecht, Utrecht, the Netherlands. 23. MUMC Maastricht, the Netherlands. 24. KU Leuven, Leuven, Belgium. 25. DBIM, Hospital Saint-Louis, Paris, France. 26. Hospital Haut-Leveque, Pessac, France.
Abstract
BACKGROUND & AIMS: A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn's disease (CD). Patients have the best outcomes when their serum concentrations of these drugs are above a determined therapeutic threshold. We performed a prospective, randomized trial to determine whether therapeutic drug monitoring (TDM) to maintain serum levels of infliximab above 3 μg/mL produced higher rates of clinical and endoscopic remission than adapting dose based only on symptoms. METHODS: We performed a double-blind trial in which 122 biologic-naïve adult patients with active CD (71 female, median age 29.8 years) received induction treatment with infliximab in combination with an immunosuppressant, from July 2012 through September 2015 at 27 centers in Europe. At week 14 of treatment, patients were randomly assigned (1:1:1) to 3 infliximab maintenance groups: dose increases (2 maximum) in steps of 2.5 mg/kg based on clinical symptoms and biomarker analysis and/or serum infliximab concentrations (dose intensification strategy [DIS]1 group); dose increase from 5 to 10 mg/kg based on the same criteria (DIS2 group); dose increase to 10 mg/kg based on clinical symptoms alone (controls). Patients' CD activity index scores, levels of C-reactive protein, fecal levels of calprotectin, and serum concentrations of infliximab were determined at baseline and at weeks 2, 4, 6, 12, and 14 of treatment, and then every 4 weeks thereafter until week 54. The primary endpoint was sustained corticosteroid-free clinical remission (CD activity index <150) from weeks 22 through 54 with no ulcers at week 54. RESULTS: The primary endpoint was reached by 15 (33%) of 45 patients in the DIS1 group, 10 (27%) of 37 patients in the DIS2 group, and 16 (40%) of 40 patients in the control group (P = .50). CONCLUSIONS: In a prospective randomized exploratory trial of patients with active CD, we found increasing dose of infliximab based on a combination of symptoms, biomarkers, and serum drug concentrations does not lead to corticosteroid-free clinical remission in a larger proportion of patients than increasing dose based on symptoms alone. EUDRACT NUMBER: 2011-003038-14.
RCT Entities:
BACKGROUND & AIMS: A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn's disease (CD). Patients have the best outcomes when their serum concentrations of these drugs are above a determined therapeutic threshold. We performed a prospective, randomized trial to determine whether therapeutic drug monitoring (TDM) to maintain serum levels of infliximab above 3 μg/mL produced higher rates of clinical and endoscopic remission than adapting dose based only on symptoms. METHODS: We performed a double-blind trial in which 122 biologic-naïve adult patients with active CD (71 female, median age 29.8 years) received induction treatment with infliximab in combination with an immunosuppressant, from July 2012 through September 2015 at 27 centers in Europe. At week 14 of treatment, patients were randomly assigned (1:1:1) to 3 infliximab maintenance groups: dose increases (2 maximum) in steps of 2.5 mg/kg based on clinical symptoms and biomarker analysis and/or serum infliximab concentrations (dose intensification strategy [DIS]1 group); dose increase from 5 to 10 mg/kg based on the same criteria (DIS2 group); dose increase to 10 mg/kg based on clinical symptoms alone (controls). Patients' CD activity index scores, levels of C-reactive protein, fecal levels of calprotectin, and serum concentrations of infliximab were determined at baseline and at weeks 2, 4, 6, 12, and 14 of treatment, and then every 4 weeks thereafter until week 54. The primary endpoint was sustained corticosteroid-free clinical remission (CD activity index <150) from weeks 22 through 54 with no ulcers at week 54. RESULTS: The primary endpoint was reached by 15 (33%) of 45 patients in the DIS1 group, 10 (27%) of 37 patients in the DIS2 group, and 16 (40%) of 40 patients in the control group (P = .50). CONCLUSIONS: In a prospective randomized exploratory trial of patients with active CD, we found increasing dose of infliximab based on a combination of symptoms, biomarkers, and serum drug concentrations does not lead to corticosteroid-free clinical remission in a larger proportion of patients than increasing dose based on symptoms alone. EUDRACT NUMBER: 2011-003038-14.
Authors: Christopher Andrew Lamb; Nicholas A Kennedy; Tim Raine; Philip Anthony Hendy; Philip J Smith; Jimmy K Limdi; Bu'Hussain Hayee; Miranda C E Lomer; Gareth C Parkes; Christian Selinger; Kevin J Barrett; R Justin Davies; Cathy Bennett; Stuart Gittens; Malcolm G Dunlop; Omar Faiz; Aileen Fraser; Vikki Garrick; Paul D Johnston; Miles Parkes; Jeremy Sanderson; Helen Terry; Daniel R Gaya; Tariq H Iqbal; Stuart A Taylor; Melissa Smith; Matthew Brookes; Richard Hansen; A Barney Hawthorne Journal: Gut Date: 2019-09-27 Impact factor: 23.059