Franck Carbonnel1, Jean Frédéric Colombel2, Jérome Filippi3, Konstantinos H Katsanos4, Laurent Peyrin-Biroulet5, Mathieu Allez6, Maria Nachury7, Gottfried Novacek8, Silvio Danese9, Vered Abitbol10, Fabrizio Bossa11, Jacques Moreau12, Gilles Bommelaer13, Arnaud Bourreille14, Mathurin Fumery15, Xavier Roblin16, Walter Reinisch17, Yoram Bouhnik18, Hedia Brixi19, Philippe Seksik20, Georgia Malamut21, Martti Färkkilä22, Baya Coulibaly23, Olivier Dewit24, Edouard Louis25, Dominique Deplanque26, Pierre Michetti27, Hélène Sarter28, David Laharie29. 1. CHU de Bicêtre, Service de Gastroentérologie, APHP-Université Paris Sud, Le Kremlin Bicêtre, France; CHU de Besançon, Hôpital Jean Minjoz, Service de Gastroentérologie, Besançon, France. Electronic address: fcarbonnel7@gmail.com. 2. Helmsley Inflammatory Bowel Disease Center, Icahn Medical School of Medicine at Mount Sinai, New York, New York. 3. CHU de Nice, Hôpital de l'Archet 2, Service de Gastroentérologie et Nutrition Clinique, Nice, France. 4. Department of Gastroenterology, School of Medical Sciences, University of Ioannina, Ioannina, Greece. 5. Inserm U954 and Department of Gastroenterology, Université de Lorraine, Vandoeuvre-les-Nancy, France. 6. Hôpital Saint-Louis, Service d'Hépato-Gastroentérologie, APHP-Université Paris VII, Paris, France. 7. CHU de Besançon, Hôpital Jean Minjoz, Service de Gastroentérologie, Besançon, France; CHRU de Lille, Hôpital Claude Huriez, Service des Maladies de L'Appareil Digestif-Endoscopie Digestive, Lille, France. 8. Medizinische Universität Wien, Universitätsklinik für Innere Medizin III Klinische Abteilung für Gastroenterologie und Hepatologie, Währinger Gürtel, Wien, Austria. 9. Department of Gastroenterology Istituto Clinico Humanitas, Rozzano, Milan, Italy. 10. CHU Cochin, Service de Gastroentérologie, APHP-Paris, France. 11. Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital IRCCS, San Giovanni Rotondo, Italy. 12. CHU de Toulouse, Hôpital Rangueil, Service de Gastro-Entérologie et Nutrition, Toulouse, France. 13. CHU Clermont-Ferrand, Service Hépatologie-Gastro-Entérologie, Clermont-Ferrand, France. 14. CHU de Nantes, Hôtel-Dieu, Hépato-Gastroentérologie, Institut des Maladies de l'Appareil Digestif, Nantes, France. 15. CHU Amiens, Hôpital Nord, service d'Hépato-Gastroentérologie, Amiens, France. 16. CHU de Saint-Etienne, Hôpital Nord, Service de Gastro-Entérologie et Hépatologie, Saint-Etienne, France. 17. Medizinische Universität Wien, Universitätsklinik für Innere Medizin III Klinische Abteilung für Gastroenterologie und Hepatologie, Währinger Gürtel, Wien, Austria; Department of Internal Medicine, McMaster University, Hamilton Ontario, Canada. 18. Hôpital Beaujon, Gastroentérologie, MICI et Assistance Nutritive, APHP-Université Paris VII, Clichy, France. 19. Hôpital Robert Debré, Service de Gastroentérologie, Reims, France. 20. Hôpital St-Antoine, Service de Gastroentérologie, Paris, France. 21. Université Paris Descartes-Sorbonne Paris Centre, Gastroenterology Department, Hôpital Européen Georges Pompidou APHP, Paris, France. 22. Helsinki University, and Helsinki University Central Hospital, Clinic of Gastroenterology, Helsinki, Finland. 23. Service de Gastro-Entérologie, Centre Hospitalier d' Avignon, Avignon, France. 24. UCL Saint Luc, Service de Gastroentérologie, Brussels, Belgium. 25. Department of Gastroenterology, University Hospital CHU of Liège, Liège, Belgium. 26. Université Lille, CHRU Lille, Inserm, Lille, France. 27. Gastroenterology La Source-Beaulieu and Division of Gastroenterology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 28. Public Health, Epidemiology and Economic Health, Registre Epimad, Maison Régionale de la Recherche Clinique and Biostatistics Unit and Lille Inflammation Research International Center LIRIC, Université Lille, Lille, France. 29. CHU de Bordeaux, Hôpital Haut-Lévêque, Service d'Hépato-Gastroentérologie, Université Bordeaux, Laboratoire de Bactériologie, Bordeaux, France.
Abstract
BACKGROUND & AIMS:Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS:Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.
RCT Entities:
BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS:Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.
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
Authors: Hans H Herfarth; Susan Jackson; Barbara G Schliebe; Christopher Martin; Anastasia Ivanova; Kristen Anton; Robert S Sandler; Millie D Long; Kim L Isaacs; Mark T Osterman; Bruce E Sands; Peter D Higgins; James D Lewis Journal: Inflamm Bowel Dis Date: 2017-01 Impact factor: 5.325