Article (Scientific journals)
Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.
Louis, Edouard; Resche-Rigon, Matthieu; Laharie, David et al.
2023In The Lancet Gastroenterology and Hepatology, 8 (3), p. 215-227
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Keywords :
Immunosuppressive Agents; B72HH48FLU (Infliximab); MRK240IY2L (Azathioprine); Tumor Necrosis Factor Inhibitors; Adult; Humans; Immunosuppressive Agents/adverse effects; Infliximab/adverse effects; Crohn Disease/drug therapy/chemically induced; Azathioprine/adverse effects; Tumor Necrosis Factor Inhibitors/therapeutic use; Recurrence
Abstract :
[en] BACKGROUND: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. METHODS: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. FINDINGS: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. INTERPRETATION: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. FUNDING: European Union's Horizon 2020.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Louis, Edouard  ;  Centre Hospitalier Universitaire de Liège - CHU > > Service de gastroentérologie, hépatologie, onco. digestive
Resche-Rigon, Matthieu;  Université de Paris, ECSTRRA - CRESS UMR1153, INSERM and SBIM, AP-HP, Hôpital
Laharie, David;  Service d'Hépato-gastroentérologie et oncologie digestive CHU de Bordeaux,
Satsangi, Jack;  Translational Gastroenterology Unit, Nuffield Department of Medicine, John
Ding, Nik;  Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC,
Siegmund, Britta;  Medical Department, Division of Gastroenterology, Infectious Diseases and
D'Haens, Geert;  Department of Gastroenterology and Hepatology, Amsterdam University Medical
Picon, Laurence;  Hépato-Gastro-Onco-Entérologie, Hôpital Trousseau, Tours, France.
Bossuyt, Peter;  Imelda GI Clinical Research Center, Imelda General Hospital, Bonheiden, Belgium.
Vuitton, Lucine;  Department of Gastroenterology, Besançon Univeristy Hospital, Besançon, France,
Irving, Peter;  IBD Unit, Department of Gastroenterology, Guy's and St Thomas' NHS Foundation
Viennot, Stephanie;  Department of Gastroenterology, University Hospital of Caen, Caen, France.
Lamb, Christopher A;  Translational & Clinical Research Institute, Newcastle University, Newcastle upon
Pollok, Richard;  Gastroenterology, St Georges University Hospital, London, UK.
Baert, Filip;  AZ Delta Hospital, Roeselare, Belgium.
Nachury, Maria;  U1286 - INFINITE - Institute for Translational Research in Inflammation,
Fumery, Mathurin;  Department of Gastroenterology, University Hospital of Amiens, Amiens, France,
Gilletta, Cyrielle;  Department of Gastroenterology and Pancreatology, University Hospital of Toulouse
Almer, Sven;  IBD-unit, Division of Gastroenterology, Karolinska University hospital,
Ben-Horin, Shomron;  Department of Gastroenterology, Sheba Medical Center, Tel-Aviv University,
Bouhnik, Yoram;  Department of Gastroenterology, Beaujon Hospital, APHP, Paris Cité University,
Colombel, Jean-Frederic;  Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New
Hertervig, Erik;  Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
GETAID and the SPARE-Biocycle research, group
More authors (14 more) Less
Other collaborator :
Andrews, Jane
Sparrow, Miles
Leong, Rupert
Connor, Susan
Radforth-Smith, Graham
De Cruz, Peter
Preiss, Jan
Stallmach, Andrea
Liceni, Thomas
Grip, Olaf
Halfvarson, Jonas
Durai, Dharmaraj
Cummings, Fraser
Seilinger, Christian
Parkes, Miles
Lindsay, James
Lambrecht, Guy
Van Hootegem, Philippe
Rahier, Jean-François
Dewitte, Marie
Hebuterne, Xavier
Chanteloup, Elise
Altwegg, Romain
Nancey, Stephane
Bouguen, Guillaume
Pineton de Chambrun, Guillaume
Poullenot, Floriant
Roblin, Xavier
More authors (18 more) Less
Language :
English
Title :
Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.
Publication date :
March 2023
Journal title :
The Lancet Gastroenterology and Hepatology
eISSN :
2468-1253
Publisher :
Elsevier, Gb
Volume :
8
Issue :
3
Pages :
215-227
Peer reviewed :
Peer Reviewed verified by ORBi
European Projects :
H2020 - 633168 - BIOCYCLE - BIOlogical therapy CYCLEs towards tailored, needs-driven, safer and cost-effective management of Crohn’s disease
Funders :
Union Européenne [BE]
Commentary :
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Available on ORBi :
since 28 June 2023

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