Withdrawal of Anti-Tumour Necrosis Factor in Inflammatory Bowel Disease Patients in Remission: A Randomised Placebo-Controlled Clinical Trial of GETECCU

Aims: Primary: to compare the rates of clinical remission at 12 months in patients treated with anti-TNF and immunomodulators who withdraw anti-TNF treatment vs. those who maintain it. Secondary objectives: to evaluate the effect of anti-TNF withdrawal on relapse-free time, endoscopic and radiologic activity, safety, quality of life, and work productivity; and to identify predictive factors for relapse. Methods: Prospective, quadruple-blind, multicentre, randomised, controlled trial. Patients with ulcerative colitis or Crohn’s disease in clinical remission for >6 months and absence of severe lesions in endoscopy (or MRI in CD) were randomised to maintain anti-TNF treatment [maintenance arm (MA)] or to withdraw it [withdrawal arm (WA)]. All patients maintained immunomodulators. Patients were followed-up until month 12 or up to the time of clinical relapse. Results: One-hundred forty patients were randomised: 70 were allocated to the MA and 70 to the WA. The proportion of patients who maintained clinical remission remaining without significant endoscopic lesions at the end of follow-up were similar in the MA and WA: 59/70 (84%), 95% confidence interval (CI)=74-92% vs. 53/70 (76%), 95%CI=64-85%. Only the proportion of patients with faecal calprotectin >250 μg/g was higher in the WA at the end of follow-up. Maintenance of clinical remission was not different between groups. The same percentage of patients in both groups had at least one adverse event (69%). The proportion of patients with serious adverse events was also similar in both groups (4% in MA vs. 7% in WA). Conclusions: Anti-TNF withdrawal in selected IBD patients in clinical, endoscopic, and radiological remission could be feasible without an increase in the risk of clinical relapse at one year. Trial Registration: The study protocol was registered in both European and United States clinical trial registers (EudraCT number 2015-001410-10, and ClinicalTrials.gov identifier NCT02994836). Funding: This is an independent study financed by grants from Instituto de Salud Carlos III (PI15/00560 and FI16/00386), Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) and Abbvie. Declaration of Interest: Manuel Barreiro-de Acosta has served as a speaker, consultant and advisory member for or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, GALAPAGOS, Pfizer, Sandoz, Biogen, Fresenius, Lilly, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma. María Chaparro has served as speaker, consultant or research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Biogen, Gilead and Lilly. Eugeni Domènech has served as a speaker, or has received research or education funding or advisory fees from AbbVie, Adacyte Therapeutics, Biogen, Celltrion, Galapagos, Gilead, GoodGut, Imidomics, Janssen, Kern Pharma, MSD, Pfizer, Roche, Samsung, Takeda, Tillots. Javier P. Gisbert has served as speaker, consultant, and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos, Lilly, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine and Vifor Pharma. Marisa Iborra reports grants and personal fees from MSD, Janssen, Abbvie, Takeda, Kern and Chiesi, during the conduct of the study. Eduardo Leo has received grants or honoraria for scientific activities, presentations or as a scientific advisor for MSD, Pfizer, Abbvie, Takeda, Janssen, Tillotts Pharma, Shire Pharmaceuticals, Ferring, Dr. Falk Pharma, Adacyte and Otsuka Pharmaceutical Pilar Nos reports grants and personal fees from MSD, grants from Otsuka, AbbVie; personal fees from Takeda, Kern, Biogen, Ferring. Julián Panés received financial support for research from AbbVie and Pfizer; consultancy fees/honorarium from AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celsius, Celltrion, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Morphic, Pandion, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Robarts, Sanofi, Takeda, Theravance and Wasserman; reports payment for lectures including service on speaker bureau from Abbott, Ferring, Janssen, Pfizer and Takeda; and reports payment for development of educational presentations from Abbott, Janssen, Pfizer Roche and Takeda. Montserrat Rivero has served as a speaker or advisory member from TaKeda, Janssen, Galapagos, Ferring and Pfizer Manuel Van Domselaar has received educational funding from Janssen. Kern Pharma. and Takeda. Rest of authors have nothing to declare. Ethical Approval: The study protocol was approved by the GETECCU and by the Clinical Research Ethics Committee of the Hospital Universitario de La Princesa, and it was previously published.Written, informed consent was obtained from all patients.