1. Treatment of Perianal Fistulas in Crohn's Disease, Seton Versus Anti-TNF Versus Surgical Closure Following Anti-TNF [PISA]: A Randomised Controlled Trial
- Author
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Apollo Pronk, Merel E. Stellingwerf, Karlien F. Bruin, Antonino Spinelli, Silvio Danese, David D. E. Zimmerman, Sebastiaan A.C. van Tuyl, Marcel G. W. Dijkgraaf, Cyriel Y. Ponsioen, Geert R. D'Haens, Jarmila D. W. van der Bilt, Karin A. T. G. M. Wasmann, Christianne J. Buskens, Krisztina B Gecse, E. Joline de Groof, Michael F. Gerhards, Willem A Bemelman, M.W. Mundt, Jeroen M. Jansen, Graduate School, Surgery, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Epidemiology and Data Science, APH - Methodology, Wasmann, Katgm, de Groof, Ej, Stellingwerf, Me, D'Haens, Gr, Ponsioen, Cy, Gecse, Kb, Dijkgraaf, Mgw, Gerhards, Mf, Jansen, Jm, Pronk, A, van Tuyl, Sac, Zimmerman, Dde, Bruin, Kf, Spinelli, A, Danese, S, van der Bilt, Jdw, Mundt, Mw, Bemelman, Wa, and Buskens, Cj
- Subjects
Male ,Crohn’s disease ,Fistula ,Perianal fistula ,law.invention ,Anti-TNF ,Primary outcome ,0302 clinical medicine ,Crohn Disease ,Quality of life ,Randomized controlled trial ,law ,Data monitoring committee ,Crohn's disease ,Medical treatment ,Gastroenterology ,General Medicine ,Combined Modality Therapy ,Outcome and Process Assessment, Health Care ,030220 oncology & carcinogenesis ,Early Termination of Clinical Trials ,Cohort ,Drainage ,Female ,030211 gastroenterology & hepatology ,Medical Futility ,Adult ,Reoperation ,medicine.medical_specialty ,Randomization ,03 medical and health sciences ,medicine ,Humans ,Rectal Fistula ,Trial registration ,AcademicSubjects/MED00260 ,Wound Closure Techniques ,business.industry ,General surgery ,Adalimumab ,Patient Acuity ,Consolidated Standards of Reporting Trials ,Original Articles ,medicine.disease ,Infliximab ,Surgery ,Clinical trial ,Good clinical practice ,Quality of Life ,Tumor Necrosis Factor Inhibitors ,business - Abstract
Background: Most patients with perianal Crohn's disease fistulas receive medical treatment with anti-TNF. So far, outcomes of anti-TNF have not been directly compared to chronic seton drainage or surgical closure. We hypothesized that chronic seton drainage would result in fewer re-interventions compared to anti-TNF and surgical closure. Methods: This multicentre, randomised trial was performed in 19 European centres. Patients with high perianal Crohn's fistulas with a single internal opening were randomly assigned in a 1:1:1 ratio to chronic seton drainage, long-term anti-TNF therapy, or surgical closure using a central web-based system without stratification. Patients were analysed according to the intention-to-treat principle. The primary outcome was the cumulative number of patients with fistula-related re-intervention(s) at 1.5 year. Patients refusing randomisation due to a specific treatment preference were included in a parallel prospective PISA registry cohort. Findings: Between September 14, 2013 and November 20, 2017, 44 of the 126 planned patients were randomised. The study was stopped by the data safety monitoring board because of futility. Seton treatment was associated with the highest re-intervention rate (10/15, versus 6/15 anti-TNF and 3/14 surgical closure patients, P = 0·02). No substantial differences in perianal disease activity and quality of life between the three treatment groups were observed. Interestingly, in the PISA prospective registry (n = 50), inferiority of chronic seton treatment was not observed for any outcome measure. Interpretation: The results imply that chronic seton treatment should not be recommended as the sole or superior treatment for perianal Crohn's fistulas. However, the statistical inferiority of seton treatment should be interpreted with caution, due to the crucial aspects of small numbers and as this inferiority could not be confirmed in the PISA registry data. Trial Registration Number: The trial is registered with the Dutch Trialregister.nl number NTR4137. Funding Statement: The Netherlands Organization for Health Research and Development and the Crohn and Colitis Foundation. Declaration of Interests: KAW, EJdG, MES, MGD, MFG, JMJ, AP, SAvT, DDZ, KFB, JvdB, MWM, WAB, and CJB have no conflicts of interests to declare. GRD’H has served as advisor for Abbvie, Ablynx, Allergan, Amakem, Amgen, AM Pharma, Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Meiers Squibb, Boerhinger Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronics, Echo Pharmaceuticals, Eli Lilly, Engene, Ferring, DrFALK Pharma, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Gossamerbio, Hospira/Pfizer, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Photopill, Prometheus laboratories/Nestle, Progenity, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor; received speaker fees from Abbvie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts and Vifor. CYP has served as adviser for Abbvie, Takeda, and Pliant, declares a grant from Takeda, and received speaker’s fees from Abbvie, Tillotts, and Takeda. KBG has served as speaker and/or advisor for Amgen, AbbVie, Biogen, Boehringer Ingelheim, Ferring, Hospira, MSD, Pfizer, Samsung Bioepis, Sandoz, Takeda and Tigenix. AS has served as speaker and/or advisor for Takeda. SD has served as a speaker, a consultant and an advisory board member for Abbvie, Ferring, Hospira, Johnson & Johnson, Merck, Millennium Takeda, Mundipharma, Pfizer, Tigenix, UCB Pharma, and Vifor. Ethics Approval Statement: The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines, and is reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. The trial received central approval from the medical ethics committee at the Amsterdam UMC, location AMC, and from the corresponding committees in all participating centres.
- Published
- 2020