Fecal Microbiota Transplantation in Crohn's Disease as Relay After Anti-TNF Withdrawal (MIRACLE)

Crohn's disease (CD) is a chronic inflammatory bowel disease. CD pathogenesis remains poorly understood but involves an inappropriate immune response toward an unbalanced gut microbiota in predisposed hosts. The purpose of this study is to evaluate de clinical efficacy of the fecal microbiota transplantation (FMT) as a maintenance treatment following anti-TNF agent withdrawal in CD's patient.

Crohn's disease (CD) is a chronic inflammatory bowel disease affecting approximately 120000 patients in France, mostly at young age, and altering their quality of life. Immunosuppressive treatments in CD are expensive and associated with potentially severe complications. Alternative treatment strategies are thus required. This is particularly the case for CD patients in remission under anti-TNF agents for which no specific recommendation are available. CD pathogenesis remains poorly understood but involves an inappropriate immune response toward an unbalanced gut microbiota in predisposed hosts. Fecal microbiota transplantation (FMT) is currently recommended for treating recurrent Clostridium difficile infection. Although the pathogenesis involved in CD differs, FMT is a potential therapeutic strategy that could restore the appropriate host-microbiota crosstalk by transferring a healthy microbiota in a CD patient. However, as the gut microbiota is dramatically altered by intestinal inflammation, transferring a massive amount of microbes in an inflamed gut with epithelial barrier disruption might be a suboptimal strategy and could even have detrimental effects by allowing bacterial translocation. Results of randomized controlled trial (RCT) in CD are lacking to date. We performed a pilot RCT (NCT02097797), evaluating the impact of a single FMT in 18 CD patients who achieved remission by corticosteroid treatment. A higher rate of steroid free clinical remission was observed in the FMT arm at 24 weeks (57.1% vs 33.3% in FMT and control arm respectively). CD Endoscopic Index of Severity was also improved at 6 weeks in FMT (median 8.5 vs 3.5 p=0.03) but not in sham group (median 2.4 vs 2.7 p=0.8). Moreover, the only 2 patients who early relapsed in the FMT group were those who did not show any engraftment of donor microbiota at week 6. These promising data, currently submitted for publication, suggest that using FMT as a maintenance treatment in CD can be effective. However, these promising findings need to be confirmed by a Phase III RCT.

Patients receiving the fecal microbiota transplantation (FMT) in 3 times after inclusion and randomisation (endoscopic and oral)

Patients receiving the sham-transplantation in 3 times after inclusion and randomisation (endoscopic and oral)

The colonoscopy for FMT will be planned between 7 and 14 days after the last adalimumab or sub-cutaneous infliximab administration and 6 weeks +/- 7 days after the last intravenous infliximab administration 14 and 28 days following the last sub-cutaneous golimumab administration. After colon cleansing using polyethylene glycol, the patient will have a colonoscopy under general anesthesia. The patient will then receive either FMT (frozen preparation of 50g of stools in 300ml of saline (NaCl 0.9%), (FMT vehicle in the terminal ileum or the colon. At W12 and W24 after first colonoscopy, the patient receives treatment by capsule (15 capsules contain 0.8g of stools by visit).

The colonoscopy for sham-transplantation will be planned between 7 and 14 days after the last adalimumab or sub-cutaneous infliximab administration and 6 weeks +/- 7 days after the last intravenous infliximab administration, 14 and 28 days following the last sub-cutaneous golimumab administration. After colon cleansing using polyethylene glycol, the patient will have a colonoscopy under general anesthesia. The patient will then receive either sham transplantation (frozen preparation of NaCl 0.9% with 10% glycerol) in the terminal ileum or the colon. At S12 and S24 after first colonoscopy, the patient receives treatment by capsule (15 capsules contain placebo).

Evaluate the clinical efficacy of FMT versus sham transplantation as a maintenance treatment following anti-TNF agent withdrawal in patients with Crohn's disease in steroid-free clinical remission for at least 6 months under anti-TNF agent

Clinical remission (defined by a Crohn's disease activity index (CDAI) <150) at week 52 (V8) without any flare between week 0 (colonoscopy (V2)) and week 52 (V8). Flare is defined by a CDAI (Addendum 2) above 250 or between 150 points and 250 points with a 70-point increase from baseline over 2 consecutive weeks and the need

Proportion of endoscopic remission (SES-CD ≤2) at week 52 (V8) and change (in %) in endoscopic score (SES-CD) between week 0 (V2) and 52 (V8)

Inclusion Criteria for patients : Age ≥ 18 years and < 75 years Crohn's disease (according to the Lennard-Jones criteria) for at least 6 months Patient in steroid-free clinical remission for at least 6 months under anti-TNF agent (no clinical evidence of flare nor change in Crohn's disease specific treatment (anti-TNF, immunosuppressive, …) within 6 months before inclusion) and CDAI <150 the week before inclusion) and willing to withdraw anti-TNF treatment Female of child-bearing age with an active contraception and this during at least the period of treatment (week 52) Patient with health insurance Informed Written consent Inclusion Criteria for healthy volunteer donor : Age ≥ 18 years and < 50 years 17 kg/m² < body mass index < 30 kg/m² Regular bowel movement defined as at least 1 stool every other day and maximum 2 stools per day Subject with health insurance (AME excepted) Informed written consent Exclusion Criteria for patients : Crohn's Disease complication requiring surgical treatment Contraindication to colonoscopy or anesthesia Pregnancy or breastfeeding during the study (Cf. Addendum 4) Diagnosis of Crohn's disease restricted to the upper gastrointestinal tract (oesophagus, stomach, duodenum, jejunum) Patient with active perineal disease (defined as evidence of perineal abscess or active draining fistula or presence of seton or presence of perineal ulceration) History of more than one small bowel resection or small intestine resection > 1 meter Current stoma (Ileostomy or a colostomy) or stoma in the last 6 months or any other intra-abdominal surgery within 3 months prior to inclusion Participation in any other interventional study Patient under legal protection Exclusion Criteria for healthy volunteer donor : - For details, please see protocol

Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015 Apr;12(4):205-17. doi: 10.1038/nrgastro.2015.34. Epub 2015 Mar 3.

Angelberger S, Reinisch W, Makristathis A, Lichtenberger C, Dejaco C, Papay P, Novacek G, Trauner M, Loy A, Berry D. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am J Gastroenterol. 2013 Oct;108(10):1620-30. doi: 10.1038/ajg.2013.257. Epub 2013 Sep 24.

Beaugerie L, Itzkowitz SH. Cancers Complicating Inflammatory Bowel Disease. N Engl J Med. 2015 Jul 9;373(2):195. doi: 10.1056/NEJMc1505689. No abstract available.

Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in Crohn's disease. Aliment Pharmacol Ther. 2011 May;33(9):987-95. doi: 10.1111/j.1365-2036.2011.04612.x. Epub 2011 Mar 2.

Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology. 1976 Mar;70(3):439-44.

Borody T, Fischer M, Mitchell S, Campbell J. Fecal microbiota transplantation in gastrointestinal disease: 2015 update and the road ahead. Expert Rev Gastroenterol Hepatol. 2015;9(11):1379-91. doi: 10.1586/17474124.2015.1086267. Epub 2015 Sep 28.

Colman RJ, Rubin DT. Fecal microbiota transplantation as therapy for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis. 2014 Dec;8(12):1569-81. doi: 10.1016/j.crohns.2014.08.006. Epub 2014 Sep 13. Erratum In: J Crohns Colitis. 2022 Aug 16;:

Cui B, Li P, Xu L, Zhao Y, Wang H, Peng Z, Xu H, Xiang J, He Z, Zhang T, Nie Y, Wu K, Fan D, Ji G, Zhang F. Step-up fecal microbiota transplantation strategy: a pilot study for steroid-dependent ulcerative colitis. J Transl Med. 2015 Sep 12;13:298. doi: 10.1186/s12967-015-0646-2.

Cui B, Feng Q, Wang H, Wang M, Peng Z, Li P, Huang G, Liu Z, Wu P, Fan Z, Ji G, Wang X, Wu K, Fan D, Zhang F. Fecal microbiota transplantation through mid-gut for refractory Crohn's disease: safety, feasibility, and efficacy trial results. J Gastroenterol Hepatol. 2015 Jan;30(1):51-8. doi: 10.1111/jgh.12727.

D'Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ, Lemann M, Marteau P, Rutgeerts P, Scholmerich J, Sutherland LR. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology. 2007 Feb;132(2):763-86. doi: 10.1053/j.gastro.2006.12.038. Epub 2006 Dec 20. No abstract available.

Debast SB, Bauer MP, Kuijper EJ; European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014 Mar;20 Suppl 2:1-26. doi: 10.1111/1469-0691.12418.

Grinspan AM, Kelly CR. Fecal Microbiota Transplantation for Ulcerative Colitis: Not Just Yet. Gastroenterology. 2015 Jul;149(1):15-8. doi: 10.1053/j.gastro.2015.05.030. Epub 2015 May 27. No abstract available.

Kennedy NA, Warner B, Johnston EL, Flanders L, Hendy P, Ding NS, Harris R, Fadra AS, Basquill C, Lamb CA, Cameron FL, Murray CD, Parkes M, Gooding I, Ahmad T, Gaya DR, Mann S, Lindsay JO, Gordon J, Satsangi J, Hart A, McCartney S, Irving P; UK Anti-TNF withdrawal study group; Lees CW. Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease: an observational study, plus systematic review and meta-analysis. Aliment Pharmacol Ther. 2016 Apr;43(8):910-923. doi: 10.1111/apt.13547. Epub 2016 Feb 19.

Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, Aroniadis O, Barto A, Borody T, Giovanelli A, Gordon S, Gluck M, Hohmann EL, Kao D, Kao JY, McQuillen DP, Mellow M, Rank KM, Rao K, Ray A, Schwartz MA, Singh N, Stollman N, Suskind DL, Vindigni SM, Youngster I, Brandt L. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014 Jul;109(7):1065-71. doi: 10.1038/ajg.2014.133. Epub 2014 Jun 3.

Kelly CR, Kahn S, Kashyap P, Laine L, Rubin D, Atreja A, Moore T, Wu G. Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook. Gastroenterology. 2015 Jul;149(1):223-37. doi: 10.1053/j.gastro.2015.05.008. Epub 2015 May 15.

Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011 Jun 15;474(7351):307-17. doi: 10.1038/nature10209.

Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G, Bridonneau C, Jegou S, Hoffmann TW, Natividad JM, Brot L, Taleb S, Couturier-Maillard A, Nion-Larmurier I, Merabtene F, Seksik P, Bourrier A, Cosnes J, Ryffel B, Beaugerie L, Launay JM, Langella P, Xavier RJ, Sokol H. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016 Jun;22(6):598-605. doi: 10.1038/nm.4102. Epub 2016 May 9.

Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, Almeida M, Arumugam M, Batto JM, Kennedy S, Leonard P, Li J, Burgdorf K, Grarup N, Jorgensen T, Brandslund I, Nielsen HB, Juncker AS, Bertalan M, Levenez F, Pons N, Rasmussen S, Sunagawa S, Tap J, Tims S, Zoetendal EG, Brunak S, Clement K, Dore J, Kleerebezem M, Kristiansen K, Renault P, Sicheritz-Ponten T, de Vos WM, Zucker JD, Raes J, Hansen T; MetaHIT consortium; Bork P, Wang J, Ehrlich SD, Pedersen O. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013 Aug 29;500(7464):541-6. doi: 10.1038/nature12506.

Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, Weese JS, Collins S, Moayyedi P, Crowther M, Ropeleski MJ, Jayaratne P, Higgins D, Li Y, Rau NV, Kim PT. Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2016 Jan 12;315(2):142-9. doi: 10.1001/jama.2015.18098.

Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989;170:2-6; discussion 16-9. doi: 10.3109/00365528909091339.

Manichanh C, Borruel N, Casellas F, Guarner F. The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol. 2012 Oct;9(10):599-608. doi: 10.1038/nrgastro.2012.152. Epub 2012 Aug 21.

Moayyedi P, Surette MG, Kim PT, Libertucci J, Wolfe M, Onischi C, Armstrong D, Marshall JK, Kassam Z, Reinisch W, Lee CH. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology. 2015 Jul;149(1):102-109.e6. doi: 10.1053/j.gastro.2015.04.001. Epub 2015 Apr 7.

Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D, Leong RWL, Connor S, Ng W, Paramsothy R, Xuan W, Lin E, Mitchell HM, Borody TJ. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017 Mar 25;389(10075):1218-1228. doi: 10.1016/S0140-6736(17)30182-4. Epub 2017 Feb 15.

Rossen NG, Fuentes S, van der Spek MJ, Tijssen JG, Hartman JH, Duflou A, Lowenberg M, van den Brink GR, Mathus-Vliegen EM, de Vos WM, Zoetendal EG, D'Haens GR, Ponsioen CY. Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology. 2015 Jul;149(1):110-118.e4. doi: 10.1053/j.gastro.2015.03.045. Epub 2015 Mar 30.

Sokol H, Leducq V, Aschard H, Pham HP, Jegou S, Landman C, Cohen D, Liguori G, Bourrier A, Nion-Larmurier I, Cosnes J, Seksik P, Langella P, Skurnik D, Richard ML, Beaugerie L. Fungal microbiota dysbiosis in IBD. Gut. 2017 Jun;66(6):1039-1048. doi: 10.1136/gutjnl-2015-310746. Epub 2016 Feb 3.

Sokol H, Galperine T, Kapel N, Bourlioux P, Seksik P, Barbut F, Scanzi J, Chast F, Batista R, Joly F, Joly AC, Collignon A, Guery B, Beaugerie L; French Group of Faecal microbiota Transplantation (FGFT). Faecal microbiota transplantation in recurrent Clostridium difficile infection: Recommendations from the French Group of Faecal microbiota Transplantation. Dig Liver Dis. 2016 Mar;48(3):242-7. doi: 10.1016/j.dld.2015.08.017. Epub 2015 Sep 7.

Sokol H. Toward Rational Donor Selection in Faecal Microbiota Transplantation for IBD. J Crohns Colitis. 2016 Apr;10(4):375-6. doi: 10.1093/ecco-jcc/jjw005. Epub 2016 Jan 7. No abstract available.

Sokol H, Lalande V, Landman C, Bourrier A, Nion-Larmurier I, Rajca S, Kirchgesner J, Seksik P, Cosnes J, Barbut F, Beaugerie L. Clostridium difficile infection in acute flares of inflammatory bowel disease: A prospective study. Dig Liver Dis. 2017 Jun;49(6):643-646. doi: 10.1016/j.dld.2017.01.162. Epub 2017 Jan 30.

Suskind DL, Singh N, Nielson H, Wahbeh G. Fecal microbial transplant via nasogastric tube for active pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr. 2015 Jan;60(1):27-9. doi: 10.1097/MPG.0000000000000544.

Toruner M, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, Colombel JF, Egan LJ. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008 Apr;134(4):929-36. doi: 10.1053/j.gastro.2008.01.012. Epub 2008 Jan 11.

van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. doi: 10.1056/NEJMoa1205037. Epub 2013 Jan 16.

Vermeire S, Joossens M, Verbeke K, Wang J, Machiels K, Sabino J, Ferrante M, Van Assche G, Rutgeerts P, Raes J. Donor Species Richness Determines Faecal Microbiota Transplantation Success in Inflammatory Bowel Disease. J Crohns Colitis. 2016 Apr;10(4):387-94. doi: 10.1093/ecco-jcc/jjv203. Epub 2015 Oct 29.

Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van Hylckama Vlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, de Vos WM, Hoekstra JB, Nieuwdorp M. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012 Oct;143(4):913-6.e7. doi: 10.1053/j.gastro.2012.06.031. Epub 2012 Jun 20. Erratum In: Gastroenterology. 2013 Jan;144(1):250.

Youngster I, Mahabamunuge J, Systrom HK, Sauk J, Khalili H, Levin J, Kaplan JL, Hohmann EL. Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection. BMC Med. 2016 Sep 9;14(1):134. doi: 10.1186/s12916-016-0680-9.

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