Lyophilised Oral Faecal Microbiota Transplantation in Ulcerative Colitis - a Randomised Placebo-Controlled Trial

Abstract

Background: Colonoscopic infusion and enemas of faecal microbiota transplantation (FMT) induce remission in ulcerative colitis (UC) but whether oral FMT achieves induction and maintenance of remission in UC is unknown.Methods: A double-blind, randomised placebo-controlled trial was conducted. Following 2-weeks of amoxicillin, metronidazole and doxycycline, patients with active UC were randomised 1:1 to FMT or placebo capsules for 8-weeks. The primary outcome was steroid-free clinical remission with endoscopic remission or response. At week-8, FMT-responders were re-randomised 1:1 to continue or withdraw FMT for a further 48-weeks. Modified intention-to-treat analysis was performed and included all patients who received at least one study dose. The gastrointestinal microbiota was profiled using 16S rRNA and ITS region amplicon sequencing. This report presents the final analysis.Findings: From May 2019 to March 2020, 35 subjects were randomised (15 FMT/ 20 placebo). Recruitment was terminated early due to the SARS-COV-2 pandemic. The primary outcome was achieved in 8/15(53%) with FMT versus 3/20(15%) with placebo (difference:38·3% [95%CI: 8·6–68·0]; P =0·027; OR:5·0[95%CI: 1·8–14·1]). Ten FMT-responders entered the maintenance phase. By 56-weeks, 6/6 (100%) subjects randomised to withdraw FMT relapsed (median time to treatment escalation 24-weeks); whereas 4/4(100%) subjects on maintenance-FMT had endoscopic and histologic mucosal healing. Adverse events occurred in 10/15(67%) FMT and 18/20(85%) placebo subjects and were generally mild and self-limiting. Serious adverse events included worsening UC (2 FMT, 1 placebo) and PR bleeding (1 placebo). Antibiotics reduced pathobionts and FMT increased species richness relative to placebo (P<0·0001). Therapeutic effectiveness was associated with high donor microbial alpha-diversity and Bacteroides species, and increases in Bacteroides ovatus-like taxa in recipients.Interpretation Antibiotics followed by orally-administered FMT induces remission in subjects with active UC with corresponding microbial changes. Maintenance FMT in responders was safe, well tolerated and appeared to sustain the response achieved during induction therapy. Trial Registration: The study was registered with the Australian New Zealand Clinical Trial Registry ACTRN12619000611123.Funding: The study was supported by: St Vincent’s Clinic Foundation (2019), Gastroenterological Society of Australia (2020) and Gutsy Group (202-2021). CH is supported by a Research Entry Scholarship through the Royal Australasian College of Physicians; SP is supported by an NHMRC Investigator Grant, NOK is supported by a Scientia Fellowship from UNSW.Declaration of Interest: CH reports speaker fees and educational support from Janssen, Pfizer, Takeda, Ferring, Sandoz and Abbvie. SP has served as a consultant for Finch Therapeutics and has received speaker fees from Ferring, Janssen and Takeda. SG reports Speaker fees, educational grants or travel sponsorship from Janssen Cilag, AbbVie, Takeda, Ferring, Shire, Pfizer. Advisory board fees Pfizer and AbbVie. TJB has a pecuniary interest in the Centre for Digestive Diseases, is a medical advisor to Finch therapeutics and holds patents in FMT treatment. RWL reports personal fees from AbbVie, personal fees from Aspen, personal fees from Ferring, grants and personal fees from Hospira/ Pfizer, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from Shire, grants from NHMRC, personal fees from Celgene, personal fees from Dr Falk Pharma, personal fees from Novartis, personal fees from MSD, grants from Gutsy Group, personal fees from Chiesi, personal fees from BMS, personal fees from Glutagen, outside the submitted work. All other authors have no conflicts of interest to declare.Ethical Approval: This investigator-initiated study was approved by the St Vincent’s Hospital Sydney Human Research Ethics Committee (HREC/18/SVH/219) with The University of Sydney serving as study sponsor. All patients provided written informed consent.