Title: A double blinded randomised controlled trial to investigate the efficacy of faecal microbiota transplantation (FMT) in achieving and maintaining remission for patients with ulcerative colitis 13/179.
Funder: Department of Health and Social Care

Abstract: Patients with inflammatory bowel disease (IBD) have reduced bacterial diversity compared to healthy individuals and at the phylum level a reduction in Firmicuites and a relative increase in Proteobacteria [2,9]. Recent data has suggested that alteration in the microbiome plays a central role in driving UC; studies highlight the importance of Roseburia hominid [10], Faecalibacterium prausnitzii [11] and Akkermansia muciniphila [12]. Probiotics have shown promise in UC [13,14]. Although data is limited to case series, there is evidence for a positive efficacy signal for FMT in IBD[15]. The inflammatory effects associated with the dysbiosis may be due to differential carbohydrate and protein fermentation [12], the metabolic end products of which modulate inflammatory pathways [17]. We have shown that major bacterial fermentation metabolites change during induction of remission in IBD using enteral nutrition treatment [3]. Thus the central role of colonic bacteria makes manipulation of the colonic microbiome a potentially fruitful endeavour in the treatment of IBD. Current data are limited but the signals are encouraging. Reports of FMT in IBD are generally individual case reports or small case series and this technique has not yet been subject to rigorous clinical trials. A recent meta-analysis reported that, from the small numbers studied, FMT achieved remission in over 50%. Encouragingly about three quarters of the patients were able, in the short term, to stop all other IBD related medication [19]. The majority of studies with FMT in IBD have been undertaken by delivering the transplant directly into the colon either through the colonoscope or using enemas. Delivery of the faecal transplant into the upper gut via a naso-gastric tube into the stomach is an alternative and C. difficile treatment studies have shown that use of either route seems equally effective [20]. Naso-gastric (NG) FMT has been used in one small cases series in UC [21]. In this study of patients with very severe disease 1 of 5 responded with a dramatic reduction in MAYO score from 11 to 3 and associated reduction in Enterobacteriaceae. Interim results from the only placebo controlled enema FMT RCT in UC [24] presented this year showed a 23% remission rate compared to placebo (7%). To summarise, data regarding FMT as a treatment for UC are limited at this time and furthermore numerous questions regarding treatment protocol remain to be answered; for example what is the optimum method of donor/ patient selection and preparation and the best route of delivery. In Birmingham we have the first HTA-approved treatment for C. difficile via the NG route and a well-developed protocol for donor screening and transplant preparation. We will use this to supply FMT and adapt it to study the two possible routes of FMT delivery. This becomes feasible with recent data demonstrating that freeze-thawing stool does not lead to deterioration in bacterial diversity and clinical efficacy for CDI over 12 weeks [20,26]. The proposal presented here is a two-stage study to investigate firstly the optimum route of FMT delivery for the treatment of UC and then the efficacy of one of these treatments in patients with UC which is refractory to standard treatment. On the basis of a suitable treatment effect and patient acceptability in the pilot, we propose to proceed with the chosen method to a randomised placebo-controlled trial with an efficacy outcome

Lay abstract: Recently we have begun to understand the importance of the relationship between ourselves and the many bacteria which share our gastrointestinal tract. What is becoming clearer is the vital role these bacteria play in maintaining health and the damage that can result when the delicate partnership between us and our gut bacteria is disrupted. We now know that there is a difference in the proportion of various colonic bacteria between people with and without Ulcerative Colitis (UC). It is believed that this difference is related to the colonic inflammation seen in people with UC - and that changing the balance of bacteria may have a beneficial effect in reducing the inflammation. To date, there have been numerous small studies concerning the effects of replacing the bacteria in the gut of patients with UC. The technique of attempting to alter the gut bacteria makeup with bacteria derived from a healthy person is termed Faecal Microbial Transplant (FMT). It has been administered by both the colonic route and via a nasogastric tube (NGT). This latter method has been particularly successful in treating colitis caused by clostridium difficile infection (C Diff). In general, the results of FMT in UC have been encouraging and the treatments have been administered without causing harm. However, these studies in most part have been ‘uncontrolled’ -with no comparison between the FMT treatment and an alternative therapy to accurately gauge the effect of FMT in UC. In addition the variability in design and processes used makes the results of these studies difficult to compare. To date, there have been no fully published randomised controlled trials in this field. In the current proposal, which is a collaboration between the West Midlands, Glasgow and St Marks Hospital, we aim to undertake a pilot study to compare FMT delivered directly to the colon with an NGT delivery system. Following this eight week pilot, we will be able to compare the clinical response seen with the two treatments, as well as assessing the tolerance and acceptability of the two treatment methods amongst our patients. We will then choose one treatment method to take forward into a blinded placebo controlled randomised study of the effectiveness of FMT in treating both adult and child patients with active UC who are not responding to standard medical treatment. We will assess responses to the treatment using the widely used and well validated MAYO scoring system which is a clinical index comprising symptoms, endoscopic appearance and clinician's general assessment. We will compare this treatment with a placebo "control" treatment to which both the investigators and patients will be blinded (unaware of). Patients in both FMT and placebo arms will be able to continue standard maintenance treatment for UC where the dosage of this treatment has been stable. We will take stool and blood samples from the subjects over one year to assess the stability of any changes in the genetic material related to the bacteria in the gut (the microbiome) and the chemicals they produce. In addition to looking at its efficacy, we will carefully monitor for adverse effects and the acceptability and tolerability of the therapy from the point of view of both patients and clinicians. The ultimate aim of this study, if beneficial, will be to promote early adoption of this novel treatment into the routine practice of clinicians treating patients with UC in the NHS.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;ORAL AND GASTROINTESTINAL