Title: A prospective, randomised placebo controlled feasibility trial of Faecal microbiota Transplant to ERadicate gastrointestinal carriage of Antibiotic Resistant Organisms (FERARO)
Funder: Department of Health and Social Care

Abstract: Research question: What is the feasibility of conducting a substantive trial of Faecal Microbiota Transplant (FMT) to eradicate gastrointestinal carriage of Multi Drug Resistant Gram Negative Organisms (MDRGNOs)? Background: Antimicrobial Resistance (AMR) is a growing global threat. The human gastrointestinal tract is the main reservoir of MDRGNOs. Colonisation with these organisms precedes, and is a significant risk for, subsequent invasive infection. Invasive MDRGNOs infection (e.g. bloodstream infection, intra-abdominal infection and urinary tract infection) is difficult to treat, resulting in high mortality and significant burden to the healthcare economy. Attempts to decolonise MDRGNO patients using orally administered antibiotics have been unsuccessful. Faecal Microbiota Transplant (FMT) is the transfer of a consortia of gut bacteria from healthy donors to those with underlying dysbiosis, with the aim of restoring a healthy and diverse microbiome. FMT is very effective in treating patients with recurrent Clostridium difficile Infection, with success rates of >80%, and is well tolerated. There are case reports suggesting FMT may be effective in eradicating MDRGNO carriage, but no randomised controlled trial has been conducted. Aims and Objectives: This is a feasibility study to determine whether FMT can be administered to MDRGNO colonised patients with the eventual aim of eradication (and thereby prevent invasive infection). It is not clear wether patients will accept this treatment or be willing to undergo randomisation. This and other key information is required before a larger, more expensive, substantive randomised controlled trial can be designed and conducted. The primary outcome measure is the consent rate of patients who fulfil inclusion and exclusion criteria. Methods: We will randomise 80 patients colonised with an MDRGNO (and who have had a systemic infection with the same organism in the preceding 6 months) to receive with FMT or an identical placebo. FMT will be administered as capsules (administered as 15-20 capsules on two consecutive days). FMT will be derived from healthy human volunteers who have undergone full screening and testing, using our existing MHRA licensed FMT donor programme. We will follow patients up at 5 timepoints (days 9, 16, 32, 92 and 182) to assess tolerability and incidence of any adverse events. Patients will be asked to submit stool samples (either in person by post) which will be analysed using a microarray test to detect a number of antimicrobial resistance genes). This will allow an estimation of the effectiveness and durability of the FMT (although as a feasibility trial, it will not be powered to detect any statistically significant difference). Timelines for delivery: We will recruit the first patient in November 2019, with the last patient randomised in December 2020. Follow up of the final patient will be complete by June 2021. Results will be analysed and disseminated by September 2021 with a plan to proceed to an application for a substantive trial if feasible. Anticipated Impact and Dissemination: Results will be published in peer reviewed journals and other outputs aimed at patients and the public, and will determine feasibility of proceeding to a substantive trial.

Lay abstract: What is this study about? The human gut has trillions of bacteria (bugs) which are important to keep us healthy. In total these bugs are called the microbiota. The bugs are always evolving to beat antibiotics used to fight them (resistance). Resistance to antibiotics allows bugs to survive and spread. This is a growing and serious threat to worldwide health, and means that doctors may be limited in the types of treatments that they can offer to patients. Without effective antibiotics even simple infections could become deadly, making routine medical procedures too dangerous to perform. There is an urgent need to find new antibiotics, but this takes time and is very expensive. There is growing interest in non-antibiotic treatments like Faecal Microbiota Transplant (FMT) to deal with this problem. FMT is the transfer of bacteria from the guts of healthy donors (taken from their poo) into the gut of a patient. The aim is to restore a healthy balance of bacteria (reducing harmful ones and increasing good ones). It is currently used to treat patients with repeated Clostridium difficile infection. This is an infection causing severe diarrhoea and stomach pain, normally after having antibiotics which have harmed the microbiota. FMT is very effective and safe in treating this group of patients, with success rates of over 80%. Initial research shows that it may be helpful in other conditions. Especially for excluding antibiotic resistant bacteria (ARB) found in some patients' guts. How will this study help people? This study will look at whether giving FMT to patients with ARB is an achievable treatment. We will see if it is both safe and acceptable to patients, without side effects. This will allow doctors to treat infections in these patients better. If the treatment works it could be rapidly brought into the NHS. This could help patients who have ARB and can't be treated with current antibiotics. What will we do in this study? We will involve patients and members of the public by inviting then to have a say in how the study is designed, performed and reported. 40 patients with ARB will be randomly chosen to receive FMT (swallowed as capsules). Another 40 patients will be randomly chosen to receive identical capsules without the bugs. This is known as a placebo . Patients will have stool (poo) samples collected before and after FMT. These will be taken at days 9, 16, 32, 92 and 182. We will use these to see what impact the treatment has on their gut bugs. We will also see if the treatment causes any side effects like bad taste, burping, diarrhoea and infection.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION