Victoria T. Kronsten, Yevedzo Ntuli, Ellis Kobina Paintsil, Charlotte A. Woodhouse, Thomas H. Tranah, Sue Cheung, Daryl Hagan, Blair Merrick, Angela Cape, Francesca Maher, Kirin Sultana, Désirée Prossomariti, Steven Rodrigues, Christine Masterson, Vanessa Hebditch, Ane Zamalloa, Benjamin H. Mullish, Arjuna Singanayagam, Vishal Patel, Mark Thursz, PROMISE study group, Gavin Wright, Manuel Jasper, Tahir Khan, Syeda Amber Ali, Sarah Fairclough, Bushena Miyesa, Michael Villaruel, Princess Gabiana, Keval Naik, Caroline Fox, Miranda Forsey, Prem Karthikeyan, Jennifer Child, Yvonne Lester, Gautham Appanna, Hannah Donnelly, Alice Lagnado, Robbie Adamson, Joanne Elliot, Gifthy Perez, Rose Fyfe-Beedell, Siby Varghese, Chiaki Shioi, Bindu Mary Jinesh, Shannah O’Sullivan, Hannah Whitehouse, Eunice Akintemi, Matthew Cramp, Glen Marsh, Angela Downing, Gabriella Smallwood, Sasa Topol, Nelly Imbwana, Natasha Wilmshurst, Kelly Bowers, Elanor Haughan, Steven Masson, Juliet Obhiozele, Sarah Hogg, Sheenu Thomas, Lynsey Corless, George Abouda, Kim Dearnley, Jane Rice, Lisa Burton, Julie Gracie, Angie Good, Amy Hicks, Ali Elgadari, Nurun Tania, Ani Kingsbury, Mark McPhail, Michael Ihimekpen, Ruairi Lynch, Damien Leith, Jude Wellens-Mensah, Ann Elliott, Leanne Cosgrove, Abigail Grieve, Paul Johnson, Dina Mansour, Rajan Bhandari, Ann Wilson, Dorothy Carman, Kara Wilshire, Rachael Swann, Laura Davidson, Michael Lumsden, Keziah Lewis, Dominic Rimmer, Faye McMeeken, Shona Perry, Nicole Stoddart, Kirsty Fallon, Lesley Gilmour, Hayley King, Deborah McGlynn, Katherine Burrows, Gemma Duff
Abstract Background Patients with cirrhosis have reduced gut bacterial diversity and a gut microbiota dominated by pathobionts. These changes, coupled with increased gut permeability and bacterial translocation, increase susceptibility to infection and death. There is also considerable concern that high antimicrobial exposure in the cirrhotic population drives the development of antimicrobial resistance (AMR). We previously performed a randomised feasibility trial of endoscopically administered jejunal faecal microbiota transplant (FMT) slurry derived from stringently screened donors, and showed it to be safe and well-tolerated in patients with cirrhosis (PROFIT Trial: NCT02862249). FMT was associated with reduced enteropathogenic bacteria in the gut, augmented ammonia excretion, ameliorated systemic inflammation, and enhanced innate immune responses to pathogen challenge. The trial was not powered to detect differences in clinical outcomes. The PROMISE study will evaluate the efficacy of lyophilised encapsulated FMT to reduce infection, decompensating events and mortality in patients with cirrhosis secondary to alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD) cirrhosis and metabolic dysfunction and alcohol-related liver disease (MetALD). Methods The PROMISE study is a phase 3 multicentre, randomised, double-blinded, placebo-controlled trial that will evaluate encapsulated lyophilised FMT in 300 participants with ALD, MetALD or MASLD cirrhosis (Model for End-Stage Liver Disease Sodium (MELD-Na) score 8–16). Participants will be randomly allocated (1:1) to receive FMT or matched placebo capsules every 91 days for 21 months, with 24-month follow-up. The primary endpoint is time-to-infection or decompensating event resulting in presentation to the emergency department or hospitalisation. Secondary endpoints include all hepatic decompensation, all-cause infection, antibiotic usage, incidence of AMR, hospitalisation rates, liver disease severity scores, quality of life scores, Hospital Anxiety and Depression Scale score (HADS), alcohol use, and mortality. Mechanistic endpoints include quantification of plasma bacterial DNA, plasma and faecal cytokines/biomarkers, plasma and faecal metabolome, faecal proteome, faecal microbiome composition and diversity (including resistome) and monocyte and mucosal-associated invariant T (MAIT) cell frequency, phenotype and function. Recruitment commenced in June 2023. Results will be disseminated via peer-reviewed journals, international conferences and patient support groups. Discussion The PROMISE study will assess the efficacy and evaluate the mechanisms of action of FMT in patients with ALD, MASLD and MetALD cirrhosis. FMT may provide an alternative non-antibiotic treatment for these patients through ecological reconstitution of microbial balance. Trial registration ISRCTN, ISRCTN17863382. Registered on 25th March 2022, https://www.isrctn.com/ISRCTNISRCTN17863382 . ClinicalTrials.gov NCT06461208. Registered on 4th June 2024, https://clinicaltrials.gov/study/NCT06461208#study-overview .