FAecal Microbiota Transplantation in primaRy sclerosinG chOlangitis

Inclusion Criteria:

1. Written informed consent

2. Age ≥ 18 years

3. Participants must be able to understand and comply with the purpose and proceduresthat are involved in the trial

4. An established diagnosis of colonic inflammatory bowel disease, with willingness toparticipate in an annual colonoscopic surveillance program, as per routine standardof care

5. An established clinical diagnosis of large duct PSC, with compatible features asassessed by magnetic resonance cholangiopancreatography (MRCP) or endoscopicretrograde cholangiopancreatography (ERCP)

6. A persistent ALP value above normal (at least 2 readings at this value over 6 monthsbefore screening)

7. Evidence of early to moderate stage liver fibrosis, as suspected by any of thefollowing:

8. Median VCTE score of ≤14.4kPa, with an interquartile range ≤30%

9. Previous liver biopsy indicating at an absence of established cirrhosis, Ishakfibrosis stage <IV (or equivalent) in the last 24 months

10. Serum enhanced liver fibrosis score (ELF) ≤9.8

11. A colonoscopy showing no evidence of dysplasia/neoplasia within 24 months beforescreening

12. No evidence of active colitis, as evidenced by a Partial Mayo Score of ≤4, with ascore of <2 on the rectal bleeding domain at screening

13. Individuals with IBD who are receiving treatment with biologics, immunosuppressionor corticosteroids must be taking a stable dose for at least twelve weeks prior toscreening, and be expected to remain on the same medication/same dose for theduration of the trial

14. Individuals with PSC having overlapping features of autoimmune hepatitis may beincluded, provided:

15. The dosage of immunosuppression has remained stable for at least twelve weeksprior to screening, and be expected to remain on the same medication/same dosefor the duration of the trial; and

16. There is evidence of concomitant colitis

Exclusion Criteria:

1. Secondary causes of sclerosing cholangitis including, but not limited to,IgG4-related cholangitis, cholangiopathy due to acquired immunodeficiency syndrome,drug-induced sclerosing cholangitis, trauma, ischaemic cholangiopathy,choledocholithiasis (investigator discretion), or sclerosing cholangiopathy as asequelae of hepatopancreatobiliary resection

2. Other causes of liver disease, including, but not limited to, IgG4-related disease;viral hepatitis; alcohol-related liver disease; clinically significant metabolicassociated fatty liver disease (at investigator discretion); drug-induced liverdisease; hereditary haemochromatosis; alpha-1-antitrypsin disease; primary biliarycholangitis; Wilson disease; Budd-Chiari Syndrome; or primary or secondaryhepatopancreatobiliary cancer

3. Presence of a clinically significant dominant stricture based on the combination ofradiological, biochemical and clinical features. Patients can be included in thetrial with a dominant extrahepatic stenosis if it has been stable for 6 months ormore (as evidenced on imaging and also clinically), and one of the following aresatisfied:

4. The PI does not plan for any biliary intervention (endoscopic, percutaneous orsurgical) for the duration of the trial OR

5. The investigator decides that they do not wish to perform any biliaryintervention (endoscopic, percutaneous or surgical) on the dominant stenosisfor clinical reasons of stability/patient choice

6. Presence of a percutaneous drain or bile duct stent

7. Evidence of hepatic decompensation within twelve weeks prior to screening; orconcern by the Principal Investigator that the participant may decompensate duringthe trial period. Hepatic decompensation as evidenced by variceal haemorrhage,ascites, hepatic hydrothorax, or hepatic encephalopathy (Appendix 1)

8. Biochemical/laboratory evidence of very advanced hepatic dysfunction, as evidencedby a serum bilirubin value >55 µmol/L (unless Gilbert Syndrome or another conditionassociated with unconjugated hyperbilirubinaemia, including but not limited to,spherocytosis and disorders of bilirubin conjugation where a bilirubin value>45 µmol/L is allowable), serum albumin <32 g/L, platelet level of <140x109/L,Child-Turcotte-Pugh (CTP) score >B7, or a MELD score >15

9. Ascending cholangitis as assessed clinically within twelve weeks of screening

10. Use of antibiotics within twelve weeks of screening

11. Participant already listed for liver transplantation, or concerns (investigatordiscretion) that they may need to be listed for liver transplantation during thetrial period

12. Small duct PSC

13. Advanced-stage liver fibrosis, as evidenced by a VCTE score >14.4kPa, a liver biopsyshowing >Ishak stage III fibrosis (or equivalent)

14. Significant renal dysfunction as evidenced by an estimated glomerular filtrationrate of <60 ml/min according to the Cockcroft-Gault formula, or need for dialysis

15. Human Immunodeficiency Virus (HIV) infection

16. A symptomatic positive test result for Serious Acute Respiratory SyndromeCoronavirus 2 (SARS-CoV-2) in the four weeks prior to screening

17. History of malignancy within the past three years, or ongoing malignancy, other thannon-melanomatous skin cancer, or treated cervical carcinoma in situ

18. Any history of small bowel or colonic resection, or likelihood of resection duringthe trial period. Individuals with a sub-total colectomy and ileal pouch analanastomosis are permitted to participate.

19. Patients who are pregnant or breastfeeding

20. Women of childbearing potential (see Appendix 2 for definition) who confirm they arenot willing to practise effective contraception (see Appendix 3 for further details)for the duration of the trial and for four weeks after the last dose of trial drug.Women who are taking hormonal contraception must confirm stable formulation anddosage for at least 6 weeks prior to treatment

21. Alcohol consumption >21 units per week for men, and >14 units per week for women.

22. Positive urine drug screen at screening

23. Positive stool test for Clostridioides Difficile toxin or microscopy/culturepositivity for enteric infection within twelve weeks prior to screening

24. Participation in an interventional trial, or use of a non-licensed investigationalagent for any indication within twelve weeks before screening, or five half-lives ofthe investigational drug, whichever is longer

25. Newly introduced or a change in dosage of any of the following medications withintwelve weeks of screening: fibric acid derivatives, farnesoid X-receptor agonists,anti-gastrointestinal motility agents (e.g., loperamide or opioids), bile acidsequestrants (e.g. colestyramine) or ursodeoxycholic acid (UDCA)

26. Use of any of the following medications within twelve weeks of screening: oral orintravenous antibiotics, including (but not limited to) vancomycin, rifaximin,rifampicin and metronidazole; probiotic or prebiotic preparations, including (butnot limited to) VSL#3 and Symprove