Fecal Microbiota Transplant for Primary Sclerosing Cholangitis

FARGO: A Randomised, Phase IIa, Multi-centre, Placebo-controlled Trial of FAecal Microbiota Transplantation in primaRy sclerosinG chOlangitis

This study is testing whether a stool transplant from healthy donors can help people with Primary Sclerosing Cholangitis feel better and improve their quality of life.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 58 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Birmingham (Academic / other)
• Locations: 5 sites (Birmingham and 4 other locations)
• Trial ID: NCT06286709 on ClinicalTrials.gov

What this trial studies

The FARGO trial is a randomized, phase IIa, multi-center, placebo-controlled trial designed to evaluate the efficacy of Fecal Microbiota Transplant (FMT) in patients suffering from Primary Sclerosing Cholangitis (PSC) and inflammatory bowel disease (IBD). The study aims to restore the gut microbiome balance through FMT, which involves transplanting stool from healthy donors to patients with PSC. The trial will recruit 58 participants, with half receiving FMT and the other half receiving a placebo, to assess the treatment's impact on symptoms and quality of life. The stool used for FMT is carefully screened and processed to ensure safety and efficacy.

Who should consider this trial

Good fit: Ideal candidates for this study are adults aged 18 and older with a diagnosis of large duct PSC and concomitant inflammatory bowel disease.

Not a fit: Patients with established cirrhosis or those who do not meet the eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve symptoms and quality of life for patients with PSC and IBD.

How similar studies have performed: Previous studies have shown FMT to be safe and effective in treating conditions like IBD and C. difficile infections, suggesting potential for success in this novel application.

Eligibility criteria

Inclusion Criteria:

1. Written informed consent
2. Age ≥ 18 years
3. Participants must be able to understand and comply with the purpose and procedures that are involved in the trial
4. An established diagnosis of colonic inflammatory bowel disease, with willingness to participate in an annual colonoscopic surveillance program, as per routine standard of care
5. An established clinical diagnosis of large duct PSC, with compatible features as assessed by magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP)
6. A persistent ALP value above normal (at least 2 readings at this value over 6 months before screening)
7. Evidence of early to moderate stage liver fibrosis, as suspected by any of the following:

   1. Median VCTE score of ≤14.4kPa, with an interquartile range ≤30%
   2. Previous liver biopsy indicating at an absence of established cirrhosis, Ishak fibrosis stage \<IV (or equivalent) in the last 24 months
   3. Serum enhanced liver fibrosis score (ELF) ≤9.8
8. A colonoscopy showing no evidence of dysplasia/neoplasia within 24 months before screening
9. No evidence of active colitis, as evidenced by a Partial Mayo Score of ≤4, with a score of \<2 on the rectal bleeding domain at screening
10. Individuals with IBD who are receiving treatment with biologics, immunosuppression or corticosteroids must be taking a stable dose for at least twelve weeks prior to screening, and be expected to remain on the same medication/same dose for the duration of the trial
11. Individuals with PSC having overlapping features of autoimmune hepatitis may be included, provided:

    1. The dosage of immunosuppression has remained stable for at least twelve weeks prior to screening, and be expected to remain on the same medication/same dose for the duration of the trial; and
    2. 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 a sequelae 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 metabolic associated fatty liver disease (at investigator discretion); drug-induced liver disease; hereditary haemochromatosis; alpha-1-antitrypsin disease; primary biliary cholangitis; Wilson disease; Budd-Chiari Syndrome; or primary or secondary hepatopancreatobiliary cancer
3. Presence of a clinically significant dominant stricture based on the combination of radiological, biochemical and clinical features. Patients can be included in the trial with a dominant extrahepatic stenosis if it has been stable for 6 months or more (as evidenced on imaging and also clinically), and one of the following are satisfied:

   1. The PI does not plan for any biliary intervention (endoscopic, percutaneous or surgical) for the duration of the trial OR
   2. The investigator decides that they do not wish to perform any biliary intervention (endoscopic, percutaneous or surgical) on the dominant stenosis for clinical reasons of stability/patient choice
4. Presence of a percutaneous drain or bile duct stent
5. Evidence of hepatic decompensation within twelve weeks prior to screening; or concern by the Principal Investigator that the participant may decompensate during the trial period. Hepatic decompensation as evidenced by variceal haemorrhage, ascites, hepatic hydrothorax, or hepatic encephalopathy (Appendix 1)
6. Biochemical/laboratory evidence of very advanced hepatic dysfunction, as evidenced by a serum bilirubin value \>55 µmol/L (unless Gilbert Syndrome or another condition associated 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
7. Ascending cholangitis as assessed clinically within twelve weeks of screening
8. Use of antibiotics within twelve weeks of screening
9. Participant already listed for liver transplantation, or concerns (investigator discretion) that they may need to be listed for liver transplantation during the trial period
10. Small duct PSC
11. Advanced-stage liver fibrosis, as evidenced by a VCTE score \>14.4kPa, a liver biopsy showing \>Ishak stage III fibrosis (or equivalent)
12. Significant renal dysfunction as evidenced by an estimated glomerular filtration rate of \<60 ml/min according to the Cockcroft-Gault formula, or need for dialysis
13. Human Immunodeficiency Virus (HIV) infection
14. A symptomatic positive test result for Serious Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the four weeks prior to screening
15. History of malignancy within the past three years, or ongoing malignancy, other than non-melanomatous skin cancer, or treated cervical carcinoma in situ
16. Any history of small bowel or colonic resection, or likelihood of resection during the trial period. Individuals with a sub-total colectomy and ileal pouch anal anastomosis are permitted to participate.
17. Patients who are pregnant or breastfeeding
18. Women of childbearing potential (see Appendix 2 for definition) who confirm they are not 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 and dosage for at least 6 weeks prior to treatment
19. Alcohol consumption \>21 units per week for men, and \>14 units per week for women.
20. Positive urine drug screen at screening
21. Positive stool test for Clostridioides Difficile toxin or microscopy/culture positivity for enteric infection within twelve weeks prior to screening
22. Participation in an interventional trial, or use of a non-licensed investigational agent for any indication within twelve weeks before screening, or five half-lives of the investigational drug, whichever is longer
23. Newly introduced or a change in dosage of any of the following medications within twelve weeks of screening: fibric acid derivatives, farnesoid X-receptor agonists, anti-gastrointestinal motility agents (e.g., loperamide or opioids), bile acid sequestrants (e.g. colestyramine) or ursodeoxycholic acid (UDCA)
24. Use of any of the following medications within twelve weeks of screening: oral or intravenous antibiotics, including (but not limited to) vancomycin, rifaximin, rifampicin and metronidazole; probiotic or prebiotic preparations, including (but not limited to) VSL#3 and Symprove

Where this trial is running

Birmingham and 4 other locations

• Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust — Birmingham, United Kingdom (Recruiting)
• St Mark's Hospital, London North West University Healthcare NHS Trust — London, United Kingdom (Recruiting)
• Royal Free Hospital, Royal Free London NHS Foundation Trust — London, United Kingdom (Recruiting)
• King's College Hospital, King's College Hospital NHS Foundation Trust — London, United Kingdom (Recruiting)
• John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust — Oxford, United Kingdom (Recruiting)

Study contacts

• Study coordinator: Helen Coulthard

Conditions Primary Sclerosing Cholangitis; Inflammatory Bowel Diseases