FAecal Microbiota Transplantation in primaRy sclerosinG chOlangitis

Inflammatory Bowel Diseases Clinical Trial

— FARGO  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06286709
• Other study ID #: RG_22-063
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: February 29, 2024
• Est. completion date: July 29, 2026

Study information

• Verified date: February 2024
• Source: University of Birmingham
• Contact: Alexandra Vince
• Phone: +44 (0121) 3718157
• Email: FARGO[@]trials.bham.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

FARGO is a randomised, phase IIa, multi-centre, placebo-controlled trial to compare Faecal Microbiota Transplant (FMT) with placebo in patients with primary sclerosing cholangitis (PSC) and concomitant inflammatory bowel disease.

Description:

Primary Sclerosing Cholangitis (PSC) is a chronic liver disease and there is no medical therapy proven to slow disease progression. Many patients with PSC also develop inflammatory bowel disease (IBD). It has been shown that there is an imbalance of 'normal' microbiome (e.g. bacteria, viruses, fungi) in the gut of people with PSC and IBD. This imbalance is believed to contribute to the development (and possibly worsening) of liver disease in PSC. It is believed that Faecal Microbiota Transplant (FMT) treatment can restore the balance in the gut microbiome and that this can lead to reduction in symptoms of PSC and IBD and improve quality of life. FMT involves the transplantation of faeces (or stool) from a healthy individual to a person with PSC. FMT is prepared from stool collected from unrelated, anonymous, healthy donors. The stool is treated in a laboratory at the University of Birmingham. The donors are carefully screened and the donated stool carefully tested to ensure that it is as clean and safe as possible before it is made into doses of FMT suitable for treatment purposes. Data from treatment with FMT in other conditions including Inflammatory Bowel Disease (IBD), Clostridioides difficile (C.diff) infection and PSC has shown FMT to be safe. The primary aim of the FARGO trial is to determine the efficacy of FMT in patients with PSC. The FARGO trial will recruit 58 patients. Half will be randomised to FMT and half to placebo. The trial will be offered at a number of hospitals across England. Patients will be involved in the trial for 50 weeks, including a 2-week screening, 8 treatments over 8 weeks, and follow-up to 48 weeks post-randomisation. Trial visits will include the collection of health history, blood tests, stool tests, pregnancy tests (if applicable), medication reviews, disease specific measures, patient questionnaires and possible symptom and side-effect review. Research blood, urine, stool and colonic biopsy samples will also be collected.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 58
• Est. completion date: July 29, 2026
• Est. primary completion date: April 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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. 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

7. A colonoscopy showing no evidence of dysplasia/neoplasia within 24 months before screening

8. 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

9. 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

10. 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 3)

6. Biochemical/laboratory evidence of very advanced hepatic dysfunction, as evidenced by a serum bilirubin value >55 µmol/L (or conjugated hyperbilirubinaemia >45 µmol/L), serum albumin <32 g/L, platelet level of <140x10^9/L, Child-Turcotte-Pugh (CTP) score >B7, or a Model for end stage liver disease (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 1 for definition) who confirm they are not willing to practise effective contraception (see Appendix 2 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

Related Conditions & MeSH terms

• Cholangitis
• Cholangitis, Sclerosing
• Inflammatory Bowel Diseases
• Primary Sclerosing Cholangitis

Intervention

Biological:
• Faecal Microbiota Transplant
FMT is 50mL aliquots of filtered suspension of stool (0.6g/mL). FMT for administration via colonoscopy will be made up of 150g stool in 250mL (5 aliquots). FMT for administration via enema will be made up of 30g stool in 50mL (1 aliquot) made up to 100mL by the addition of 50mL normal saline

Other:
• FMT Placebo
FMT Placebo is 50mL aliquots containing 0.9% w/v saline and glycerol in a ratio of 9 parts saline: 1 part glycerol v/v. FMT Placebo for administration via colonoscopy will be made up of 250mL (5 aliquots). FMT Placebo for administration via enema will be made up of 50mL (1 aliquot) made up to 100mL by the addition of 50mL normal saline

Locations

Country	Name	City	State
United Kingdom	Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust	Birmingham
United Kingdom	King's College Hospital, King's College Hospital NHS Foundation Trust	London
United Kingdom	Royal Free Hospital, Royal Free London NHS Foundation Trust	London
United Kingdom	St Mark's Hospital, London North West University Healthcare NHS Trust	London
United Kingdom	Norfolk and Norwich University Hospital, Norfolk and Norwich University Hospitals NHS Foundation Trust	Norwich
United Kingdom	John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust	Oxford

Sponsors (3)

Lead Sponsor	Collaborator
University of Birmingham	Life Arc, PSC Support

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum Alkaline Phosphatase (ALP)	Reduction in serum ALP values from baseline, measured at 48 weeks following the first dose of FMT or FMT Placebo.	ALP at Screening (Week -2), Week 1, Week 3, Week 5, Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Patient-reported outcome (PRO) measures	Patient-reported outcome (PRO) measure: Primary Sclerosing Cholangitis -Patient Reported Outcome (PSC-PRO) Questionnaire	PSC-PRO at Screening (Week -2), Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Patient-reported outcome (PRO) measures	Patient-reported outcome (PRO) measure: short-form (SF)-36 Questionnaire	SF-36 at Screening (Week -2), Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Patient-reported outcome (PRO) measures	Patient-reported outcome (PRO) measures: 5 dimensional itch scale (5D itch) Questionnaire	5D-Itch at Screening (Week -2), Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Patient-reported outcome (PRO) measures	Patient-reported outcome (PRO) measures: Short Inflammatory Bowel Disease Questionnaire (SIBDQ)	SIBDQ at Screening (Week -2), Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Surrogate biomarkers of liver fibrosis	Surrogate biomarkers of liver fibrosis: vibration-controlled transient elastography (VCTE)	Surrogate biomarkers of liver fibrosis: VCTE at Screening (Week -2) and Week 48
Secondary	Surrogate biomarkers of liver fibrosis	Surrogate biomarkers of liver fibrosis: enhanced liver fibrosis score (ELF)	Surrogate biomarkers of liver fibrosis: ELF at Week 1, Week 5, Week 12, and Week 48
Secondary	Routine liver laboratory parameters	Routine liver laboratory parameters: serum alanine transaminase (ALT)	Routine liver laboratory parameters: ALT at Screening (Week -2), Week 1, Week 3, Week 5, Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Routine liver laboratory parameters	Routine liver laboratory parameters: serum aspartate aminotransferase (AST)	Routine liver laboratory parameters: AST at Screening (Week -2), Week 1, Week 3, Week 5, Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Routine liver laboratory parameters	Routine liver laboratory parameters: bilirubin	Routine liver laboratory parameters: bilirubin at Screening (Week -2), Week 1, Week 3, Week 5, Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Routine liver laboratory parameters	Routine liver laboratory parameters: gamma glutamyl transferase	Routine liver laboratory parameters: gamma glutamyl transferase at Screening (Week -2), Week 1, Week 3, Week 5, Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Routine liver laboratory parameters	Routine liver laboratory parameters: albumin	Routine liver laboratory parameters: albumin at Screening (Week -2), Week 1, Week 3, Week 5, Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	PSC specific prognostic scores	PSC specific prognostic scores: the UK-PSC Score	PSC specific prognostic scores: UK-PSC Score at Screening (Week -2), Week 1, Week 3, Week 5, Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	PSC specific prognostic scores	PSC specific prognostic scores: the Amsterdam-Oxford PSC score	PSC specific prognostic scores: Amsterdam-Oxford PSC Score at Screening (Week -2), Week 1, Week 3, Week 5, Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Quantitative assessment of Inflammatory Bowel Disease (IBD) activity	Quantitative assessment of IBD activity: The Mayo colitis score	Quantitative assessment of IBD activity: Mayo colitis score at Week 1, Week 12 and Week 48
Secondary	Quantitative assessment of IBD activity	Quantitative assessment of IBD activity: The Simple Endoscopic Score for Crohn's Disease (SES-CD);	Quantitative assessment of IBD activity: SES-CD at Week 1, Week 12 and Week 48
Secondary	Quantitative assessment of IBD activity	Quantitative assessment of IBD activity: faecal calprotectin	Quantitative assessment of IBD activity: faecal calprotectin at Screening (Week -2), Week 1, Week 5, Week 12 and Week 48
Secondary	The incidence of clinical non-trial endpoint events	The incidence of clinical non-trial endpoint events: acute cholangitis flares (including those that are resistant to single course antibiotic treatment), acute colitis flares, and episodes/time to hepatic decompensation	The incidence of clinical non-trial endpoint events at Screening (Week -2), Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	The incidence of trial endpoint events	The incidence of trial endpoint events: cholangiocarcinoma / hepatopancreatobiliary malignancy, referral for liver transplantation, colonic resection or colorectal cancer, and/or mortality	The incidence of trial endpoint events at Screening (Week -2), Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 12, Week 24, Week 36 and Week 48
Secondary	Occurrence of adverse events	Occurrence of adverse events as measured by CTCAE v5.0	Occurrence of adverse events at Screening (Week -2), Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 12, Week 24, Week 36 and Week 48