Fecal Microbiota Transplantation for Primary Sclerosing Cholangitis - Randomized Study Versus Sham Transplantation

Primary Sclerosing Cholangitis (PSC) is a rare cholestatic liver disease, commonly associated with inflammatory bowel disease (IBD) and characterized by progressive obliterative fibrosis of the biliary tree. PSC can lead to cirrhosis, end-stage liver disease, and hepatobiliary and colorectal cancer. Serum levels of alkaline phosphatase (ALP) and bilirubin are markers of cholestasis and have a prognostic value in PSC.

Liver transplantation is the only validated treatment since no medication has been reported to improve survival of PSC patients. However, ursodeoxycholic acid (UDCA), which has shown efficacy to improve liver tests, notably ALP, is approved for treatment of PSC and is prescribed in all PSC patients in France. Several studies have demonstrated that the gut microbiota plays an important role in the pathogenesis and the progression of PSC. First, PSC patients display an intestinal dysbiosis, regardless of IBD status. This dysbiosis is characterized by a decrease in diversity and some changes in the composition of gut microbiota. Second, fecal microbiota transplantation (FMT) from PSC patients into mice aggravate the cholestatic liver disease, suggesting an impact of the gut microbiota on PSC. Third, modulation of gut microbiota by antibiotic therapy can improve liver tests in PSC patients. A recent uncontrolled study, performed in 10 PSC patients, showed that FMT was safe. Moreover, in this study, a single FMT was associated with a reduction of ALP levels in 33% patients. FMT also increased bacterial diversity in all patients, and abundance of engrafted bacteria in patients post-FMT tended to be correlated with decreased ALP levels. Thus, FMT could be a useful therapy in PSC patients. The aim of the present trial is to assess the efficacy of FMT on ALP and bilirubin compared to sham transplantation in addition to UDCA treatment in PSC patients.

• Fecal microbiota transplantation (FMT) (Drug): One to 4 weeks after randomization, the patient will be hospitalized in one of the hepato-gastroenterology department involved in the study for the colonoscopy. The patient will then receive either FMT (suspension of 50g of stools in 300ml of cryopreservative solution) in the terminal ileum or the caecum. At W12 and W24 after first colonoscopy , the patient will receive orally 20 FMT (capsules swallowed in front of a physician or a nurse in hospital)
• Sham-transplantation (placebo) (Drug): One to 4 weeks after randomization, the patient will be hospitalized in one of the hepato-gastroenterology department involved in the study for the colonoscopy. The patient will then receive sham transplantation (FMT vehicle, i.e. 300ml of cryopreservative solution) in the terminal ileum or the caecum. At W12 and W24 after first colonoscopy , the patient will receive orally 20 sham capsules (capsules swallowed in front of a physician or a nurse in hospital)

Primary outcomes

• To assess in patients with PSC the efficacy of FMT versus sham transplantation on ALP and bilirubin at week 48 addition to standard UDCA therapy. [at week 48]: Proportion of success at week 48. Success is defined as patients with serum ALP <1.3 ULN at week 48 and a reduction of, at least 15%, compared to baseline ALP level AND normal total bilirubin ≤ 1 ULN at week 48

Secondary outcomes

• Efficacy of FMT on reduction of ALP and normalization of bilirubin level at week 12, 24, 36 and 48 individually [at week 12, 24, 36 and 48]: Proportion of success at week 12, 24 , 36 and 48. Success is defined as patients with serum ALP <1.3 ULN and a reduction of, at least 15%, compared to baseline ALP level AND normal total bilirubin ≤ 1 ULN
• Efficacy of FMT on biochemical liver tests at week 12, 24, 36 and 48 (ALP, GGT, AST, ALT and bilirubin) [at week 12, 24, 36 and 48]: Proportion of patients that normalized all liver tests (ALP <1ULN and GGT <1 ULN and AST <1 ULN and ALT <1 ULN and total bilirubin <1 ULN) at week 12 24 36 and 48
• Efficacy of FMT on liver fibrosis progression [at week 48]: assessed by transient elastography at week 48 versus week 0
• PSC prognostic scores [at week 0, 24 and 48]: PSC Prognostic scores including the MELD score, the Revised PSC Mayo Risk Score, the Amsterdam-Oxford prognostic model (week 0, week 48)
• Occurrence of liver events during the study period [between randomization and week 104]: Percentage of patients with clinical or biological adverse events
• Occurrence of liver events during the study period [at week 48]: Survival rate without liver events

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Males or females
* Age ≥18 and ≤75 years
* Large duct PSC verified by retrograde, operative, percutaneous or magnetic resonance cholangiography (MRC) demonstrating intrahepatic and /or extrahepatic biliary duct changes consistent with PSC
* IBD diagnosed according to international guidelines (presence of endoscopic and histologic signs)
* IBD inactive for at least 6 months (defined by no evidence of flare and no change in treatment)
* ALP ≥ 1.3 ULN (at least 2 times within a 3 months pre-inclusion period) or elevated total bilirubin ≤50 umol/l (with concomitant elevated direct bilirubin).
* Treatment with UDCA (13-23 mg/kg/d) for at least 6 months and at the same dosage for at least 3 months
* Using contraceptive in women of childbearing potential and agrees to pursue it from inclusion until week 48. Women of childbearing potential, i.e. fertile, following menarche and until becoming post-menopaused unless permanently sterile, who are sexually active have to apply a highly effective method of birth control with a low failure rate (i.e. less than 1% per year) when used constantly and correctly.
* Written informed consent signed
* Subject affiliated to the French
* Social Security System

Exclusion Criteria:

* Small duct PSC
* Autoimmune hepatitis defined by the presence of moderate to severe interface hepatitis documented on liver biopsy and at least 1 of the 2 following criteria: AST or ALT > 5 ULN, Positive anti smooth muscle auto antibodies or serum IgG > 1.5 ULN
* Secondary sclerosing cholangitis (notably IgG4-associated cholangitis)
* Cirrhosis defined by Liver elastometry >14.4 kPa or by current or past decompensation of cirrhosis
* AST or ALT > 7 ULN in the last 3 months
* Platelets count in the last 3 months < 100 000/mm3
* Albumin in the last 3 months <35g/L
* Prothrombin index in the last 3 months < 70%
* Hepatic comorbidity: HBV infection (defined by positive Ag HBS), HCV infection (defined by positive HCV RNA), alcohol abuse (defined by alcohol intake > 30g/day), metabolic dysfunction associated steatohepatitis, primary biliary cholangitis, Hemochromatosis, Wilson disease, α1-antitrypsin deficiency, celiac disease
* History of acute cholangitis in the last 3 months prior to inclusion or current acute cholangitis
* HIV infection
* Prior liver transplantation
* Endoscopic treatment for bile duct stenosis ≤ 3 months prior to inclusion or planned within 3 months post randomization date
* History of or established or suspected hepatobiliary carcinoma.
* Any severe comorbidity that may reduce life expectancy
* History of malignancy diagnosed or treated within 2 years (recent localized treatment of squamous or non-invasive basal skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to inclusion)
* Dosage changes of treatment for liver disease in the last 3 months or new treatment for liver disease started in the last 3 months
* History of colorectal carcinoma or high-grade dypsplasia in previous screening colonoscopy
* History of total colectomy
* Current active IBD defined by a partial Mayo score > 2 in patients with ulcerative colitis (UC), unclassed colitis or a Crohn's Disease Activity Index (CDAI) > 150 in patients with Crohn's disease
* Changes in IBD treatment or initiation of a new treatment for IBD in the last 3 months
* Current treatment with biologics (anti-TNF agent, vedolizumab, ustekinumab) or JAK inhibitors (tofacitinnib) or prednisone > 10 mg/day or budesonide > 3 mg /day) (or treatment initiated less than one month)
* Any contra-indication to swallow capsules
* Renal insufficiency (clearance<60 ml/min)
* Unable to consent, subject to legal or administrative decision (protection measure or deprivation of liberty) or involuntary psychiatric care.
* Participation in another interventional research without prior consultation with the investigator responsible for the patient's monitoring in the present study (participation in other non-interventional studies is permitted)
* Pregnancy or desire for pregnancy or breastfeeding

Randomization criteria

* No pregnancy (or desire for in the next year)
* No other hepatic pathology: HBV (positive HBs Ag), HCV (positive HCV antibody and positive PCR), autoimmune hepatitis
* No HIV infection (positive serology HIV1+2 antibodies)
* No documented Clostridium difficile infection at inclusion or < 10 days preceding randomization (in case of infection discovered at inclusion)
* No treatment with antibiotics, antifungics or probiotics < 4 weeks.
* Available FMT with EBV and CMV compatibility

• Sara LEMOINNE, MD, PhD, PU-PH, Principal investigator, APHP

NIH grants: 2023