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

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