Fecal microbiota transplantation for primary sclerosing cholangitis - randomized study versus sham transplantation (FMT-SCLER).

The primary objective of this study is to assess the efficacy of fecal microbiota transplantation (FMT) versus sham transplantation on alkaline phosphatase (ALP) and bilirubin levels at week 48 in patients with primary sclerosing cholangitis (PSC) receiving standard ursodeoxycholic acid (UDCA) therapy. ALP and bilirubin serve as surrogate markers of transplantation-free survival in PSC patients, making their normalization clinically relevant for disease prognosis and management.

The secondary objectives include:

• Comparison of FMT efficacy on normalization of ALP and bilirubin levels individually at weeks 12, 24, 36, and 48

• Comparison of FMT efficacy on biochemical liver tests (ALP, gamma-glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, and bilirubin) at weeks 12, 24, 36, and 48

• Comparison of FMT efficacy on liver fibrosis progression assessed by transient elastography at week 48 versus baseline

• Comparison of PSC prognostic scores at weeks 0, 24, and 48

• Comparison of occurrence of hepatic events (decompensation of cirrhosis, acute cholangitis, jaundice, need for endoscopic retrograde cholangiopancreatography) during the study period

• Comparison of safety during the study period

• Comparison of symptoms, quality of life, and fatigue at weeks 24 and 48; pruritus at weeks 12, 24, 36, and 48

• Comparison of changes in bile acids and cholangiographic abnormalities between week 48 and baseline

• Comparison of changes in inflammatory bowel disease (IBD) clinical symptoms, fecal calprotectin, and endoscopic scores between week 48 and baseline

• Comparison of changes in gut microbiota composition at weeks 12, 24, 36, and 48

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of both **male and female subjects** aged between **18 and 75 years** who are affiliated to the French Social Security System. Participants are adults diagnosed with **large duct Primary Sclerosing Cholangitis** verified by cholangiography demonstrating intrahepatic and/or extrahepatic biliary duct changes consistent with PSC. All subjects have concomitant **inflammatory bowel disease** diagnosed according to international guidelines with endoscopic and histologic confirmation, which must be inactive for at least 6 months prior to enrollment. Participants are required to have elevated **alkaline phosphatase** levels at least 1.3 times the upper limit of normal documented on at least two occasions within a 3-month pre-inclusion period, or elevated **total bilirubin** not exceeding 50 µmol/L with concomitant elevated direct bilirubin. All subjects must have been receiving **ursodeoxycholic acid** therapy at a dose of 13-23 mg/kg/day for at least 6 months, with a stable dosage maintained for at least 3 months before study entry. Women of childbearing potential participating in the study are required to use highly effective contraceptive methods. The trial excludes vulnerable populations.

This is a randomized, placebo-controlled clinical trial evaluating the efficacy of **fecal microbiota transplantation** in patients with **primary sclerosing cholangitis**. The study is designed as a **Phase 2** trial investigating the therapeutic potential of **allogeneic faecal microbiota, pooled** administered via different routes and formulations. Participants will be randomized to receive either active fecal microbiota transplantation or **placebo** (sham transplantation) in addition to standard **ursodeoxycholic acid** therapy. The trial employs multiple formulations including double encapsulated oral transplant of fecal microbiota administered via **rectal use**, enema transplant of fecal microbiota administered via **oral** route, and corresponding placebo formulations. The investigational products are provided as **suspension for oral suspension** or **suspension**. The maximum daily dose for the encapsulated formulation is 330 millilitres administered over 1 day, while the enema formulation involves 12 grams daily with a maximum total dose of 24 grams administered over 2 days.

The primary objective is to assess the efficacy of fecal microbiota transplantation versus sham transplantation on **alkaline phosphatase** and **bilirubin** levels at week 48, which serve as surrogate markers of transplantation-free survival in patients with primary sclerosing cholangitis. The **primary endpoint** is defined as the proportion of patients achieving success at week 48, where success requires serum alkaline phosphatase less than 1.3 times the upper limit of normal with at least 15% reduction compared to baseline, and total bilirubin at or below 1 times the upper limit of normal at week 48. Secondary endpoints include the proportion of patients achieving normalized alkaline phosphatase levels at weeks 12, 24, 36, and 48, normalization of total bilirubin at these timepoints, normalization of all liver tests, changes in **elastometry**, prognostic scores including **MELD score** and Revised PSC Mayo Risk Score, safety assessments including infectious events and increased **inflammatory bowel disease** activity, **pruritus** assessment, quality of life measures, **bile acids** analysis, **cholangiographic abnormalities** assessed by **magnetic resonance cholangiography**, changes in inflammatory bowel disease activity evaluated through clinical scores, **fecal calprotectin**, and endoscopic scores, and analysis of gut microbiota composition.

Eligible participants include males and females aged 18 to 75 years with large duct primary sclerosing cholangitis verified by appropriate cholangiography demonstrating biliary duct changes consistent with the disease. Participants must have **inflammatory bowel disease** diagnosed according to international guidelines that has been inactive for at least 6 months, defined by no evidence of flare and no change in treatment. Alkaline phosphatase must be at least 1.3 times the upper limit of normal documented at least twice within a 3-month pre-inclusion period, or elevated total bilirubin up to 50 micromoles per litre with concomitant elevated direct bilirubin. Treatment with ursodeoxycholic acid at a dose of 13 to 23 milligrams per kilogram per day for at least 6 months and at the same dosage for at least 3 months is required. Women of childbearing potential must use highly effective contraceptive methods. All participants must be affiliated to the French Social Security System and provide written informed consent.

The estimated recruitment start date is December 2025, with an estimated study completion date of February 2030, indicating an overall trial duration of approximately 4 years. Individual participant involvement extends to week 48 as the primary assessment timepoint, with follow-up continuing to week 104 for certain safety assessments. The study involves multiple visits including screening, baseline assessment at week 0, and follow-up visits at weeks 12, 24, 36, and 48 for clinical and laboratory evaluations. Specific assessments such as magnetic resonance cholangiography and **colonoscopy** are performed at baseline and week 48. Gut microbiota analysis is conducted at weeks 0, 12, 24, 36, and 48. Safety monitoring includes assessment of clinical and biological adverse events, survival rate without liver events such as decompensation of **cirrhosis**, acute **cholangitis**, jaundice, and need for **endoscopic retrograde cholangiopancreatography**. Conditions that may lead to early termination from the study include development of serious adverse events, disease progression requiring alternative interventions, withdrawal of consent, or investigator decision based on safety concerns.

The experimental treatment consists of **double encapsulated oral transplant of fecal microbiota** in the pharmaceutical form of **suspension for oral suspension**, containing **allogeneic faecal microbiota, pooled** as the active substance. The product is administered via **rectal use** at a maximum daily dose of 330 millilitres. The maximum total dose amount is 330 millilitres administered over a treatment period of 1 day. This formulation represents one of the investigational medicinal products being evaluated in the study.

An additional experimental treatment formulation is the **enema transplant of fecal microbiota**, presented as a **suspension** containing **allogeneic faecal microbiota, pooled**. This product is administered via the **oral** route at a maximum daily dose of 12 grams. The maximum total dose amount is 24 grams administered over a treatment period of 2 days. This formulation serves as an alternative investigational medicinal product in the clinical trial.

The **placebo double encapsulated oral transplant of fecal microbiota** is provided as a suspension for oral suspension containing **placebo** as the substance. This comparator treatment is administered via rectal use at a maximum daily dose of 330 millilitres. The maximum total dose amount is 330 millilitres administered over a treatment period of 1 day. This placebo formulation is designed to match the experimental double encapsulated oral transplant formulation.

The **placebo coloscopic transplant of fecal microbiota** is formulated as a suspension containing placebo. This comparator is administered via **oral use** at a maximum daily dose of 12 grams. The maximum total dose amount is 24 grams administered over a treatment period of 2 days. This placebo formulation corresponds to the enema transplant formulation and serves as a control in the sham transplantation arm of the study.

Efficacy will be assessed using biochemical markers and clinical parameters in patients with **primary sclerosing cholangitis**. The primary endpoint is the proportion of patients achieving success at week 48, defined as serum **alkaline phosphatase** (ALP) less than 1.3 times the upper limit of normal with at least a 15% reduction compared to baseline and total **bilirubin** at or below 1 times the upper limit of normal. Secondary endpoints include the proportion of patients with serum ALP less than 1.3 times the upper limit of normal and at least 15% reduction from baseline at weeks 12, 24, 36, and 48. Additional secondary endpoints evaluate the proportion of patients with normalized total bilirubin at weeks 12, 24, 36, and 48, defined as total bilirubin less than 1 times the upper limit of normal, and the proportion with normalized ALP at the same timepoints, defined as ALP less than 1 times the upper limit of normal. The proportion of patients achieving normalization of all liver tests (ALP, gamma-glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin all less than 1 times the upper limit of normal) will be assessed at weeks 12, 24, 36, and 48.

Changes in **elastometry** between week 0 and week 48 will be measured. Prognostic scores including the Model for End-Stage Liver Disease (MELD) score, the Revised PSC Mayo Risk Score, and the Amsterdam-Oxford prognostic model will be evaluated at weeks 0, 24, and 48. Pruritus will be assessed using a visual analog scale and the 5D pruritus scale at weeks 0, 12, 24, 36, and 48. Symptoms, quality of life, and fatigue will be evaluated using patient-reported outcome questionnaires (PRO-CSP questionnaire, QMCF questionnaire, and PBC 40 questionnaire) at weeks 0, 24, and 48. Bile acids will be measured by chromatography at weeks 0 and 48. Cholangiographic abnormalities will be assessed by **magnetic resonance cholangiography** at weeks 0 and 48. Changes in **inflammatory bowel disease** activity will be evaluated using clinical scores (Harvey-Bradshaw Index and Crohn's Disease Activity Index for Crohn's disease, Mayo score for ulcerative colitis), fecal **calprotectin**, and endoscopic scores assessed by colonoscopy (Crohn's Disease Endoscopic Index of Severity for Crohn's disease and Ulcerative Colitis Endoscopic Index of Severity for ulcerative colitis) between week 0 and week 48. Analysis of gut **microbiota** will be performed at weeks 0, 12, 24, 36, and 48.