Evaluation of Fecal Microbiome Transplantation in Decompensated Cirrhosis: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the efficacy of **fecal microbiome transplantation (FMT)** in halting the progression of decompensated cirrhosis. This is assessed by the time to the first incidence of a decompensated episode during the study period. This objective is clinically relevant as it aims to address the progression of decompensated cirrhosis, a severe stage of liver disease that significantly impacts patient morbidity and mortality.

Secondary objectives include:

• Analyzing the impact of FMT on survival, assessed by transplant-free survival time and mortality incidence.
• Assessing the efficacy of FMT in the development or worsening of cirrhosis complications.
• Evaluating the effect of FMT on hospital admission frequency due to cirrhosis complications.
• Studying the impact of FMT on the incidence and severity of acute-on-chronic liver failure (ACLF), as assessed by organ failures.
• Analyzing the effect of FMT on systemic inflammatory response, including inflammatory cytokines and peripheral blood mononuclear cells (PBMCs).
• Evaluating the effect of FMT on plasma and urine biomarker levels.
• Assessing the effects of FMT on systemic hemodynamics and vasoactive hormones.
• Studying the effect of FMT on blood levels of bacterial DNA and/or bacterial products.
• Evaluating the effect of FMT on liver function, using MELD score, CLIF-C AD score, and Child-Pugh Score.
• Evaluating the effect of FMT on microbiome composition in saliva and feces.
• Assessing the impact of FMT on portal hypertension, measured by changes in hepatic venous pressure gradient (HVPG).
• Analyzing the impact of FMT on quality of life, functional assessment, and minimal hepatic encephalopathy, using CLDQ, Liver Frailty score, and PHES questionnaires.
• Studying the effect of FMT on alcohol consumption patterns.
• Studying the impact of FMT on electrocardiogram (ECG) changes.
• Evaluating the type and severity of treatment-related adverse events.

The clinical trial focuses on evaluating the efficacy of fecal microbiome transplantation (FMT) in patients with **decompensated cirrhosis**. The study population includes both male and female participants aged 18 years and older. Participants are selected based on the presence of cirrhosis, defined by standard clinical criteria, ultrasonographic findings, and/or histology, with the exclusion of those with cirrhosis due to autoimmune hepatitis. Patients with cholestatic liver disease are included only if they exhibit clinical decompensation, such as ascites. The trial includes individuals classified as Child-Pugh B or C, with scores ranging from 7 to 12 points. Women of child-bearing potential are required to have a negative pregnancy test and must agree to use highly effective contraceptive methods during the study. The sponsor has not provided information regarding the total number of participants. The trial population is considered vulnerable, and lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **fecal microbiome transplantation** (FMT) in patients with **decompensated cirrhosis**. This is a randomized, double-blind, placebo-controlled trial. The primary objective is to assess the treatment's ability to halt the progression of decompensated cirrhosis by measuring the time to the first incidence of a decompensated episode during the study period. The trial is expected to commence recruitment on January 2, 2025, and conclude by June 1, 2028. Participants will be involved for a duration of up to 12 months, with study visits scheduled at baseline, 1 month, 3 months, 6 months, and 12 months. The inclusion criteria require participants to be 18 years or older, with cirrhosis defined by standard clinical criteria, and classified as Child-Pugh B or C. Women of child-bearing potential must have a negative pregnancy test and agree to use highly effective contraceptive methods. Exclusion criteria include cirrhosis due to autoimmune hepatitis and certain cholestatic liver diseases unless clinical decompensation is present.

The trial involves the administration of lyophilized capsules of fecal microbiota or a placebo, with a maximum daily dose of 6000 mg and a total dose of 12000 mg over a 3-month treatment period. The primary endpoint is the efficacy of the treatment in preventing the progression of decompensated cirrhosis, assessed by the time to the first decompensation event, such as acute kidney injury, ascites, bacterial infection, gastrointestinal bleeding, or hepatic encephalopathy. Secondary endpoints include transplant-free survival, mortality rates, and the development or worsening of cirrhosis complications, assessed at various intervals throughout the study. Participants will undergo comprehensive assessments, including systemic inflammatory response, plasma and urine biomarkers, systemic hemodynamics, and microbiome composition analysis. Conditions for early termination from the study include the development of severe adverse events or non-compliance with study protocols. The trial is categorized as a Phase III clinical trial, indicating its advanced stage in the clinical research process.

The clinical trial involves the administration of **lyophilized capsules of fecal microbiota** as the experimental treatment. These capsules contain **allogeneic fecal microbiota, pooled**, and are manufactured by Mikrobiomik Healthcare Company S.L. The pharmaceutical form of the experimental medication is a capsule, and it is administered orally. The dosing regimen includes a maximum daily dose of 6000 mg, with a total maximum dose of 12000 mg over a treatment period of up to 3 months. The primary objective of this treatment is to evaluate its efficacy in halting the progression of decompensated cirrhosis.

In addition to the experimental treatment, the study utilizes **microcrystalline cellulose** as a placebo. This substance is used to match the appearance and administration route of the experimental capsules, ensuring the study remains double-blinded. The placebo is administered orally in a similar capsule form, although specific dosage and administration details are not provided. The use of microcrystalline cellulose as a placebo is intended to maintain the integrity of the study's control group, allowing for accurate assessment of the experimental treatment's efficacy.

The efficacy of fecal microbiome transplantation (FMT) in patients with decompensated **cirrhosis** will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on evaluating the efficacy of the treatment in halting the progression of decompensated cirrhosis, specifically by measuring the time to the first decompensation event, which includes acute kidney injury (AKI), ascites, bacterial infection, gastrointestinal bleeding, and hepatic encephalopathy (HE) during the study period.

Secondary endpoints will include a comprehensive assessment of various clinical and biochemical parameters. These will be measured at baseline and at subsequent timepoints of 1 month, 3 months, 6 months, and 12 months. Key secondary endpoints include time to transplant-free survival and mortality rates, development or worsening of individual complications of cirrhosis, frequency of hospital admissions due to cirrhosis complications, and development of acute-on-chronic liver failure (ACLF). Additionally, changes in systemic inflammatory response, plasma and urine prognostic biomarkers, systemic hemodynamics, and liver function will be evaluated. The study will also analyze microbiome composition from saliva and stool, changes in hepatic venous pressure gradient (HVPG), and quality of life assessments using the Chronic Liver Disease Questionnaire (CLDQ), Liver Frailty Index, and Psychometric Hepatic Encephalopathy Score (PHES).

These efficacy parameters will be collected and analyzed using validated scales, laboratory tests, and patient-reported outcomes. The study will employ tools such as flow cytometry, functional analysis, RNAseq single cell analysis, and microbial gene analysis to gather comprehensive data on the impact of FMT on cirrhosis progression and patient health outcomes.