Randomized, double-blind and multicentric study to assess the efficiency, security and tolerability of the faecal microbiota transfer in capsule form vs. placebo for the treatment of patients with non-alcoholic steatohepatitis (EMOTION)

The primary objective of this randomized, double-blind, multicentric study is to evaluate the **efficiency** of fecal microbiota transfer (FMT) in capsule form compared to placebo in improving liver function in patients with non-alcoholic steatohepatitis (NASH) over a period of 72 weeks. Additionally, the study aims to assess the **security** and **tolerability** of FMT in these patients during the same treatment duration. These objectives are clinically relevant as they address the potential of FMT as a therapeutic intervention for NASH, a condition with limited treatment options and significant health implications.

Secondary objectives include: - Assessing changes in liver histology related to NASH with FMT compared to placebo after 72 weeks. - Evaluating the effect of FMT on liver fibrosis using non-invasive markers. - Assessing the impact of FMT on liver fat content. - Determining the effect of FMT on various metabolic factors after 72 weeks. - Evaluating the impact of FMT on cardiovascular risk. - Assessing the effect of FMT on patient-perceived health outcomes.

The clinical trial focuses on patients diagnosed with **non-alcoholic steatohepatitis** (NASH). The study population includes both male and female participants aged between 18 and 75 years. Participants are required to have a body mass index of less than 40 kg/m² and a histological diagnosis of NASH, confirmed by a liver biopsy conducted within 24 weeks prior to consent. The trial includes individuals with a NASH histological activity score of 4 or higher, with specific scores in steatosis, lobular inflammation, and hepatocyte ballooning. Additionally, participants must exhibit histological evidence of stage 1 to stage 3 fibrosis as per the NASH CRN fibrosis score. The trial population is selected based on these criteria, ensuring a focus on individuals with varying degrees of liver fibrosis. The sponsor has not provided information regarding the total number of participants. The study also considers lifestyle factors, requiring participants of childbearing potential to adhere to contraceptive measures for safety. The trial includes a vulnerable population, emphasizing the need for careful monitoring and ethical considerations throughout the study.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy, safety, and tolerability of **fecal microbiota** transfer in capsule form compared to a placebo in patients with **non-alcoholic steatohepatitis** (NASH). The trial will span approximately 72 weeks, with an estimated recruitment start date of February 1, 2024, and an anticipated end date of October 30, 2026. Participants will be randomly assigned to receive either the active treatment, which consists of lyophilized capsules of fecal microbiota, or a placebo, which is microcrystalline cellulose in hypromellose capsules. The primary endpoints include the resolution of NASH without fibrosis worsening and the occurrence of adverse events, while secondary endpoints focus on changes in inflammation biomarkers, fibrosis, and other health parameters.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including age, body mass index, and histological diagnosis of NASH. Following successful screening, participants will undergo regular follow-up visits throughout the treatment period to monitor efficacy and safety outcomes. These visits will include assessments of liver function, adverse events, and other health indicators. The end-of-study visit will occur at the conclusion of the 72-week treatment period, where final evaluations will be conducted to determine the overall impact of the treatment.

Participant involvement is expected to last for the entire duration of the trial, approximately 72 weeks. However, conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The trial is conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of two types of treatments: a **test** treatment and a **placebo**. The test treatment consists of **lyophilized capsules of fecal microbiota**. These capsules contain **allogeneic fecal microbiota, pooled**, which is a structurally diverse substance. The pharmaceutical form of the test treatment is a capsule, and it is administered orally. The maximum daily dose is 6 grams, with a total treatment period of up to 48 weeks. The test treatment is identified by the sponsor product code MBK-01 and is provided by Mikrobiomik Healthcare Company S.L.

The placebo used in this study is composed of **microcrystalline cellulose Ph Eur**, encapsulated in hypromellose capsules. This placebo is designed to match the appearance and administration route of the test treatment, ensuring the double-blind nature of the trial. The placebo is also administered orally in capsule form, with the same dosing schedule as the test treatment to maintain consistency across the study groups.

The clinical trial aims to assess the efficacy of **faecal microbiota transfer (FMT)** in capsule form compared to a placebo for the treatment of patients with non-alcoholic steatohepatitis (NASH). Efficacy will be evaluated using several primary and secondary endpoints. The primary endpoints include the patient ratio with NASH resolution without fibrosis worsening, the patient ratio without fibrosis or activity worsening, and the patient ratio with MRI-PDFF improvement without fibrosis or activity worsening. Additionally, the occurrence of adverse events, severe adverse events, and changes in vital signs and laboratory results during the 72-week treatment period will be monitored.

Secondary endpoints will focus on the patient ratio with improvement in lobular inflammation and/or ballooning without fibrosis worsening, changes in fibrosis biomarkers, MRI-PDFF, anthropometric measurements, lipid profile, inflammation biomarkers, insulin resistance, vital signs, emerging cardiovascular risk factors, carotid ultrasound, and quality of life assessments using the SF-36 and CLDQ-NAFLD questionnaires. These parameters will be measured and collected at various timepoints throughout the study, ensuring a comprehensive analysis of the treatment's efficacy over the 72-week period.