Efficacy and safety of oral lyophilized allogeneic faecal microbiota (pooled) capsules vs placebo in patients with non‑alcoholic steatohepatitis

The primary objective of this randomized, double-blind, multicentric study is to evaluate the **efficiency** of faecal microbiota transfer (FMT) in capsule form compared to a 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 timeframe. These objectives are clinically relevant as they address the potential of FMT as a therapeutic intervention for NASH, a condition characterized by liver inflammation and damage due to fat accumulation, which can progress to cirrhosis or liver cancer.

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.
• Determining the impact of FMT on liver fat content.
• Investigating the effect of FMT on various metabolic factors after 72 weeks of treatment.
• Assessing the influence of FMT on cardiovascular risk.
• Evaluating the health outcomes as perceived by patients receiving FMT.

The clinical trial involves participants diagnosed with **non-alcoholic steatohepatitis** (NASH). The study population includes both male and female subjects 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 does not include a vulnerable population. The sponsor has not provided the total number of participants. Participants are selected based on specific histological criteria, including a NASH activity score of 4 or higher and evidence of fibrosis stages 1 to 3. Lifestyle factors such as diet and physical activity are not specified, but participants of childbearing potential must adhere to contraceptive measures for safety. The trial aims to assess the efficacy and safety of FMT in capsule form over a 72-week period.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy, safety, and tolerability of **faecal microbiota** transfer in capsule form compared to a placebo in patients with **non-alcoholic steatohepatitis** (NASH). The trial will span a total duration of 72 weeks, with the primary objective being to assess liver improvement in patients with NASH. Participants will be randomly assigned to receive either the active treatment or placebo, ensuring that neither the participants nor the investigators are aware of the group assignments, thus maintaining the double-blind nature of the study.

The study will commence with an inclusion visit, where potential participants will undergo screening to confirm eligibility based on criteria such as age, body mass index, and histological diagnosis of NASH. Following successful screening, participants will be enrolled and begin the treatment phase. The trial will include several follow-up visits at regular intervals to monitor the participants' health, assess the occurrence of any adverse events, and evaluate the primary and secondary endpoints. These endpoints include the resolution of NASH without fibrosis worsening, changes in fibrosis biomarkers, and improvements in various health parameters such as lipid profile and insulin resistance.

The end-of-study visit will occur at the conclusion of the 72-week treatment period, where final assessments will be conducted to determine the overall outcomes of the trial. Participants are expected to be involved in the study for the entire duration unless specific conditions necessitate early termination. Such conditions may include the occurrence of severe adverse events or any other health-related issues that compromise the safety of the participant. The trial is structured to ensure comprehensive data collection and analysis, contributing valuable insights into the treatment of NASH with faecal microbiota transfer.

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 intended for **oral use**. The maximum daily dose is 6 grams, with a total treatment period of up to 48 weeks. The dosing schedule is designed to ensure participant compliance, with regular monitoring throughout the study duration.

The comparator treatment in this study is a placebo, consisting of **microcrystalline cellulose Ph Eur, in hypromellose capsules**. This placebo is designed to match the experimental treatment in appearance and administration route, ensuring the double-blind nature of the trial. The placebo capsules are also administered orally, with the same frequency and dosing schedule as the experimental treatment, to maintain consistency across the study arms.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints related to the treatment of patients with non-alcoholic steatohepatitis (NASH). The primary endpoints include the patient ratio with a resolution of NASH without worsening of fibrosis, the patient ratio without worsening of fibrosis or activity, and the patient ratio with improvement in MRI-PDFF without worsening of fibrosis or activity. Additionally, the occurrence of adverse events (AE), severe AE (SAE), AE leading to study treatment interruption, AE of special interest, and changes in vital signs and laboratory results will be monitored over the 72-week treatment period.

Secondary endpoints will focus on various parameters, including 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 efficacy parameters will be measured and collected at specified timepoints throughout the trial, utilizing validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.