Evaluation of Encapsulated Fecal Microbiota Transfer Using INTESTIFIX for Immune Modulation in Cirrhosis and Ascites: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **safety** of Fecal Microbiota Transfer (FMT) capsules in the treatment of immune activation in patients with **cirrhosis and ascites**. Assessing safety is crucial as it determines the potential risks associated with the use of FMT capsules in this patient population, ensuring that the treatment does not exacerbate the condition or introduce new health concerns.

Secondary objectives include evaluating signals of clinical efficacy of FMT capsules for the treatment of immune activation in patients with cirrhosis and ascites. This involves assessing the potential therapeutic benefits of FMT capsules, which could lead to improved management of immune activation in these patients.

The clinical trial involves participants diagnosed with **cirrhosis and ascites**, with an age range of 18 to 70 years. Both male and female subjects are included in the study population. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants were selected based on their diagnosis of cirrhosis of any etiology, confirmed through clinical standard criteria, imaging findings, or histology, and must have undergone paracentesis or a diagnostic ascitic tap within the last 30 days prior to study inclusion. Subjects must be able to swallow the Investigational Medicinal Product (IMP) Fecal Microbiota Transfer capsules or placebo and be mentally and physically capable of understanding the study's significance and scope, as well as complying with the study protocol. Written informed consent is required prior to participation. The trial includes a vulnerable population, indicating that special considerations are in place to ensure the safety and ethical treatment of participants.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** phase IIa pilot study to evaluate the safety of Fecal Microbiota Transfer (FMT) capsules in patients with **cirrhosis and ascites**. The trial will involve the administration of the investigational medicinal product, INTESTIFIX 001, in capsule form, with a maximum daily dose of 8 capsules and a total dose not exceeding 24 capsules over a treatment period of up to 3 months. The study will also include a placebo group receiving Intestifix 001 placebo. The trial is expected to commence recruitment on September 1, 2024, and conclude by March 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-70 years), diagnosis of cirrhosis and ascites, and the ability to swallow the capsules. Following successful screening, participants will be randomized to receive either the active treatment or placebo. The study will include follow-up visits at day 7 (±2 days), day 28 (±3 days), and an end-of-study visit at day 90 (±14 days). These visits will assess primary endpoints, including the occurrence of serious adverse events and treatment-emergent adverse events, as well as secondary endpoints such as systemic and gut inflammation, organ dysfunction, quality of life, and antibiotic-free days.

The expected duration of participant involvement is approximately 3 months, with conditions for early termination including the occurrence of serious adverse events or inability to comply with the study protocol. Participants will be monitored closely throughout the trial to ensure safety and adherence to the study procedures. The trial aims to provide valuable insights into the safety and potential therapeutic benefits of FMT capsules in this patient population.

The clinical trial involves the administration of **INTESTIFIX 001**, an experimental medication formulated as a **capsule**. The active substance, **INTESTIFIX**, is classified as a structurally diverse substance. The medication is administered **orally** with a maximum daily dose of **8 capsules** and a total maximum dose of **24 capsules** over a treatment period of **3 days**. The trial aims to evaluate the safety of fecal microbiota transfer (FMT) capsules in treating immune activation in patients with cirrhosis and ascites. The pharmaceutical form of the medication is a capsule, and it is not a pediatric formulation.

In addition to the experimental medication, the study includes a **placebo** group. The placebo, referred to as **Intestifix 001 placebo**, does not contain any active substance and serves as a comparator to assess the efficacy and safety of the experimental treatment. The placebo is administered in a manner consistent with the experimental medication to maintain the double-blind nature of the study. The placebo is not associated with any specific pharmaceutical form or route of administration as per the available data.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The study is designed as a randomized, double-blind, placebo-controlled phase IIa clinical pilot study, focusing on the safety evaluation of the treatment in the specified patient population.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the occurrence of serious adverse events (SAEs) and the occurrence and severity of treatment-emergent adverse events (TEAEs) and adverse events (AEs) up to the end of the study. Secondary endpoints will evaluate systemic inflammation by measuring differences in white blood cell count, C-reactive protein, procalcitonin, and **IL-6** levels at baseline (day 0) and subsequent visits on day 7±2 (V3), day 28±3 (V4), and at the end of the study (day 90+14). Gut inflammation will be assessed by changes in fecal calprotectin at the same time points.

Organ dysfunction will be evaluated using the Child-Pugh score, Model of End Stage Liver Disease (MELD) score, and Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA / CLIF-C OF) score, comparing baseline values to those at V3, V4, and EOS. Quality of life will be measured using the EQ-5D-5L and CLDQ scores, with assessments conducted at baseline and EOS. Additionally, the number of antibiotic-free days, excluding oral use of norfloxacin or rifaximin, will be recorded from baseline to EOS. These efficacy parameters will be collected and analyzed according to the specified schedule to determine the impact of the investigational treatment on patients with cirrhosis and ascites.