Randomized, Double-Blind, Multicenter Trial of Oral Fecal Microbiota Transplantation Versus Placebo in Severe Irritable Bowel Syndrome

The primary objective of this study is to evaluate the **efficacy** of oral capsules containing frozen fecal microbiota transplantation (FMT) compared to sham FMT in reducing the severity score of irritable bowel syndrome (IBS) at 12 weeks in patients with severe IBS that is refractory to conventional treatments. This is clinically relevant as it addresses the need for effective treatment options for patients who do not respond to standard therapies, potentially improving their quality of life and symptom management.

Secondary objectives include:

• Assessing the efficacy of FMT on IBS severity score at 12 weeks, with a target of at least a 50-point decrease in IBS-SSS.
• Evaluating FMT success by comparing the patient's microbiota 12 weeks post-FMT to that of the donor.
• Analyzing intestinal microbiota composition and diversity at weeks 12 and 24 using 16s sequencing.
• Determining efficacy based on a decrease in IBS severity of more than 75 points at week 24 according to FMT success.
• Assessing efficacy according to the European Medical Agency endpoint in IBS, defined by the percentage of responders for IBS-D, IBS-C, and IBS-M at weeks 12 and 24.
• Evaluating IBS severity at 12 weeks by donors, where one donor provides FMT to multiple patients.
• Assessing IBS severity (IBS-SSS) at 12 and 24 weeks by IBS subtypes according to transit pattern.
• Evaluating IBS Quality of Life (IBS-QoL score) at 12 and 24 weeks.
• Assessing patient's perception of FMT through a questionnaire evaluating FMT or placebo acceptability.
• Comparing safety between groups by monitoring Serious Adverse Events and Adverse Events.

The clinical trial involves participants diagnosed with **Severe Irritable Bowel Syndrome (IBS)**, specifically those with a severe form of the disease that is refractory to conventional treatments. The study population includes both male and female subjects, aged between 18 and 74 years, who meet the criteria defined by the Rome IV classification for IBS, including subtypes IBS-C, IBS-D, or IBS-M. Participants must have a severe disease, indicated by an IBS Severity Scoring System (IBS-SSS) score greater than 300, and must have previously failed at least two treatment strategies. The trial does not include a vulnerable population. Participants are required to have health insurance, excluding AME, and women of childbearing potential must use effective contraception throughout the study. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of oral capsules containing frozen **fecal microbiota transplantation (FMT)** versus placebo in patients with severe **irritable bowel syndrome (IBS)**. The trial aims to assess the impact on IBS severity score at 12 weeks in patients with severe disease refractory to conventional treatments. The study will involve participants aged 18 to 74 years, diagnosed with IBS according to the Rome IV criteria, and who have not responded to at least two previous treatment strategies. The trial is expected to commence recruitment on January 31, 2025, and conclude by March 1, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the inclusion criteria, including informed consent and health insurance verification. Following randomization, participants will receive either the FMT or placebo treatment. The primary endpoint is a decrease in IBS severity at 12 weeks, defined by a reduction of at least 75 points in the IBS Severity Scoring System (IBS-SSS). Secondary endpoints include various measures of microbiota composition and diversity, efficacy at 24 weeks, and safety assessments.

Study visits will include follow-up assessments at 12 and 24 weeks to evaluate the primary and secondary endpoints. The end-of-study visit will occur at 24 weeks, where final assessments of IBS severity, microbiota composition, and quality of life will be conducted. Participant involvement is expected to last approximately 24 weeks, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety.

The clinical trial involves the administration of two treatments to evaluate their efficacy in patients with severe **irritable bowel syndrome** (IBS). The first treatment is a **placebo** designed as a double encapsulated oral transplant of fecal microbiota. This placebo is presented in the form of a suspension for oral suspension. The dosage is set at a maximum daily dose of 32 grams, with the total dose not exceeding 32 grams over the treatment period. The administration route is oral, and the treatment is to be taken once daily for a maximum period of one day. The placebo is structurally diverse and does not contain active therapeutic substances, serving as a control to assess the efficacy of the experimental treatment.

The experimental treatment in this trial is a double encapsulated oral transplant of **allogeneic fecal microbiota, pooled**. Similar to the placebo, this treatment is also provided as a suspension for oral suspension. The dosage mirrors that of the placebo, with a maximum daily and total dose of 32 grams, administered orally once daily for a single day. The active substance, allogeneic fecal microbiota, is pooled from multiple donors and is intended to modulate the gut microbiota of the participants. This treatment aims to assess its impact on the severity of IBS symptoms in comparison to the placebo. Both treatments are manufactured and provided by Assistance Publique - Hôpitaux de Paris, ensuring consistency and quality in the trial's execution.

The efficacy of the clinical trial will be assessed by evaluating the impact of oral capsules containing frozen fecal microbiota transplantation (FMT) compared to a placebo on the severity of **irritable bowel syndrome (IBS)**. The primary endpoint for efficacy is defined as a decrease in IBS severity at 12 weeks, measured by the percentage of patients achieving at least a 75-point reduction in the IBS Severity Scoring System (IBS-SSS). Secondary endpoints include a decrease in IBS severity at 12 weeks with at least a 50-point reduction in IBS-SSS, and the success of FMT, which will be determined by comparing the composition of the patient's fecal microbiota before and after FMT using the Sorensen similarity index. The FMT will be considered successful if the Sorensen index [patient after FMT vs donor] is greater than the Sorensen index [patient after FMT vs patient before FMT] and is at least 0.6. The composition of fecal microbiota will be measured by pyrosequencing (16S RNA).

Additional secondary endpoints include the assessment of intestinal microbiota composition and diversity at weeks 12 and 24 using 16S sequencing, with comparisons made to baseline and healthy volunteer donors. Microbiota composition will be analyzed using the Qiime pipeline at all phylogenetic levels, and diversity will be evaluated using the Shannon index, Simpson index, Chao1 index, and the number of observed species. Efficacy at week 24 will also be assessed based on FMT success, defined as a decrease in IBS severity of more than 75 points. The trial will also evaluate the EMA endpoint at weeks 12 and 24, defined as a patient meeting the response criteria for at least 50% of the observation time, and the percentage of responders in different IBS subgroups (IBS-D, IBS-C, and IBS-M) using the primary endpoint at weeks 12 and 24. Mean IBS-SSS and IBS Quality of Life (IBS-QoL) scores will be compared between FMT and placebo groups at weeks 12 and 24. Patient perception of FMT will be assessed through questionnaires regarding FMT or placebo assessment and acceptability, as well as secondary effects. Safety will be monitored by comparing serious adverse events and adverse events between groups.