Evaluation of Oral and Enema Fecal Microbiota Transplantation for Maintenance Therapy in Pediatric Ulcerative Colitis

The primary objective of this study is to evaluate the **success** of Fecal Microbiota Transplantation (FMT) using frozen stool capsules in pediatric patients with **Ulcerative Colitis**. Success is defined by an increase in the richness of the recipient's microbiota at 6 months. This is clinically relevant as enhancing microbiota diversity may contribute to maintaining remission and improving gut health in patients with Ulcerative Colitis.

Secondary objectives include:

• Assessing the increase in microbiota richness at 12 months post-FMT with stool capsules and at 6 and 12 months post-FMT with stool enema.
• Evaluating changes in microbiota composition to resemble that of a healthy donor at 6 and 12 months post-FMT with both stool capsules and enema.
• Assessing changes in mucosal microbiota composition at 12 months post-FMT with both methods.
• Evaluating the feasibility of FMT with frozen stool capsules and enema in children.
• Assessing the efficiency of FMT in preventing clinical and endoscopic relapse of Ulcerative Colitis.
• Evaluating the effects of FMT on inflammatory blood markers and fecal biomarkers, such as fecal calprotectin.
• Assessing the quality of life using the IMPACT-3 questionnaire for patients aged 10 and older between baseline and 12 months.
• Evaluating the treatment tolerance and safety.

The clinical trial involves participants diagnosed with **Ulcerative Colitis**. The study population includes both male and female subjects aged between 8 to 17 years. Participants are required to have moderate active ulcerative colitis, defined by a PUCAI score greater than 35, and must respond to corticosteroid treatment with a PUCAI score less than 10 at enrollment. The trial does not involve a vulnerable population. Participants must have a stable treatment regimen for ulcerative colitis, including 5-ASA, immunosuppressants, or biotherapies, for more than three months. They should be able to swallow test capsules and have health insurance. For female participants of childbearing age, a negative pregnancy test and agreement to use reliable contraception are mandatory. The sponsor has not provided information regarding the total number of participants. Informed consent is required from both parents or legal guardians. The selection criteria ensure that participants are in a stable health condition suitable for the trial's requirements.

The clinical trial is a **phase 2**, multisite, open-labelled, controlled, randomized, non-comparative study designed to evaluate the efficacy of fecal microbiota transplantation (FMT) in pediatric patients with **ulcerative colitis**. The trial will utilize two forms of FMT: a double encapsulated oral transplant and an enema transplant, both containing **allogeneic fecal microbiota, pooled**. The primary objective is to assess the success of FMT with frozen stool capsules by measuring the increase in the richness of the recipient's microbiota at six months, evaluated using the Shannon index. The trial is expected to commence recruitment in February 2025 and conclude by May 2029.

Participants will be randomly assigned to receive either the oral or enema form of FMT. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress, and an end-of-study visit to evaluate outcomes. The inclusion criteria specify that participants must be aged 8 to 17 years, have a diagnosis of moderate active ulcerative colitis, and meet other health and consent requirements. The expected duration of participant involvement is up to 12 months, with the possibility of early termination if adverse events occur or if the participant withdraws consent.

Study visits will be structured as follows: the inclusion visit will involve screening for eligibility, including a review of medical history and current treatments. Follow-up visits will occur at regular intervals to assess the microbiota richness, clinical status, and any adverse events. The end-of-study visit will involve a comprehensive evaluation of the primary and secondary endpoints, including microbiota diversity and clinical outcomes. Participants will be monitored for any signs of clinical relapse or adverse events throughout the study period.

Conditions that may lead to early termination from the study include significant adverse reactions, non-compliance with study procedures, or withdrawal of consent by the participant or their guardians. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their health and safety are prioritized throughout the study.

The clinical trial involves the administration of two experimental treatments, both utilizing **allogeneic fecal microbiota, pooled** as the active substance. The first treatment is the "Double encapsulated oral transplant of fecal microbiota," which is formulated as a **suspension for oral suspension**. This treatment is administered orally, with a maximum daily dose of 19.5 ml and a total maximum dose of 39 ml over a treatment period of up to 8 weeks. The active substance is derived from the fresh feces of healthy volunteer donors, ensuring a diverse microbial composition. The encapsulation process is designed to protect the microbiota during transit through the gastrointestinal tract, enhancing the potential for successful colonization in the recipient's gut.

The second treatment is the "Enema transplant of fecal microbiota," which is provided as a **suspension** for rectal administration. This treatment allows for a maximum daily dose of 200 ml and a total maximum dose of 300 ml, also over a treatment period of up to 8 weeks. Similar to the oral formulation, the active substance is sourced from healthy donors, ensuring a rich and diverse microbial profile. The rectal route of administration is intended to deliver the microbiota directly to the colon, potentially increasing the efficacy of the transplant in altering the recipient's gut microbiome.

Both treatments are part of a pilot study aimed at evaluating the success of fecal microbiota transplantation (FMT) using frozen stool capsules for the maintenance treatment of pediatric **ulcerative colitis**. The primary objective is to assess the increase in microbiota richness in the recipient at 6 months post-treatment. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints focused on evaluating the success of **Fecal Microbiota Transplantation (FMT)** in pediatric patients with Ulcerative Colitis. The primary endpoint is defined by an increase in the richness of the recipient's microbiota at 6 months, measured by the alpha diversity using the Shannon index. Success is determined by an increase of 0.5 points in the Shannon index between the recipient's microbiota at baseline (M0) and at 6 months (M6).

Secondary endpoints include similar assessments at 12 months, with the success of FMT evaluated by the Shannon index and the Bray Curtis (BC) Index. The BC Index will compare the similarity of the recipient's microbiota post-FMT to that of the healthy donor, with success defined by a BC Index of at least 0.6. Additional secondary endpoints involve changes in mucosal microbiota, clinical and endoscopic relapse rates, and the effect of FMT on inflammatory blood markers such as CRP, VS, leucocytes, and fecal calprotectin at various timepoints (M0, M6, M9, and M12).

Quality of life will be assessed using the IMPACT-3 questionnaire, which consists of 35 closed questions rated on a Likert scale. The trial will also monitor the feasibility of long-term FMT administration, including the number of capsules and enemas, ease of intake, and acceptance. Adverse events such as fever, sepsis, infection, and inflammatory disease relapse will be collected throughout the follow-up period. These assessments will provide comprehensive data on the efficacy of FMT in maintaining treatment for pediatric Ulcerative Colitis.