Evaluation of Allogeneic Fecal Microbiota Transfer on Glycemic Control in Post-Bariatric Surgery Patients with Non-Remission Type 2 Diabetes

The primary objective of this study is to assess the efficacy of **Fecal Microbiota Transfer (FMT)** on the change in HbA1c levels from baseline to 6 months (24 weeks) follow-up in patients with non-diabetic remission (NDR) who have undergone bariatric surgery 1 to 5 years prior. This is clinically relevant as it aims to determine the potential of FMT in improving glycemic control in this specific patient population, which could lead to better management of Type 2 Diabetes (T2D) post-bariatric surgery.

Secondary objectives include evaluating the efficacy of FMT on various metabolic and clinical parameters over different time frames. These include:

• Change in HbA1c from baseline within 2 years of follow-up.
• Change in endogenous insulin production via C peptide levels from baseline to 2 years.
• Change in insulin resistance from baseline to 24 weeks.
• Change in holter glycemic profile at 6 and 24 weeks.
• Number and type of anti-T2D drugs required if HbA1c does not change from baseline to 1 and 2 years.
• Number of patients achieving partial or complete diabetic remission (DR) at 24 weeks and maintaining it at 1 and 2 years.
• Proportion of patients needing a "safety" glucose-lowering treatment to control HbA1c despite FMT or placebo.
• Duration of FMT effects in terms of HbA1c reduction in the FMT group.
• Number of FMT cures needed to achieve the primary endpoint of a 0.75% reduction in HbA1c.
• Proportion of good responders and characteristics related to good response in both receivers and donors.
• Identification of gut microbiota signature and changes in gut microbiota diversity and composition.
• Changes in systemic gut microbiota-related metabolites.
• Evaluation of FMT safety and quality of life post-FMT.

The clinical trial involves **adult** participants aged 18 to 65 years, comprising both male and female subjects. The study population includes individuals who have undergone bariatric surgery, specifically Roux-en-Y gastric bypass or sleeve gastrectomy, 1 to 5 years prior to the trial. These participants are in non-diabetic remission from Type 2 Diabetes (T2D) following their surgery. The trial does not involve a vulnerable population. Participants were selected based on their post-surgery status, with a focus on those who have uncontrolled diabetes, indicated by an HbA1c level greater than 7%, and are willing to receive a proton pump inhibitor. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The selection criteria emphasize compliance with follow-up visits during the first year post-surgery and affiliation with a social security regime, excluding AME. The trial also involves healthy donors aged 18 to 50 years, who are euglycemic and have regular bowel movements, with no current drug prescriptions except for contraception or painkillers other than AINS.

The clinical trial is designed to evaluate the efficacy of **fecal microbiota transfer** (FMT) in improving glycemic control in adults with Type 2 Diabetes (T2D) who have not achieved diabetes remission following bariatric surgery. This study is a randomized, double-blind, controlled trial, with participants receiving either a double encapsulated oral transplant of fecal microbiota or a placebo. The trial is expected to span approximately three years, with recruitment starting in January 2024 and concluding in January 2027.

Participants will undergo a series of study visits, beginning with an inclusion visit to assess eligibility based on specific criteria, such as age, previous bariatric surgery, and current diabetes status. The primary endpoint is the change in **HbA1c** levels from baseline to six months post-randomization, with secondary endpoints including the evolution of HbA1c, C-peptide, and insulin secretion over a two-year period. Study visits will occur at baseline, 6, 12, 18, and 24 weeks, and at 1 and 2 years post-randomization, to monitor these parameters and assess the safety and efficacy of the treatment.

Participant involvement is expected to last for the entire duration of the trial, with conditions for early termination including non-compliance with study procedures or adverse events that may compromise participant safety. The trial aims to provide insights into the potential of FMT as a therapeutic intervention for improving diabetes control in this specific patient population. The study will also explore the characteristics of good responders and the gut microbiota signature associated with a positive response to FMT.

The clinical trial involves the administration of a **double encapsulated oral transplant of fecal microbiota**. This experimental medication is formulated as a suspension for oral suspension. The active substance in this treatment is **allogeneic fecal microbiota, pooled**, which is derived from a structurally diverse substance. The medication is administered orally, with a maximum daily dose of 19.5 ml and a total maximum dose of 58.5 ml over a treatment period of up to 12 weeks. The primary objective of this treatment is to assess its efficacy in altering HbA1c levels in non-diabetic remission patients who have undergone bariatric surgery.

In addition to the experimental treatment, a **placebo** is used as a comparator in the study. The placebo is also a double encapsulated oral transplant of fecal microbiota, formulated as a suspension for oral suspension. It is administered orally, mirroring the dosing schedule of the experimental treatment, with a maximum daily dose of 19.5 ml and a total maximum dose of 58.5 ml over a 12-week period. The placebo is designed to match the experimental treatment in appearance and administration to ensure blinding in the study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

Efficacy in the clinical trial titled "Diabete RemIssion using Fecal TransfER post bariatric surgery (DRIFTER)" will be assessed primarily through the change in **HbA1c** levels from baseline to 6 months post-randomization. The primary endpoint expects a reduction of at least 0.75% in HbA1c. Secondary endpoints include the evolution of HbA1c and C-peptide levels from baseline to 2 years post-randomization, with measurements scheduled at baseline, 6, 12, 18, and 24 weeks, as well as 1 and 2 years post-randomization. Additional secondary endpoints involve the evaluation of insulin secretion and resistance using the HOMA-B and HOMA-IR calculators, respectively, and the Disse index, with assessments conducted up to 24 weeks.

Further efficacy assessments will include changes in glycaemia profiles using glycemic holter from baseline to 6 and 24 weeks, and the analysis of the number and type of anti-diabetic drugs at baseline, 1, and 2 years post-randomization. The trial will also evaluate the proportion of patients achieving partial or complete diabetes remission at 24 weeks and maintaining it at 1 and 2 years. Additional analyses will focus on the duration of FMT effects, the number of FMT cures required to achieve the primary endpoint, and the identification of characteristics associated with good response to FMT, including gut microbiota signatures and systemic metabolites. Changes in quality of life post-FMT will be evaluated using the SF36 questionnaire.