Evaluation of EXL01, a New Live Biotherapeutic Product to Prevent Recurrence of Clostridioides Difficile Infection in High-risk Patients

Inclusion Criteria:

• Adult patient ≥18 years of age

• ≥3rd episode of proven C. difficile infection (≥3 liquid stools per day anddetection of toxigenic C. difficile in stool by PCR or enzyme-linked immunosorbentassay or immunochromatography or toxigenic culture) within 6 months with an interval ≤ 12 weeks since the end of treatment of the previous episode of resolved CDI or 2ndepisode of proven C. difficile infection (≥3 liquid stools per day and detection oftoxigenic C. difficile in the stools by PCR or enzyme-linked immunosorbent assay orimmunochromatography or toxigenic culture) within 6 months with an interval ≤ 12weeks since the end of treatment of the previous episode of resolved CDI with atleast one of the following risk factors:

• Age ≥70 years

• Chronic renal failure (haemodialysis or GFR<60ml/min

• History of severe or severe-complicated CDI (excluding current episode)according to ESCMID 2021 criteria

• ≥3 CDI in the last 12 months (including current episode)

• CDI associated with care defined as CDI occurring during hospitalisation (<3months)

• On current or planned vancomycin treatment per os

• Patient able to give free, informed and written consent

• Enrolled in compulsory national social security scheme

Exclusion Criteria:

• Currently participating or has participated in a study with an investigationalcompound or device within 3 months prior to the first dose of the studyintervention.

• Severe C. difficile infection severe (defined by the presence of a white blood cellcount >15×10⁹ cells/L or a body temperature >38.5°C or >50% increase in thepatient's baseline creatinine related to CDI at the time of V1) and/or complicated (defined by any of the factors attributed to current Clostridioides difficileinfection (CDI): hypotension, septic shock, elevated serum lactate, ileus, toxicmegacolon, intestinal perforation or any fulminant course of the disease)

• Refractory C. difficile infection defined as lack of response to well-conducted peros vancomycin or fidaxomicin treatment with ≥3 liquid stools per day after ≥5 daysof treatment

• Cirrhosis with Child C score

• Hospitalization in continuing care unit or intensive care unit

• Immunosuppression including :

• Malignant hemopathy under treatment (excluding CLL)

• HIV AIDS stage

• Stem cell allograft ≤ 12 months

• Aplasia (<500 PNN/mm3) at inclusion

• Treatment with >20mg prednisone equivalent within 14 days prior to inclusion (excluding inhaled or topical treatment).

• Personal history of gastrointestinal resection other than appendectomy (gastrectomy,esophagectomy, colonic or small bowel resection, short small bowel syndrome).

• Personal history of small intestinal microbial overgrowth

• Inflammatory bowel disease

• Proven celiac disease

• Current stoma (ileostomy or colostomy) or within the last 6 months, or any otherintra-abdominal surgery within the 3 months prior to treatment

• major surgery or trauma ≤ 4 weeks before the start of treatment

• Antibiotic therapy in progress or planned during the study for an infection otherthan CDI

• Surgery scheduled during the study requiring perioperative antibiotics.

• -Women without contraception*, pregnant or breastfeeding women

• History of hypersensitivity to EXL01 and/or to any of its excipients (D-mannitol,sucrose, maltodextrin, L-cysteine, L-cysteine hydrochloride, magnesium stearate andhydroxypropylmethylcellulose), and/or to soy or soy-containing products.

• History of hypersensitivity to vancomycin as mentioned in local prescribinginformation.

• Personal history of fecal microbiota transplantation < 12 months

• Persons deprived of liberty by judicial or administrative decision

• Adults under legal protection or unable to give consent

• Swallowing disorders making oral treatment impossible

• Participation in another interventional study within 3 months prior to inclusion. (Patients who have entered the follow-up phase of an interventional study mayparticipate provided that more than 3 months have elapsed since the lastintervention).

• Expected life expectancy of less than 6 months

• Presents a known psychiatric disorder that would interfere with adequate cooperationwith study requirements.

• Regular use of illicit or recreational drugs

• Anticipated administration during the study of treatment that is expected to causediarrhea (chemotherapy, colonic preparation prior to colonoscopy)

• History of chronic diarrhea (> 3 watery stools per day for > 4 weeks) not related togastrointestinal infection.

• Clinically significant medical or surgical condition not mentioned in the abovecriteria which, in the opinion of the investigator, could interfere with theadministration of study drug, the interpretation of study safety or efficacy data,or compromise the safety or well-being of the subject.