Clostridioides difficile infection (CDI) is the leading cause of nosocomial diarrhea in Europe, with over 120,000 cases and almost 3,700 deaths per year. This infection is characterized by a high risk of recurrence after cure, ranging from almost 20% after a first episode to over 60% after 2 recurrences, or in the case of specific risk factors.
Currently, first-line treatment of CDI is based on oral antibiotics such as fidaxomicin or vancomycin. These antibiotic treatments, which are effective in 89% and 86% of first-episode cases respectively, do not correct the microbiological imbalance underlying the onset of CDI and may, on the contrary, encourage recurrence by contributing to the maintenance of a deleterious change in the microbiota (dysbiosis) through the elimination of bacteria other than C. difficile, due to their spectrum of activity. In a number of patients, this ecological imbalance can no longer be restored after antibiotic treatment, leading to multiple recurrences of CDI.
In this context, fecal microbiota transplantation (FMT) has been validated for over 10 years for the prevention of recurrence in multi-recurrent CDI. The principle of FMT is based on the use of a pharmaceutical preparation made from the stool of a healthy donor, administered within the digestive tract of a patient for therapeutic purposes.
Currently, in the case of multiple recurrences, it is the recommended first-line treatment (from 2 recurrences) and the most effective, with a clinical efficacy preventing recurrence of CDI in 69% to 89% of cases at 8 weeks post-treatment, with a good safety profile.
Among the microbial factors promoting CDI, the loss of the bacterial species Faecalibacterium prausnitzii constitutes a specific therapeutic target. F. prausnitzii is a commensal bacterium of the human gut, making up nearly 5% of the fecal microbiota, and has been shown to be associated with an individual's state of health. A drop in its relative abundance is associated with an increased risk of numerous diseases, such as Crohn's disease and colorectal cancer. In CDI, F prausnitzii is greatly diminished. Moreover, low abundance of F. prausnitzii is predictive of C. difficile recurrence. Its abundance in stools is increased after FMT and is also predictive of response to treatment. From a pathophysiological point of view, one of the preventive effects of F. prausnitzii on recurrence would be mediated by its ability to hydrolyze the bile acids involved in the germination of C. difficile spores.
The aim of this Phase I/II trial is to assess the efficacy and safety of oral administration of EXL01, a single isolated unmodified strain of F. prausnitzii, in preventing CDI recurrence in high-risk patients at W8. The study will be conducted in 2 parts. The phase I (Part A) is planned to include 6 patients. The phase II (Part B) will include 50 patients in two arms (25 patients respectively in the placebo and EXL01 arm).
Adult patient ≥18 years of age
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
Currently participating or has participated in a study with an investigational compound or device within 3 months prior to the first dose of the study intervention.
Severe C. difficile infection severe (defined by the presence of a white blood cell count >15×10⁹ cells/L or a body temperature >38.5°C or >50% increase in the patient's baseline creatinine related to CDI at the time of V1) and/or complicated (defined by any of the factors attributed to current Clostridioides difficile infection (CDI): hypotension, septic shock, elevated serum lactate, ileus, toxic megacolon, intestinal perforation or any fulminant course of the disease)
Refractory C. difficile infection defined as lack of response to well-conducted per os vancomycin or fidaxomicin treatment with ≥3 liquid stools per day after ≥5 days of treatment
Cirrhosis with Child C score
Parallel
EXL01
DrugFollowing a at least 10-days vancomycin treatment : Oral EXL01 including: * 10 capsules per day in week 1 and 2 * 4 capsules per day, in weeks 3 and 4 * 1 capsule per day in weeks 5 to 8 Phase I : EXL01 during a 8 weeks open-label period
EXL01
DrugFollowing a at least 10-days vancomycin treatment : Oral EXL01 including: * 10 capsules per day in week 1 and 2 * 4 capsules per day, in weeks 3 and 4 * 1 capsule per day in weeks 5 to 8 Phase II: EXL01 during a 8 weeks double blind placebo-controlled period
Placebo
DrugFollowing a at least 10-days vancomycin treatment: Oral placebo including: * 10 capsules per day in week 1 and 2 * 4 capsules per day, in weeks 3 and 4 * 1 capsule per day in weeks 5 to 8 Phase II : Placebo during a 8 weeks double blind placebo-controlled period
Incidence of Treatment-Emergent Adverse Events
Phase I The primary endpoint is the occurrence of serious adverse events (CTCAE grade≥3) during treatment and follow-up and discontinuation of treatment due to adverse events attributed to treatment
Evaluation of the efficacy of EXL01 in preventing recurrence of C. difficile infection in patients at high risk of recurrence
Phase II The primary endpoint is the proportion of patients at W8 after the start of treatment who had a recurrence of toxigenic C. difficile defined by ≥3 liquid stools per day for more than 48 hours + detection of C. difficile toxin in stool (enzyme-linked immunosorbent assay or toxigenic culture +/- PCR) resulting in the initiation of CDI-specific treatment.
Evaluation of the efficacy of EXL01 in preventing recurrence of C. difficile infection in patients at high risk of recurrence
Phase I Proportion of patients at W8 after the start of treatment who had a recurrence of toxigenic C. difficile defined by ≥3 liquid stools per day for more than 48 hours + detection of C. difficile toxin in stool (enzyme-linked immunosorbent assay or toxigenic culture +/- PCR) resulting in the initiation of specific treatment for CDI.
Evaluation of the safety and tolerability profile of oral EXL01
Phase II Occurrence of adverse events (CTCAE grade≥3) during treatment and follow-up, and discontinuation of treatment due to adverse events
Number of stools per day over the past 24 hours
Phase I Assessment of digestive symptoms during treatment and follow-up Digestive symptoms are measured at each visit using a stool calendar
Stool consistency, as assessed by the Bristol scale, over the past 24 hours
Phase I Digestive symptoms are measured at each visit using the stool calendar
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Hospices Civils de Lyon
Lead sponsor
Exeliom Biosciences
Collaborator
