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

Overview

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).

Interventions

• Drug EXL01
  Following 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
• Drug EXL01
  Following 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
• Drug Placebo
  Following 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

Primary outcome measures

• Incidence of Treatment-Emergent Adverse Events [Time frame: at Week 1, Week 2, Week 4, Week 8, Week 16]
• Evaluation of the efficacy of EXL01 in preventing recurrence of C. difficile infection in patients at high risk of recurrence [Time frame: at Week 8]

Secondary outcome measures (12)

• Evaluation of the efficacy of EXL01 in preventing recurrence of C. difficile infection in patients at high risk of recurrence [Time frame: at Week 8]
• Evaluation of the safety and tolerability profile of oral EXL01 [Time frame: at Week 2, Week 4, Week 8, Week 16]
• Number of stools per day over the past 24 hours [Time frame: at Week 0, Week 1, Week 2, Week 4, Week 8, Week 16]
• Stool consistency, as assessed by the Bristol scale, over the past 24 hours [Time frame: at Week 0, Week 1, Week 2, Week 4, Week 8, Week 16]
• Abdominal discomfort assessed by a validated irritable bowel syndrome scale [Time frame: at Week 8, Week 16]
• Number of stools per day over the past 24 hours [Time frame: at Week 0, Week 2, Week 4, Week 8, Week 16]
• Stool consistency, as assessed by the Bristol scale, over the past 24 hours [Time frame: at Week 0, Week 2, Week 4, Week 8, Week 16]
• Abdominal discomfort assessed by a validated irritable bowel syndrome scale [Time frame: at Week 8, Week 16]
• Assessment of patient quality of life during treatment and follow-up [Time frame: At Week 8 and Week 16]
• Assessment of recurrence of C. difficile infection [Time frame: At Week 16]
• Evaluation of the presence of EXL01 in the fecal microbiota [Time frame: At Week 8]
• Assessment of EXL01 persistence in the intestinal microbiota [Time frame: At Week 0 and Week 16]

Eligibility criteria

Inclusion criteria

• Adult patient ≥18 years of age
• ≥3rd episode of proven C. difficile infection (≥3 liquid stools per day and detection of toxigenic C. difficile in stool by PCR or enzyme-linked immunosorbent assay 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 2nd episode of proven C. difficile infection (≥3 liquid stools per day and detection of toxigenic C. difficile in the stools by PCR or enzyme-linked immunosorbent assay 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 with at least 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 (<3 months)
• 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 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
• Hospitalization in continuing care unit or intensive care unit
• Personal history of gastrointestinal resection other than appendectomy (gastrectomy, esophagectomy, colonic or small bowel resection, short small bowel syndrome).
• Personal history of gastrointestinal resection resulting in chronic diarrhea (>3 loose stools per day)
• Inflammatory bowel disease
• Proven uncontrolled celiac disease
• Current stoma (ileostomy or colostomy) or within the last 6 months, or any other intra-abdominal surgery within the 3 months prior to treatment
• major surgery or trauma ≤ 4 weeks before the start of treatment or, if > 4 weeks ago, with an unresolved healing process that could affect the assessment or safety of the study treatment.
• Antibiotic therapy in progress or planned during the study for an infection other than 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 and hydroxypropylmethylcellulose), and/or to soy or soy-containing products.
• History of hypersensitivity to vancomycin as mentioned in local prescribing information.
• Personal history of fecal microbiota transplantation < 6 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 may participate provided that more than 3 months have elapsed since the last intervention).
• Expected life expectancy of less than 6 months
• Presents a known psychiatric disorder that would interfere with adequate cooperation with study requirements.
• Regular use of illicit or recreational drugs that may interfere with the administration of the medication or the interpretation of the data
• History of chronic diarrhea (> 3 watery stools per day for > 4 weeks) not related to gastrointestinal infection.
• Clinically significant medical or surgical condition not mentioned in the above criteria which, in the opinion of the investigator, could interfere with the administration of study drug, the interpretation of study safety or efficacy data, or compromise the safety or well-being of the subject.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 10 centers

• CH Annecy Genevois Service de Maladies infectieuses — Annecy
• Service d'hépato-gastroentérologie - CHU Estaing — Clermont-Ferrand
• CHU Grenoble Service Maladies infectieuses et tropicales — Grenoble
• CHU Lille Unité des Maladies Infectieuses et tropicales — Lille
• Service d'Hépato-gastroentérologie Hôpital de la Croix Rousse — Lyon
• APHM La Timone Service de Maladies infectieuses — Marseille
• Service d'hépato-gastroentérologie - Hôpital Saint Antoine (APHP) — Paris
• Service d'infectiologie - Hôpital Nord / CHU Saint Etienne — Saint-Etienne
• … and 2 more centers

Identifiers

NCT: NCT06306014 · 69HCL22_0980 · 2023-506232-32-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗