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

NCT06306014 | Recruiting Phase 1 DMC

• 2 other identifiers: 69HCL22_09802023-506232-32-00
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 9

Brief Summary

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).

Conditions

Clostridioides Difficile Infection; Recurrent Infection

Keywords

Clostridioides difficile Infection; Live Biotherapeutic Product; Microbiota; Recurrent Infection

Outcome Measures

Primary Outcomes (2)

• 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

  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

  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.

  at Week 8

Secondary Outcomes (20)

• Evaluation of the efficacy of EXL01 in preventing recurrence of C. difficile infection in patients at high risk of recurrence

  at Week 8

• Evaluation of the safety and tolerability profile of oral EXL01

  at Week 2, Week 4, Week 8, Week 16

• Number of stools per day over the past 24 hours

  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

  at Week 0, Week 1, Week 2, Week 4, Week 8, Week 16

• Abdominal discomfort assessed by a validated irritable bowel syndrome scale

  at Week 8, Week 16

Study Arms (3)

Part A (Open-Label EXL01)

EXPERIMENTAL

Drug: EXL01

Part B (EXL01)

EXPERIMENTAL

Drug: EXL01

Part B (Placebo)

PLACEBO COMPARATOR

Drug: Placebo

Interventions

EXL01 DRUG

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

Part A (Open-Label EXL01)

Placebo DRUG

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

Part B (Placebo)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Immunosuppression including :
• Malignant hemopathy under treatment (excluding CLL)
• HIV AIDS stage
• Stem cell allograft ≤ 12 months
• 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 other intra-abdominal surgery within the 3 months prior to treatment
• major surgery or trauma ≤ 4 weeks before the start of treatment

Sponsors & Collaborators

• Hospices Civils de Lyon: lead
• Exeliom Biosciences: collaborator

Study Sites (9)

CH Annecy Genevois Service de Maladies infectieuses

Annecy, France

NOT YET RECRUITING

Service d'hépato-gastroentérologie - CHU Estaing

Clermont-Ferrand, 63003, France

RECRUITING

CHU Grenoble Service Maladies infectieuses et tropicales

Grenoble, France

NOT YET RECRUITING

Service d'Hépato-gastroentérologie Hôpital de la Croix Rousse

Lyon, 69004, France

RECRUITING

APHM La Timone Service de Maladies infectieuses

Marseille, France

RECRUITING

Service d'hépato-gastroentérologie - Hôpital Saint Antoine (APHP)

Paris, 75012, France

RECRUITING

Service d'infectiologie - Hôpital Nord / CHU Saint Etienne

Saint-Etienne, 42100, France

NOT YET RECRUITING

Service de médecine interne - Pôle des maladies de l'appareil digestif - CHU de Toulouse

Toulouse, 31059, France

RECRUITING

Service de Maladies Infectieuses - CH de Valence

Valence, 26000, France

NOT YET RECRUITING

MeSH Terms

Conditions

Clostridium Infections; Reinfection

Condition Hierarchy (Ancestors)

Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Recurrence; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Nicolas BENECH, MD

  Hospices Civils de Lyon

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nicolas BENECH, MD

CONTACT

04 26 10 94 35; nicolas.benech@chu-lyon.fr

Fanny JOUBERT

CONTACT

04 26 73 27 27; Fanny.joubert@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Part A: None (Open-label). Part B: Double-blind.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Part A = Single Arm open label. Part B = Randomised, placebo-controlled, double-blind.

Study Record Dates

• First Submitted: February 21, 2024
• First Posted: March 12, 2024
• Study Start: May 7, 2024
• Primary Completion (Estimated): January 7, 2027
• Study Completion (Estimated): January 7, 2027
• Last Updated: March 2, 2026

Record last verified: 2026-02

Locations

FR (9)