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

Clostridioides Difficile Infection Clinical Trial

— LIVEDIFF  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06306014
• Other study ID #: 69HCL22_980
• Secondary ID: 2023-506232-32-0
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 7, 2024
• Est. completion date: January 7, 2027

Study information

• Verified date: June 2024
• Source: Hospices Civils de Lyon
• Contact: Nicolas BENECH, MD
• Phone: 04 26 10 94 35
• Email: nicolas.benech[@]chu-lyon.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 56
• Est. completion date: January 7, 2027
• Est. primary completion date: January 7, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

• 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 and/or complicated C. difficile infection

• 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 other intra-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 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 < 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

• 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

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

• 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.

Related Conditions & MeSH terms

• Clostridioides Difficile Infection
• Clostridium Infections
• Communicable Diseases
• Infections
• Recurrence

Intervention

Drug:
• EXL01
Following a 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
Following a 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
Following a 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

Locations

Country	Name	City	State
France	Service d'hépato-gastroentérologie - CHU Estaing	Clermont-Ferrand
France	Service d'Hépato-gastroentérologie Hôpital de la Croix Rousse	Lyon
France	Service d'hépato-gastroentérologie - Hôpital Saint Antoine (APHP)	Paris
France	Service d'infectiologie - Hôpital Nord / CHU Saint Etienne	Saint-Étienne
France	Service de médecine interne - Pôle des maladies de l'appareil digestif - CHU de Toulouse	Toulouse
France	Service de Maladies Infectieuses - CH de Valence	Valence

Sponsors (2)

Lead Sponsor	Collaborator
Hospices Civils de Lyon	Exeliom Biosciences

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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, Month 4
Primary	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 + 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	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 + detection of C. difficile toxin in stool (enzyme-linked immunosorbent assay or toxigenic culture +/- PCR) resulting in the initiation of specific treatment for CDI.	at Week 8
Secondary	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	at Week 2, Week 4, Week 8, Month 4
Secondary	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	at Week 0, Week 1, Week 2, Week 4, Week 8, Month 4
Secondary	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	at Week 0, Week 1, Week 2, Week 4, Week 8, Month 4
Secondary	Abdominal discomfort assessed by a validated irritable bowel syndrome scale	Phase I Assessment of digestive symptoms during treatment and follow-up Digestive symptoms are measured at each visit (IBS-SSS modified, GCSI, GERDQ)	at Week 8, Month 4
Secondary	Number of stools per day over the past 24 hours	Phase II Assessment of digestive symptoms during treatment and follow-up Digestive symptoms are measured at each visit using a stool calendar	at Week 0, Week 2, Week 4, Week 8, Month 4
Secondary	Stool consistency, as assessed by the Bristol scale, over the past 24 hours	Phase II Digestive symptoms are measured at each visit using the stool calendar	at Week 0, Week 2, Week 4, Week 8, Month 4
Secondary	Abdominal discomfort assessed by a validated irritable bowel syndrome scale	Phase II Assessment of digestive symptoms during treatment and follow-up Digestive symptoms are measured at each visit (IBS-SSS modified, GCSI, GERDQ)	at Week 8, Month 4
Secondary	Assessment of patient quality of life during treatment and follow-up	Phases I and II Patient quality of life at W8 and M4 measured by a validated digestive disease quality of life questionnaire (GIQLI)	At Week 8 and Month 4
Secondary	Assessment of recurrence of C. difficile infection	Phases I and II percentage of patients with recurrence of C. difficile infection at M4	At Month 4
Secondary	Evaluation of the presence of EXL01 in the fecal microbiota	Phases I and II Level of F. prausnitzii (qPCR) in stool at W8 versus W0	At Week 8
Secondary	Assessment of EXL01 persistence in the intestinal microbiota	Phases I and II Level of F. prausnitzii (qPCR) in stool at M4 versus W0	At Week 0 and Month 4
Secondary	16S rRNA sequencing or shotgun	Phase I Gut microbiota composition at each visit	at Week 0, Week 1, Week 2, Week 4, Week 8, Month 4
Secondary	16S rRNA sequencing or shotgun	Phase II Gut microbiota composition at each visit	at Week 0, Week 2, Week 4, Week 8, Month 4
Secondary	Assessment of the persistence of toxigenic C. difficile in the stool of patients in clinical remission during the study.	Phase I Percentage of patients at each visit with a positive stool PCR test for toxigenic C. difficile considered to be in clinical remission	at Week 0, Week 1, Week 2, Week 4, Week 8, Month 4
Secondary	Assessment of the persistence of toxigenic C. difficile in the stool of patients in clinical remission during the study.	Phase II Percentage of patients at each visit with a positive stool PCR test for toxigenic C. difficile considered to be in clinical remission	at Week 0, Week 2, Week 4, Week 8, Month 4
Secondary	Assessment of recurrences of C. difficile infection requiring hospitalization	phases I and II percentage of patients with recurrence of C. difficile infection requiring hospitalization at W8	At Week 8
Secondary	Assessment of recurrences of C. difficile infection requiring hospitalization	phases I and II percentage of patients with recurrence of C. difficile infection requiring hospitalization at M4	at Month 4
Secondary	Assessment of recurrences of C. difficile infection requiring surgery	phases I and II phases I and II percentage of patients with a recurrence of C. difficile infection requiring surgery at W8	at Week 8
Secondary	Assessment of recurrences of C. difficile infection requiring surgery	phases I and II percentage of patients with recurrent C. difficile infection requiring surgery at M4	at Month 4