Evaluation of Saccharomyces boulardii CNCM I-745 and Amoxicillin on Gut Microbiota in Patients with Erythema Migrans Undergoing Antibiotic Therapy
- Trial ID
- 2023-508694-80-01
- Protocol
- Sb 241
- Sponsor
- Biocodex
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **Saccharomyces boulardii CNCM I-745**, an antibiotic, and their combination on the gut microbiota of patients receiving antibiotic therapy in the context of erythema migrans, an early skin form of Lyme borreliosis. This is clinically relevant as alterations in gut microbiota can impact overall health and the effectiveness of antibiotic treatments.
Secondary objectives include:
- Assessing the efficacy of **Saccharomyces boulardii CNCM I-745** in preventing antibiotic-associated diarrhoea (AAD) in patients undergoing antibiotic therapy.
- Evaluating the efficacy of **Saccharomyces boulardii CNCM I-745** on stool characteristics in these patients.
- Investigating the effect of **Saccharomyces boulardii CNCM I-745**, an antibiotic, and their combination on the gut resistome of patients receiving antibiotic therapy.
- Assessing the safety and tolerability of **Saccharomyces boulardii CNCM I-745**.
Participants
The clinical trial involves **patients undergoing antibiotic therapy** in the context of **erythema migrans**, an early skin form of Lyme borreliosis. The study population includes adult patients aged 18 years and older, comprising both male and female participants. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants were selected based on their prescription of antibiotic therapy, specifically amoxicillin 1000 mg bid for 14 days, as part of routine medical practices. The trial population includes individuals who are able to comply with study requirements, provide informed consent, and maintain regular defecation patterns. Women of childbearing potential are required to have a negative urine pregnancy test prior to the study and agree to use approved contraception methods throughout the study. The trial also includes a vulnerable population, although specific details are not provided.
Plans and Procedures
The clinical trial is designed to evaluate the effect of **Saccharomyces boulardii** CNCM I-745 on gut microbiota in patients undergoing antibiotic therapy for **erythema migrans**, an early skin form of Lyme borreliosis. This is a randomized, double-blind, controlled trial involving three groups: one receiving **amoxicillin**, another receiving **Saccharomyces boulardii**, and a third group receiving a matched placebo. The trial is expected to last until December 31, 2025, with recruitment starting on March 25, 2024. The study will include adult patients aged 18 years and older who have been prescribed amoxicillin 1000 mg twice daily for 14 days as part of their routine medical care for erythema migrans.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as the ability to comply with study requirements and provide informed consent. The trial will include follow-up visits to monitor changes in gut microbiota, incidence of antibiotic-associated diarrhea (AAD), and safety assessments. The primary endpoint will focus on changes in bacterial and fungal taxonomy, while secondary endpoints will assess the incidence of AAD and changes in gastrointestinal symptoms using the Bristol Stool Form Scale and GSRS score.
The expected duration of participant involvement is up to 21 days, with conditions for early termination including non-compliance with study procedures or the occurrence of adverse events that may compromise participant safety. The trial will ensure blinding by using empty white capsules for the placebo group, similar in appearance to the active treatment capsules. Safety evaluations will be conducted through adverse event monitoring, vital signs, and physical examinations at each assessment time. The trial aims to provide insights into the impact of **Saccharomyces boulardii** on gut health during antibiotic treatment, contributing to improved management strategies for patients with erythema migrans.
Treatment
The clinical trial involves the administration of **Hiconcil 500 mg** hard capsules, which contain the active substance **amoxicillin**. This medication is classified under the ATC code J01CA04 and is produced by KRKA, D.D., Novo Mesto. The pharmaceutical form is a hard capsule, and the route of administration is oral. The maximum daily dose is 2000 mg, with a total maximum dose of 28 grams over a treatment period of up to 14 days. Amoxicillin is a chemical-origin antibiotic used in this study to assess its effects on gut microbiota in patients with erythema migrans, an early skin form of Lyme borreliosis.
Another treatment used in the trial is **Enterol 250 mg** hard capsules, containing **Saccharomyces boulardii CNCM I-745 lyophilized**. This product is manufactured by BIOCODEX BENELUX NV/SA and is classified under the ATC code A07FA02. The capsules are administered orally, with a maximum daily dose of 1000 mg and a total maximum dose of 21 grams over a treatment period of up to 21 days. Saccharomyces boulardii is a structurally diverse substance used as an antidiarrhoeal, probiotic, and gut flora replacement. The trial employs a blinding method by using empty white capsules with no imprinted mention to ensure the blinding instead of transparent imprinted capsules.
The study also includes a matched placebo, which consists of capsules similar in appearance to the 250 mg capsules of Saccharomyces boulardii CNCM I-745 but contains no active ingredient. This placebo is used to maintain the blinding of the study and ensure the validity of the results by providing a control for comparison with the active treatments.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on changes in bacterial and fungal taxonomy, specifically evaluating **alpha diversity** using the Shanon index and beta diversity metrics such as Bray Curtis dissimilarity, Jaccard distance, and Unifrac. These analyses will be conducted by treatment group at each assessment time.
Secondary endpoints include the incidence of antibiotic-associated diarrhea (AAD), which will be measured using the Bristol Stool Form Scale (BSFS) recorded daily. The proportion of patients experiencing at least one AAD episode will be compared between treatment groups. Additional secondary measures involve the time frame in hours up to the last liquid or loose stool, followed by the first 24-hour period with stool consistency improvement, as well as the average number of stools per week, and the duration and number of diarrhea episodes. Changes from baseline in the Gastrointestinal Symptom Rating Scale (GSRS) score, including total and diarrhea sub-scores, will be compared weekly between treatment groups. Safety assessments will include recorded adverse events, vital signs, and physical examinations, with quantitative statistics evaluated at each assessment time and changes from baseline.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult Patients, ≥18 years old
- Who were prescribed antibiotic therapy (as per medical routine practices, amoxicillin 1000 mg bid for 14 days) in the context of erythema migrans (early skin form of Lyme borreliosis).
- Able to comply with study requirements and to provide signed informed consent before any study procedure.
- Has no condition that may interfere with the study assessments.
- Able to fulfil in the diary stool log, according to the physician’s opinion.
- Regular defecation (frequency and stool consistency, with at least about three bowel movements a week).
- For women of childbearing potential: -A negative urine pregnancy test immediately prior to starting the study treatment, -Agreement to comply with approved methods of contraception during the whole study: unless they meet the criteria of post-menopausal, i.e. 12 months of spontaneous amenorrhea, women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner, should use one or more acceptable methods of contraception that should be maintained throughout the study)
Exclusion Criteria
- History of hypersensitivity to the study treatments (active substance or excipients), brewer’s or baker’s yeast
- Contraindication and special warning to the study drugs according to the SmPCs
- History of chronic constipation with passage of fewer than 3 spontaneous bowel movements per week on average
- History of chronic or recurrent diarrhoea with spontaneous unformed bowel movements equivalent to or more often than 3 times daily
- Prior gastrointestinal surgery (apart from appendectomy or cholecystectomy performed at least more than one year ago)
- History of Clostridium difficile infection
- Active gastrointestinal inflammatory disease
- Known chronic or recurrent systemic disorder that may interfere with the study drug evaluation
- Immunocompromised (organtransplants, leukaemia, malignant tumours, radiotherapy, chemotherapy,prolonged high dose cortisone treatment, immunosuppressant treament) or critically ill patients (such as autoimmune disease, HIV,…), patients with a central venous catheter
- Severe hepatic or renal impairment
- Systemic antibacterial therapy during the 2 months prior to study enrollment
- New prescription medications during the 2 weeks prior to study enrollment
- AUse of any drug or product that alters gut microbiota or function, such as probiotics, laxatives, antiemetics, cisapride, antisecretory or adsorbent treatments (racecadotril, smectite, activated charcoal), opiates such as loperamide, atropine and other cholinergic agents, during 4 weeks prior to study enrollment and during the study
- Intake of antifungals within 14 days prior to study enrollment
- Substantial changes in eating habits within 30 days prior to receiving the first dose of IMP product, and during the study as assessed by the Investigator
- History or presence of drug or alcohol abuse
- Heavy smoker (more than 10 cigarettes per day)
- Breast-feeding woman
- Patients enrolled in another interventional clinical trial where they received an investigation treatment within the past 30 days
- Any condition or personal circumstance that, in the opinion of the investigator, rendered the subject unlikely or unable to comply with the full study protocol
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 25 Mar 2024 | 60 |
 Lithuania | Recruiting | 25 Mar 2024 | 20 |
 Slovakia | Recruiting | 25 Mar 2024 | 40 |
 Slovenia | Recruiting | 25 Mar 2024 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Enterol 250 mg, gélules | Test | GÉLULES | ORAL USE | 1000 | 21 | PRD1584339 |
Hiconcil 500 mg trde kapsule | Other | TRDE KAPSULE | ORAL USE | 2000 | 14 | PRD4161234 |
Matched Placebo will consist in caspules similar to the 250 mg capsules of the Saccharomyces boulardii CNCM-I-745 but with no active ingredient | Placebo | N/A | — | — | — | N/A |