Fecal Microbiota Transplantation in Clostridioides Difficile Infection First Episode and First Recurrence (FENDER)

Fecal Microbiota Transplantation Versus Vancomycin or Fidaxomicin in Clostridioides Difficile Infection First Episode or First Recurrence: A Randomized Controlled, Open-label, Multicenter Phase III Clinical Trial

The clinical trial aims to evaluate the efficacy of fecal microbiota transplantation (FMT) after standard of care treatment (either vancomycin or fidaxomicin) vs the pragmatic use of standard of care treatment (either vancomycin or fidaxomicin) in severe and non-severe first episode and first recurrence of Clostridioides difficile infection (CDI).

Experimental arm: antibiotic treatment (vancomycin or fidaxomicin as initially prescribed per SoC continued for 10 days) followed by FMT by oral capsules (one FMT, i.e. 20 FMT capsules given on 2 consecutive days, and followed by a 2nd FMT in severe CDI).

Control Arm: vancomycin or fidaxomicin as initially prescribed per SoC continued for 10 days.

Study Overview

• Status: Recruiting
• Conditions: Clostridioides Difficile Infection
• Intervention / Treatment: Drug: oral capsulized Fecal Microbiota Transplantation; Drug: Vancomycin or Fidaxomicin

Detailed Description

Clostridioides difficile (CDI) is well known as major agent of healthcare-associated diarrhea in adult patients. One of the main challenges is the prevention of recurrence of Clostridioides difficile infection which occurs in 15-25% of the cases within the two months following the initial episode. A patient presenting a first recurrence has a higher risk of subsequent recurrences and may enter a cycle of multiple episodes of recurrence leading to significant morbidity, decrease in quality of life, and long courses of antimicrobial therapy. North-American, as well as the European, guidelines propose vancomycin or fidaxomicin to treat this first recurrence. All these recommendations rely on weak to moderate quality of evidence. For patients with multiple recurrences, fecal microbiota transplantation (FMT) is recommended as an option in guidelines based on several randomized controlled trials and a meta-analysis having shown superior efficacy compared to antibiotics with regard to preventing further recurrences.

FMT has never been evaluated for CDI first episode and first recurrence and could represent an attractive treatment to prevent further recurrences, avoid hospitalization (mean length of 10 days) and reduce overall mortality risk.

The aim of our study is to compare the efficacy of FMT (combined with standard treatment: vancomycin or fidaxomicin) compared to standard treatment (vancomycin or fidaxomicin) in patients with a first CDI episode presenting risk factors for recurrence and in patient with a first CDI recurrence.

This is a multicenter, randomized, open-label, phase III superiority trial comparing fecal microbiota transplantation (FMT) delivered via oral capsules after a conditioning standard antibiotic treatment (either vancomycin or fidaxomicin), to the pragmatic use of standard treatment (either vancomycin or fidaxomicin) in non-severe and severe CDI first episode or first recurrence.

Patients (100) will be randomized 1:1. Patients randomized in the FMT arm (Arm A) will continue the antibiotic treatment (vancomycin or fidaxomicin initially prescribed as SoC) for a total of 10 days.

The antibiotic will be stopped for 12h to 4 days and then all patients will receive a first FMT on 2 consecutive days (20 capsules at D1 and 20 capsules at D2). Patients with severe CDI will receive a second FMT immediately administrated at D3 (20 capsules) and at D4 (20 capsules).

Patients randomized in the standard treatment arm (Arm B) will continue the antibiotic treatment (vancomycin or fidaxomicin initially prescribed as SoC) for a total of 10 days.

Efficacy of FMT (combined with standard treatment) will be assessed by comparing the proportion of participants experiencing clinical cure 8 weeks after study treatment completion, in the FMT intervention arm (arm A) and in the standard of care control arm (arm B). Participants will be followed for 12 months.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Benoit Guery, MD; Phone Number: +41213141643; Email: benoit.guery@chuv.ch
• Study Contact Backup: Name: Project Manager; Phone Number: +41795564371; Email: crc.fender@chuv.ch

Study Locations

• Switzerland
  • Basel
    • Basel, Basel, Switzerland, 4031
      • Recruiting
      • Universitätsspital
      • Contact: Sarah Tschudin-Sutter, MD; Phone Number: +41 61 328 6810; Email: sarah.tschudin@usb.ch
  • Canton of Bern
    • Bern, Canton of Bern, Switzerland, 3010
      • Recruiting
      • Inselspital Bern
      • Contact: Anna Eichenberger, MD; Phone Number: +41 31 632 88 44; Email: anna.eichenberger@insel.ch
  • Canton of Fribourg
    • Fribourg, Canton of Fribourg, Switzerland, 1708
      • Recruiting
      • HFR Fribourg - Hôpital Cantonal
      • Contact: Véronique Erard, MD; Phone Number: +41 26 306 0836; Email: veronique.erard@h-fr.ch
  • Canton of Lucerne
    • Lucerne, Canton of Lucerne, Switzerland, 6006
      • Recruiting
      • Hirslanden Klinik St Anna
      • Contact: Rami Sommerstein, MD; Phone Number: 041 208 32 54; Email: rami.sommerstein@hirslanden.ch
  • Canton of St. Gallen
    • Sankt Gallen, Canton of St. Gallen, Switzerland, 9007
      • Recruiting
      • Kantonsspital St Gallen, HOCH
      • Contact: Werner Albrich, MD; Phone Number: 071 494 2653; Email: werner.albrich@h-och.ch
  • Canton of Vaud
    • Lausanne, Canton of Vaud, Switzerland, 1011
      • Recruiting
      • CHUV
      • Contact: Benoit Guery, MD; Email: benoit.guery@chuv.ch
  • Canton of Zurich
    • Zurich, Canton of Zurich, Switzerland, 8091
      • Recruiting
      • Universitätsspital Zürich
      • Contact: Silvio Brugger, MD; Phone Number: +41 44 255 3402; Email: silvio.brugger@usz.ch
  • Valais
    • Sion, Valais, Switzerland, 1950
      • Recruiting
      • Institut central des hôpitaux
      • Contact: Matthaios Papadimitriou Olivgeris, MD; Phone Number: +41 27 603 47 94; Email: matthaios.papadimitriou-olivgeris@hospitalvs.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults (≥18 years old) at the time of informed consent
2. Informed consent signature

3. Medical record documentation of CDI defined as:

   a. A first CDI episode associated with risks factors for recurrence, defined as: i. No CDI episode within the last 8 weeks ii. Current combination of CDI signs and symptoms, confirmed by medical record documentation of microbiological evidence of C. difficile toxin and C. difficile in stools shown by a CDI PCR positive test with Ct < 25 or a toxin A/B EIA positive test and without reasonable evidence of another cause of diarrhea, iii. Presenting at least one of the following risks factors for CDI recurrence:

   • age >65 years-old,
   • hospitalization within the last 3 months,
   • use of proton pump inhibitors (PPI) within the last 3 months,
   • Charlson comorbidity index (CCI) >2,
   • living in long term facility,
   • healthcare- associated CDI (see definition in section 7),
   • severe CDI episode (see definitions in section 6.1.2),
   • immunocompromised patient (except severely immunocompromised according to definitions in section 7.1),
   • history of prior CDI episode(s) (more than 8 weeks ago). OR b. A first CDI recurrence, defined as: i. Previous episode of treated and cured CDI within the last 8 weeks confirmed by medical record documentation of a clinical picture of CDI combined with a positive microbiological CDI test performed according to CDI diagnosis ESCMID guidelines ii. Current combination of CDI signs and symptoms, confirmed by medical record documentation of microbiological evidence of C. difficile toxin and C. difficile in stools shown by a CDI PCR positive test with Ct < 25 or a toxin A/B EIA positive test , and without reasonable evidence of another cause of diarrhea..
4. No multiple episodes (no more than 2 CDI episodes) within 3 last months.
5. Already taking since less than 10 days or will start a course of antibiotics (vancomycin or fidaxomicin) to control recurrent CDI symptoms at the time of screening.
6. Willing and able to have FMT by capsule

Exclusion Criteria:

1. Severe-complicated CDI if at least one of the following signs or symptoms are:

   • ongoing at time of screening and related to CDI: hypotension, septic shock, elevated serum lactate, ileus,
   • or were present at any time of the CDI episode and related to CDI: toxic megacolon, bowel perforation, or any fulminant course of disease (i.e. rapid deterioration of the patient.
2. Prior FMT within 6 months of randomization,
3. Prior total colectomy, colostomy, ileostomy, or gastrectomy
4. Metronidazole already given alone for the treatment of the current CDI for more than 3 days,
5. Need for continued non-anti-CDI systemic antibiotics (should be stopped at randomization at the latest), except prophylactic doses of trimethoprim/sulfamethoxazole,
6. Anticipated indication for antibiotics treatment (for a non-CDI reason) in the next 8 weeks except prophylactic doses of trimethoprim/sulfamethoxazole
7. Other causes of chronic or acute diarrhea beyond CDI (chronic diarrhea is defined as loose/watery stools, which occur three or more times within 24 hours and last for 4 or more weeks)
8. Inflammatory bowel disease,
9. Patients with swallowing disorders, Zenker's diverticulum, gastroparesis, or prior small bowel obstruction,
10. Known hypersensitivity to vancomycin or fidaxomicin,
11. Pregnant/lactating women,
12. Estimated patient's life expectancy of less than 10 weeks,
13. Inability to follow protocol study procedures,
14. Inability to give informed consent,
15. Any condition or medications that will put the participant at greater risk from FMT according to the investigator,
16. Severely immunocompromised
17. No response to anti-CDI antibiotic treatment after at least 5 days of treatment (i.e. no diminution of the daily number of stools at BSS 6-7 compared to first day of treatment; or worsening of CDI severity parameters)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: SoC; Antibiotic (vancomycin 125 mg 4 times daily or fidaxomicin 200 mg 2 times daily, as initially prescribed per SoC) for 10 days.	Drug: Vancomycin or Fidaxomicin; Vancomycin or Fidaxomicin per os as initially prescribed per SoC
Experimental: SoC + oral Fecal Microbiota Transplantation; Antibiotic (vancomycin 125 mg 4 times daily or fidaxomicin 200 mg 2 times daily, as initially prescribed per SoC) for 10 days, followed 12h to 4 days later by one oral FMT (20 capsules administered at D1 and 20 capsules at D2), and a second oral FMT if CDI is severe.	Drug: oral capsulized Fecal Microbiota Transplantation; FMT will be administered per os in the form of capsules containing faeces from a healthy donor. Capsules are manufactured at the CHUV pharmacy (University Hospital of Lausanne, Switzerland); Drug: Vancomycin or Fidaxomicin; Vancomycin or Fidaxomicin per os as initially prescribed per SoC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sustained clinical cure rate	Absence of CDI recurrence through 8 weeks after study treatment completion	8 weeks after study treatment completion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment failure	Early and late CDI recurrence rate	Before 4 weeks and at 5-8 weeks after study treatment completion
CDI new episodes	CDI new episodes occurence rate	between 8 weeks and 12 months after study treatment completion
Long-term clinical cure	Long-term clinical cure rate	6 and 12 months after study treatment completion
Recurrence-free survival rate	Time from study intervention until CDI recurrence	12 months after study treatment completion
Overall survival	Time from study intervention until death	12 months after study treatment completion
Health status EQ-5D-5L measure (mobility, self-care, usual activities, pain/discomfort, annxiety/depression)	5-digit code (score from 1 to 5 for each digit, 1 representing no problem and 5 worse problem)	Baseline, 8 weeks, 6 and 12 months after study treatment completion
Health status EQ-5D-5L measure (patient's perception of overall health)	EQ Visual Analogue Scale (VAS) score (0 representing the worst health you can imagine to 100 representing the best health you can imagine)	Baseline, 8 weeks, 6 and 12 months after study treatment completion

Collaborators and Investigators

• Sponsor: Benoit Guery
• Investigators: Principal Investigator: Benoit Guery, CHUV

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2023
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): January 31, 2028

Study Registration Dates

• First Submitted: February 18, 2022
• First Submitted That Met QC Criteria: March 1, 2022
• First Posted (Actual): March 4, 2022

Study Record Updates

• Last Update Posted (Actual): July 10, 2026
• Last Update Submitted That Met QC Criteria: July 8, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Vancomycin; Fecal Microbiota Transplantation; Clostridium difficile; Fidaxomicin; Clostridioides difficile
• Additional Relevant MeSH Terms: Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Clostridium Infections; Peptides; Amino Acids, Peptides, and Proteins; Organic Chemicals; Carbohydrates; Polycyclic Compounds; Macrolides; Lactones; Glycoconjugates; Macrocyclic Compounds; Glycopeptides; Polyketides; Fidaxomicin; Vancomycin
• Other Study ID Numbers: FENDER

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Individual de-identified participant data underlying the results reported in publications arising from this study will be made available, including demographic characteristics, baseline data, outcome measures, and relevant study variables.

Individual participant microbiome sequencing data (raw sequence files and associated metadata) will be deposited in the European Nucleotide Archive (ENA). Data will be made available following publication and according to ENA access policies

• IPD Sharing Time Frame: Data will be available upon publication of the primary study results and will remain available indefinitely in the Dryad Digital Repository and ENA.
• IPD Sharing Access Criteria: Data will be accessible through the Dryad Digital Repository and ENA. Researchers may access the de-identified dataset in accordance with Dryad's and ENA's terms of use and any applicable ethical and regulatory requirements.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No