FENDER: Fecal Microbiota Transplantation Versus Vancomycin or Fidaxomicin in Clostridioides Difficile Infection First Recurrence

Sponsor

Benoit Guery (Other)

Overall Status

Recruiting

CT.gov ID

NCT05266807

Collaborator

(none)

220

Enrollment

Location

Arms

39.5

Anticipated Duration (Months)

5.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Experimental arm: antibiotic treatment (vancomycin or fidaxomicin as initially prescribed per SoC continued for 10 days, min 7) followed by FMT by oral capsules (one FMT, i.e. 15 FMT capsules given on 2 consecutive days, and followed by a mandatory 2nd FMT in severe rCDI, or by a 2nd FMT only in case of persisting symptoms in non-severe rCDI).

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

Condition or Disease	Intervention/Treatment	Phase
Clostridioides Difficile Infection	Drug: oral capsulized Fecal Microbiota Transplantation Drug: Vancomycin or Fidaxomicin	Phase 3

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 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 recurrence of CDI.

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 recurrence.

Patients (220) 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 (min 7 days).

The antibiotic will be stopped for 24h and then all patients will receive a first FMT on 2 consecutive days (15 capsules at D1 and 15 capsules at D2). The administration of the second

FMT will depend on the severity of the rCDI:

for patients with non-severe rCDI, a second FMT is administrated only in case of persisting symptoms at D7 (±1 day)
for patients with severe rCDI, a second FMT is immediately administrated at D3 (15 capsules) and at D4 (15 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 Design

Study Type:

Interventional

Anticipated Enrollment :

220 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Randomized, Controlled, Open-label, MulticenterRandomized, Controlled, Open-label, Multicenter

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 16, 2022

Anticipated Primary Completion Date :

Jan 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
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 24h later by one oral FMT (15 capsules administered at D1 and 15 capsules at D2), and a second oral FMT depending on recurrent CDI severity.	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
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

Arm

Intervention/Treatment

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 24h later by one oral FMT (15 capsules administered at D1 and 15 capsules at D2), and a second oral FMT depending on recurrent CDI severity.

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

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

Outcome Measures

Primary Outcome Measures

Sustained clinical cure rate [8 weeks after study treatment completion]
Absence of CDI recurrence through 8 weeks after study treatment completion

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adults (≥18 years old) at the time of informed consent
Informed consent signature
Medical record documentation of first recurrence of CDI defined as:
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 CDI test performed according to CDI diagnosis ESCMID guidelines
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 test performed according to CDI diagnosis ESCMID guidelines, with a mandatory toxin A/B EIA positive test and without reasonable evidence of another cause of diarrhea.
No multiple episodes (more than one recurrence) of CDI that occurred within 3 last months.
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.
Willing and able to have FMT by capsule

Exclusion Criteria:

Complicated CDI (at least one of the following signs or symptoms are present and related to CDI: hypotension requiring vasopressors, intensive care unit admission for a complication of CDI, ileus leading to placement of nasogastric tube, toxic megacolon, colonic perforation, colectomy or colostomy)(2),
Prior FMT within 6 months of randomization,
Prior colectomy, colostomy, ileostomy, or gastrectomy.
Metronidazole already given for the treatment of the first rCDI for more than 3 days,
Need for continued non-anti-CDI systemic antibiotics,
Anticipated indication for antibiotics treatment (for a non-CDI reason) in the next 8 weeks,
Other infectious causes of diarrhea beyond CDI,
Inflammatory bowel disease,
Patients with swallowing disorders, Zenker's diverticulum, gastroparesis, or prior small bowel obstruction,
Known hypersensitivity to vancomycin or fidaxomicin,
Pregnant/lactating women,
Estimated patient's life expectancy of less than 10 weeks,
Inability to follow protocol study procedures,
Inability to give informed consent,
Any condition or medications that will put the participant at greater risk from FMT according to the investigator,
Severely immunocompromised