Fecal microbiota transplantation versus vancomycin or fidaxomicin in Clostridioides difficile infection first episode and first recurrence: a study protocol for a randomised, controlled, open-label, multicentre phase III clinical trial.

INTRODUCTION: Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated diarrhoea in adults, with recurrence rates of 15%-25% after a first episode and up to 65% after multiple recurrences. Recurrent CDI leads to significant morbidity, diminished quality of life, prolonged antimicrobial exposure and increased healthcare utilisation. Faecal microbiota transplantation (FMT) demonstrates high efficacy for multiple recurrent CDI, but its benefit when used earlier-after the first episode in high-risk patients or first recurrence-remains insufficiently studied. Emerging evidence suggests early FMT may improve sustained clinical cure rates and reduce recurrence. This trial evaluates whether early introduction of oral FMT following standard therapy improves outcomes compared with standard therapy alone. METHODS AND ANALYSIS: This is a multicentre, randomised, open-label, pragmatic phase III superiority clinical trial conducted across eight Swiss clinical centres. A total of 100 adults will be enrolled. Patients with either (1) a first CDI episode and risk factors for recurrence or (2) a first CDI recurrence and who first receive the real-world standard of care anti-CDI antibiotics (10 days of vancomycin or fidaxomicin) are randomised 1:1 to oral FMT following standard antibiotic therapy or standard therapy alone. The intervention group receives within 12 hours to 4 days of the last antibiotics administration, 15 to 20 oral FMT capsules twice on two consecutive days if the CDI is non-severe; those with severe CDI receive an additional 2-day FMT course. The control group does not receive any additional treatment after completing the 10 days of standard therapy. The primary endpoint is the proportion of patients having experienced a CDI recurrence at 8 weeks post completion of treatment (assessed per-protocol and intention-to-treat). Secondary outcomes include early and late recurrence rates, sustained cure at 6 and 12 months, quality-adjusted life years, recurrence-free and overall survival at 12 months. Exploratory analyses include microbiota diversity, biomarker identification and assessment of immunologic and microbial predictors of recurrence. Safety/tolerability is also assessed. ETHICS AND DISSEMINATION: The study will be conducted in accordance with International Council for Harmonisation Good Clinical Practice, the Declaration of Helsinki and Swiss regulatory standards. Results will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT05266807.