Secondary Prophylaxis of Recurrent Clostridioides difficile Infections During Systemic Antibiotics with Vancomycin (SPORES-V): study protocol for a randomized controlled trial.

BACKGROUND: Clostridioides difficile infection (CDI) is a prevalent, morbid, and expensive disease that recurs in approximately 25% of patients despite treatment. Re-exposure to systemic antibiotics is one of the strongest risk factors for recurrence. Observational evidence and two small randomized controlled trials suggest that secondary vancomycin prophylaxis during antibiotic re-exposure may prevent recurrences, but the current evidence is not definitive.

METHODS: SPORES-V is a Bayesian multicenter phase III double-blind randomized controlled trial. Patients with CDI in the preceding 120 days who are re-exposed to systemic antibiotics will be randomized to receive prophylactic oral vancomycin (125 mg orally twice daily while on antibiotics and then once daily for 7 days afterwards) or an equal schedule of placebo. The primary outcome is CDI recurrence at day 56, analyzed by intention to treat using an adjusted odds ratio. Secondary outcomes include adverse events, discontinuation due to toxicity, longer-term recurrences (120 days), healthcare usage (56 and 120 days), and all-cause mortality (56 and 120 days). SPORES-V has begun recruitment at the McGill University Health Centre site.

DISCUSSION: The SPORES-V trial will provide high-quality evidence on the efficacy and safety of secondary vancomycin prophylaxis in the prevention of recurrent CDI.

TRIAL REGISTRATION: ClinicalTrials.gov NCT06979609. Registered on May 13, 2025, https://clinicaltrials.gov/study/NCT06979609 .