Clinical trial NCT06979609: Secondary Prevention of Clostridioides Difficile Using Vancomycin
Official title: Secondary Prophylaxis of Recurrent Clostridioides Difficile Infections During Systemic Antibiotics With Vancomycin: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Clostridioides Difficile Infection
Clostridioides Difficile Infection Recurrence
Clostridoides Difficile Associated Disease
Keywords: Clostridioides difficile
Clostridium difficile
Vancomycin
Prophylaxis
C. difficile
Recurrence
CDI
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
First posted: 2025-05-20
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Re-exposure to systemic antibiotics (i.e., antibiotics absorbed into the bloodstream) is common after a Clostridioides difficile infection (CDI) and is the strongest risk factor for a recurrent episode. Oral vancomycin to prevent a recurrence during antibiotic re-exposure may reduce this risk but the data supporting this practice are limited. The aim of this trial is:

1) Does oral vancomycin prophylaxis prevent CDI recurrences in patients with recent CDI (within 120 days) and who are re-exposed to systemic antibiotics?

The trial will compare oral vancomycin to placebo.

Participants will:

* Take the study drug (either vancomycin or placebo) twice daily for the duration of systemic antibiotics plus once daily for 7 days after completion of systemic antibiotics.
* Attend an in-person follow-up at day 56
* Respond to weekly electronic questionnaires

Detailed description: Clostridioides difficile is a gram-positive spore-forming anaerobic bacteria that can cause severe diarrhea through colitis. While the incidence of CDI is decreasing in Canada it remains a major cause of nosocomial infections. The annual incidence of CDI in Canada is 16,000 cases with 1,300 (8.1%) associated deaths. Estimates suggest that CDI is associated with annual economic losses of \~$150 million in Canada and that 23% of these losses are attributable to recurrent cases.

Despite appropriate treatment, approximately 20% of CDI cases experience a recurrence. Recurrent CDI (rCDI) is associated with a higher risk of death than index episodes. Although treatments such as fidaxomicin reduce the recurrence rate of CDI by approximately \~10%, cost and availability prohibit their widespread use and a substantial risk of recurrence remains (10-15%). Thus, rCDI is associated with significant morbidity, mortality, and economic cost, and consequently prevention is a substantially unmet clinical need.

Antibiotic re-exposure following completion of CDI treatment is common and is one of the strongest risk factors for CDI recurrence. In a study of 18,246 index cases of CDI, 7,730 were re-exposed to antibiotics within 8 weeks of completion of CDI treatment. Antibiotic re-exposure was the strongest predictor of rCDI with an adjusted odds ratio of 3.2 (95% Confidence Interval \[95%CI\]=2.9-3.4). Although avoidance of antibiotics after an index episode of CDI would be an ideal prevention strategy, it is frequently unavoidable. Therefore, strategies to reduce the recurrence rate of CDI arising from antibiotic re-exposure are of significant clinical interest.

The pathogenesis of rCDI is thought to involve persistent C. difficile colonization in a patient with an already vulnerable microbiome that is further disrupted by re-exposure to antibiotics. Vancomycin prophylaxis has been proposed as a potential strategy to reduce the risk of rCDI by inhibiting the proliferation of C. difficile during antibiotic re-exposure.

Observational evidence suggests that vancomycin prophylaxis may reduce the recurrence rate of CDI. In a Canadian study of 551 episodes of CDI with antibiotic re-exposure, patients who received vancomycin prophylaxis (n=227, 41.2%) experienced significantly less rCDI after adjusting for age (adjusted hazard ratio=0.59, 95% CI=0.43-0.80). This benefit was only identified following recurrent episodes of CDI. However, the evidence base is inconsistent, as another study found a benefit only in patients with a first episode of CDI and another suggested no benefit at all. These inconsistencies could be attributable to varying degrees of confounding by indication, ascertainment bias, immortal time bias, and a competing risk of mortality, which preclude firm conclusions from observational studies.

A single randomized controlled trial (RCT) of primary oral vancomycin prophylaxis in patients at high risk of CDI and who continued to receive systemic antibiotics demonstrated benefit in the prevention of healthcare-onset CDI (placebo 6/50 \[12.0%\] versus prophylaxis 0/50 \[0%\], P=0.03). Results of this trial are limited by its open-label design which may have led to ascertainment bias and an extremely high loss to follow-up (\>50%) for the overall rCDI outcome. No RCTs of vancomycin prophylaxis for the prevention of rCDI during antibiotic re-exposure have been published to date. There is one small RCT of vancomycin prophylaxis versus placebo, randomized in a 2:1 ratio, underway with a target enrollment of 108 participants. This RCT uses a 10-day fixed duration of oral vancomycin; however, observational evidence suggests that vancomycin prophylaxis is more effective when given for ≥50% of the duration of systemic antibiotics. Thus, if the trial is negative, dosing based on the duration of antibiotic re-exposure might prove effective. Further, while this trial is appreciated, it is underpowered and unlikely to provide definitive evidence regardless of the result.

Guidelines are heterogeneous in their recommendations for vancomycin prophylaxis following antibiotic re-exposure. Whereas the American College of Gastroenterology and AMMI Canada recommend consideration of prophylaxis, the Infectious Disease Society of America refrain from making a recommendation, and the European Society of Clinical Microbiology and Infectious Diseases discourage prophylaxis. Heterogeneous conclusions from observational studies and conflicting international guideline recommendations implies clinical equipoise. Therefore, to definitively determine whether vancomycin prophylaxis is an efficacious strategy to prevent rCDI during antibiotic re-exposure, we propose a randomized double-blind trial comparing vancomycin prophylaxis to placebo for patients with CDI in the past 120 days who are re-exposed to antibiotics. The proposed trial will directly inform clinical practice on the use of vancomycin for CDI prophylaxis during antibiotic re-exposure. The results are expected to be of international importance given the high incidence and economic burden of rCDI and because oral vancomycin is inexpensive, safe, and widely accessible.

Eligibility criteria: Inclusion Criteria:

* Inpatient or outpatient adults (≥18 years old) treated at the participating institutions.
* An episode of CDI within the preceding 120 days (rationale in 2.4), diagnosed by both a positive C. difficile assay (including PCR toxin gene detection47, toxin enzyme immunoassay, and/or cell cytotoxicity neutralization assay29) and the presence of either ≥3 unformed stools in \<24 hours with a duration \>24 hours, endoscopic/histologic evidence of pseudomembranous colitis, or ileus29.
* Treatment of the qualifying CDI episode with vancomycin or fidaxomicin for ≥10 days, clinical cure (≤3 unformed stool per 24 hours in ≥2 days10) by the conclusion of therapy, and ≥1 day has elapsed since cessation of CDI treatment.
* Receipt of ≤3 days of at least one oral or intravenous systemic antibiotic for the treatment of an intercurrent confirmed or suspected bacterial infection, for which therapy is planned for at least one additional consecutive day in duration.

Exclusion Criteria:

* Treatment of the qualifying episode of CDI with metronidazole monotherapy or intravenous immunoglobulins.
* Planned treatment with or treatment of the qualifying episode of CDI with fecal microbiota transplantation (FMT), bezlotoxumab, VOWST, or REBYOTA.
* Inability to take medications orally or crushed by nasogastric tube.
* Prior total colectomy.
* Severe intolerance or allergy to oral vancomycin.
* Lack of achievement of clinical cure during the treatment of the qualifying CDI episode
* Ongoing or \<1 day since receiving CDI treatment or ongoing or \<1 days since receipt of CDI-active antibiotics, including oral vancomycin, oral or intravenous metronidazole, or fidaxomicin.
* The qualifying antibiotic is solely for prophylaxis (e.g., once daily trimethoprim sulfamethoxazole) or the patient is anticipated to require systemic antibiotics for \>4 weeks (e.g., lifelong suppressive therapy or for the treatment of left-sided endocarditis or a deep-seated abscess).
* Patients on ongoing systemic antibiotics since the completion of treatment for the qualifying episode of CDI that have not been interrupted by at least one day.
* Patients admitted to a palliative care ward or is anticipated to die within 3 months of enrollment from another illness.
* The qualifying antibiotic is non-systemic or is not considered a significant risk factor for CDI including: topical antibiotics, azithromycin, clarithromycin, nitrofurantoin, intravenous vancomycin, minocycline, tetracycline, doxycycline, and oral fosfomycin.
* Prior enrollment in this trial.
* Inability to consent without a healthcare proxy.
* Lack of health insurance.
* Anticipated transfer to a site not involved in this trial or to a palliative care ward.
* Patient declared anticipated inability to participate in study follow-up or lack of means for contact in the outpatient setting.

Primary outcomes:
measure: CDI Recurrence
timeFrame: 56 Days
Secondary outcomes:
measure: Late CDI Recurrence
timeFrame: 90 Days
measure: All-Cause Mortality
timeFrame: 90 Days
measure: Discontinuation of the Study Drug Due to Adverse Event
timeFrame: 56 Days
measure: Emergency Room Visits or Hospital Admissions
timeFrame: 90 Days
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
Study officials:
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Todd C. Lee, MD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Connor J. Prosty, MD
role: PRINCIPAL_INVESTIGATOR
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