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

Abstract

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.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13063-026-09883-1.

Introduction

Clostridioides difficile is a gram-positive spore-forming anaerobic bacterium that can cause severe diarrhea through toxin-mediated colitis. Over 500,000 cases of C. difficile infections (CDI) occur annually in North America, with over 20,000 (~ 4%) associated deaths [1, 2]. CDI is associated with annual economic losses of $5 billion in North America [2, 3]. Despite appropriate treatment, 20–30% of CDI cases recur [1, 4, 5]. Recurrent CDI (rCDI) is associated with a higher risk of death and attributable costs than index episodes [2, 6, 7].

Multiple therapies exist to prevent and treat rCDI, but they each have important drawbacks [8]. Fidaxomicin is equally effective as vancomycin as CDI therapy [9] and its use is associated with a ~ 10% lower risk of rCDI relative to vancomycin for first episodes or first recurrences [10], but cost prohibits its widespread use [11]. Bezlotoxumab, a monoclonal antibody targeting toxin B, was recently withdrawn from market [12]. Fecal microbiota transplantation (FMT) [13] is limited by cost [14], lack of standardization, inaccessibility, a risk of transmitting pathogenic organisms [15], and is only recommended for multiply recurrent CDI [16]. Newer microbiome therapeutics, such as SER-109 [17] and RBX2660 [18], also reduce risk of rCDI, but their use is limited by cost and inaccessibility. Therefore, strategies to prevent rCDI represent a substantially unmet clinical need.

The pathogenesis of rCDI begins with persistent C. difficile colonization [19] in a patient who recently completed treatment for CDI with an already vulnerable microbiome [20] that can be further disrupted by re-exposure to antibiotics [5]. In a study of 18,246 index cases of CDI, 42.4% were re-exposed to antibiotics within 56 days of CDI treatment; antibiotic re-exposure was the strongest independent risk factor for rCDI (adjusted odds ratio [aOR] = 3.2) [21].

Vancomycin prophylaxis during antibiotic re-exposure is a potential strategy to reduce rCDI through the inhibition of vegetative spores [22]. Observational evidence suggests that secondary vancomycin prophylaxis may reduce rCDI [23–25]. Indeed, vancomycin prophylaxis was associated with a reduced odds of rCDI (OR = 0.41, 95% confidence interval [95%CI] = 0.20–0.87) in our systematic review of 8 observational studies, encompassing 2156 patients [25]. However, the estimates were heterogeneous (I2 = 69.5%) and all the included studies were at high risk of bias due to confounding by indication, as well as immortal time, ascertainment, and performance biases [25]. An RCT of vancomycin as primary CDI prophylaxis for patients receiving systemic antibiotics demonstrated benefit in the prevention of healthcare-onset CDI (6/50 [12.0%] vs. 0/50 [0%], P = 0.03) [26]. Results of this trial are limited by its small sample size, open-label design, which may have led to ascertainment bias, and a very high loss to follow-up (> 50%) [26]. Two small placebo-controlled trials of secondary vancomycin prophylaxis have been published, but both were stopped early and did not meet their target sample sizes [27, 28]. In Keating et al., there was a risk difference of − 13.5% (95%CI = − 35.1, 8.0, P = 0.22, N = 81) for 56-day rCDI [27]. For San-Juan et al., there was a risk difference of − 28.6% (95%CI = − 69.6, 12.4, P = 0.30, N = 21) [28]. Therefore, both were insufficiently powered to confirm or refute a benefit of vancomycin prophylaxis.

Whereas the American College of Gastroenterology [29] and the Association of Medical Microbiology and Infectious Disease (AMMI) Canada [30] recommend consideration of secondary vancomycin prophylaxis in select cases, the Infectious Disease Society of America and Society for Healthcare Epidemiology of America (IDSA-SHEA) [31] refrains from making a recommendation, and the European Society of Clinical Microbiology and Infectious Diseases [16] discourages routine prophylaxis. Our recent international clinician survey found substantial geographic differences in secondary vancomycin prophylaxis use, with significantly higher ever-use in North America than Europe (84.1% vs. 31.0%) [32]. Irrespective of prophylaxis use, 83.8% of respondents supported a placebo-controlled RCT of secondary vancomycin prophylaxis [32]. Although there is significant uptake of secondary vancomycin prophylaxis into clinical practice in some jurisdictions, this uptake has been predominantly driven by low-quality observational evidence and compatible in vitro findings [25]. Numerous examples exist of RCTs overturning practices established on such low-quality evidence, a phenomenon termed medical reversal [33, 34].

Heterogeneous, low-quality observational data, underpowered RCT data, conflicting international guidelines, and varied clinician practices on secondary vancomycin prophylaxis during antibiotic re-exposure support equipoise for an RCT. To definitively address whether vancomycin prophylaxis is efficacious in the prevention of rCDI, we propose the Secondary Prophylaxis of Recurrent Clostridioides difficile Infections During Systemic Antibiotics with Vancomycin (SPORES-V) placebo-controlled double-blind RCT.

Methods

Hypothesis

We hypothesize that vancomycin prophylaxis is an efficacious means to prevent rCDI in patients who are re-exposed to systemic antibiotics.

Trial design

We propose a placebo-controlled double-blind parallel group Bayesian adaptive RCT designed for superiority (Fig. 1). A Bayesian design was selected because it allows for flexible stopping criteria, incorporation of prior information, and a nuanced probabilistic interpretation of the results [35]. The protocol was written in accordance with guidance from Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT, Supplemental File 1) [36]. The trial will be conducted in accordance with the Declaration of Helsinki [37] and Good Clinical Practice. A patient partner (S. Reinblatt) was involved in the design of the trial. SPORES-V is embedded within a platform trial called Strategies for the Treatment Of and Prevention of C. difficile Infection (STOP-CDI), which has an ongoing treatment domain (TAPER-V2, NCT07328971).

Fig. 1.

Trial schematic

Study setting

The Research Institute of the McGill University Health Centre will act as the study sponsor and coordinating center. Patients will be recruited from 27 sites across 6 provinces (Table 1) with the option to add additional sites in the future.

Table 1.

Study sites

Centre	Number of sites	City, province
Memorial University of Newfoundland	1	St. John’s, Newfoundland and Labrador
Cape Breton Regional Hospital	1	Sydney, Nova Scotia
Centre hospitalier universitaire de Sherbrooke	2	Sherbrooke, Quebec
McGill University Health Centre	2	Montreal, Quebec
Jewish General Hospital	1	Montreal, Quebec
University of Ottawa	2	Ottawa, Ontario
Queen’s University	2	Kingston, Ontario
University Health Network	7	Toronto, Ontario
Sunnybrook Hospital	1	Toronto, Ontario
McMaster University	2	St. Catharines, Ontario
University of Manitoba	3	Winnipeg, Manitoba
University of British Columbia	2	Vancouver, British Columbia
East Kootenay Regional Hospital	1	Cranbrook, British Columbia
Total	27

Eligibility criteria

Eligible patients will be adults treated for CDI within the preceding 120 days, who experienced clinical cure (≤ 3 unformed stools per 24 h in ≥ 2 days [10]), and, subsequently, have received ≤ 3 days of a systemic antibiotic for which therapy is planned for at least one additional consecutive day. A timeframe of 120 days from diagnosis of CDI was selected because it aligns with prior observational studies of secondary vancomycin prophylaxis [23, 24] and with the natural history of C. difficile colonization after infection [38]. Exclusion criteria include receipt of ≥ 72 h of vancomycin prophylaxis, inability to take medications by mouth, planned or prior treatment with a microbiome agent (i.e., SER-109, FMT), allergy or intolerance to vancomycin, < 1 day since cessation of CDI therapy, and systemic antibiotics planned for > 28 days. More detailed inclusion and exclusion criteria are presented in Table 2.

Table 2.

Study inclusion and exclusion criteria

Inclusion criteria

Exclusion criteria

● Inpatient or outpatient adults (≥ 18 years old) treated at the participating institutions ● An episode of CDI within the preceding 120 days, diagnosed by both a positive C. difficile assay (including PCR toxin gene detection, toxin enzyme immunoassay, and/or cell cytotoxicity neutralization assay) and the presence of either ≥ 3 unformed stools in < 24 h with a duration > 24 h, endoscopic/histologic evidence of pseudomembranous colitis, or ileus ● Treatment of the qualifying CDI episode with vancomycin or fidaxomicin for ≥ 10 days, clinical cure (≤ 3 unformed stool per 24 h in ≥ 2 days) 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

● ≥ 72 h of off-study oral vancomycin prophylaxis ● 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 FMT, bezlotoxumab, VOWST, REBYOTA, or other microbiome therapeutic ● Inability to take medications orally ● Ileostomy, colostomy, or total colectomy with ileorectal anastomosis ● Severe intolerance or allergy to oral vancomycin ● 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) ● Concomitant receipt of rifaximin ● Treating team declined participation ● Receipt of ≥ 2 courses of vancomycin prophylaxis since the qualifying episode of CDI or < 2 weeks since the last course of vancomycin prophylaxis ● Ongoing systemic antibiotics since the completion of treatment of the qualifying episode of CDI ● Patients admitted to a palliative care ward or is anticipated to die within 8 weeks of enrollment from another illness ● The qualifying antibiotic is non-systemic or is not considered a significant risk factor for CDI including: topical or single-dose antibiotics, macrolides, tetracyclines, nitrofurantoin, intravenous vancomycin, and oral fosfomycin ● Prior enrollment in this trial ● Inability to consent without a healthcare proxy ● Lack of provincial health insurance ● Anticipated transfer to a non-study hospital 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

Recruitment

The study team will be notified by the microbiology lab of any positive tests for C. difficile through email, fax, electronic means, or phone based on local practice. With the approval of the treating team, these patients will be approached and pre-consented for the RCT in case they subsequently have antibiotic re-exposure (Supplemental File 2). These patients, or a member of their clinical team, will then contact the study team if they are re-exposed to systemic antibiotics and have their eligibility and consent confirmed at that time (Supplemental File 2). Additionally, lists of patients receiving systemic antibiotics in hospital will be cross referenced for CDI within the preceding 120 days and eligible patients will be approached for informed consent by a member of the study team with the permission of the treating teams. The research assistant will then enroll and randomize the patient.

Randomization, allocation, and blinding

Randomization will be performed 1:1 centrally at the McGill University Health Centre using the Research Electronic Data Capture database [39]. The day of randomization will be considered as study day 0. Randomization will be stratified by the following factors that are anticipated to impact the risk of recurrence [10, 21, 23]: (1) receipt of vancomycin or fidaxomicin for the qualifying episode of CDI, (2) inpatient or outpatient status, and (3) whether the qualifying episode was a recurrence or an index episode of CDI. The randomization table with randomly ordered permuted blocks of 4, 8, and 12 will be generated using Sealed Envelope by the lead author (CP) [40], who has no role in recruiting patients.

Patients, study investigators, study coordinators, the treating team, consultants, and analysts will be blinded to allocation. Only the research pharmacist dispensing the medication, who will be uninvolved in outcome assessment, will be aware of treatment assignment. Emergency unblinding can be performed at the discretion of the principal investigator.

Study interventions

Participants randomized to the intervention will receive vancomycin 125 mg orally twice daily for the duration of systemic antibiotics plus an additional 125 mg daily for 7 days. This dose and duration align with observational studies of vancomycin prophylaxis [41–43] and the AMMI Canada guidelines [30]. Prophylaxis dosed according to the duration of systemic antibiotics was associated with less rCDI in a large observational study [23]. Halving the dose after cessation of systemic antibiotics was selected to replicate a pulse and taper regimen where there is theoretical benefit of microbiome reconstitution (TAPER-V) [44]. Participants randomized to the control group will receive a placebo according to the same dosing schedule. The same placebo was used in TAPER-V and patients were unable to distinguish it from vancomycin in surveys [44]. A placebo was used to minimize ascertainment and performance biases from knowledge of treatment assignment, which could influence CDI testing (e.g., polymerase chain reaction [PCR] [45]) and co-interventions (e.g., systemic antibiotic choice or duration), respectively. The study drug will be administered for a maximum of 35 days, which corresponds to the upper limit of duration in the observational studies of vancomycin prophylaxis [41, 43] and covers the period at highest risk of CDI after antibiotic exposure [46]. Off-study use of C. difficile-active antibiotics (e.g., metronidazole) will be discouraged, but not prohibited.

Endpoints

The primary outcome will be CDI recurrence by day 56. Patients reporting diarrhoea will be assessed in person and investigated as appropriate without unblinding. A CDI recurrence is defined by the presence of all three of the following: (1) three or more unformed stools in a 24-h period or ileus, toxic megacolon, or pseudomembranous colitis on colonoscopy; (2) a positive PCR for toxin gene [45], detection of toxin by enzyme immunoassay, or cell cytotoxicity neutralization assay; and (3) administration of CDI treatment. This is similar to the definition used in a trial of fidaxomicin [10] and is consistent with the IDSA-SHEA definition of rCDI [31, 47]. The 56-day cut-off corresponds to the IDSA-SHEA timeframe for rCDI [47] and captures the highest risk period for CDI after antibiotic exposure [46], and most recurrences in observational studies of vancomycin prophylaxis occurred within this timeframe [23]. The secondary outcomes will include all-cause emergency room visits or hospitalization at days 56 and 120, discontinuation of the study drug due to toxicity at day 56, adverse events at day 56, rCDI at day 120 to capture later recurrences [23, 26], and all-cause mortality at days 56 and 120. Quality of life will be measured as an exploratory outcome on days 0 and 56 using the EQ-5D-5L [48] Canadian Value Set questionnaires. All data will be stored securely in REDCap.

Follow-up

Surveys querying on the primary and secondary endpoints will be administered by text, email, or phone call weekly until day 56 and biweekly to day 120. Participants who report experiencing rCDI will be assessed in person. Otherwise, an in-person or over the phone follow-up will be conducted on day 56. At the 56-day follow-up, rCDI, safety, discontinuation due to toxicity, and study drug adherence will be assessed from direct history and electronic medical records. Adverse events will be assessed by a structured questionnaire and graded according to the common terminology criteria for adverse events version 6.0 [49]. Adherence will be measured by pill counting at the 56-day follow-up. A schedule of the study visits is presented in Table 3.

Table 3.

Timeline of study participation

	Trial period
	Enrollment		Post-randomization		Close-out
Timepoint	−3 to 0	0	Cessation of Systemic Antibiotics + 7 days	56	120
Enrollment
Eligibility screen	X
Informed consent	X
Randomization		X
Intervention/comparator
Vancomycin		X	X
Placebo		X	X
Assessments
Demographic and clinical data		X
Quality of life (EQ-5D-5L)		X		X
CDI recurrence and survival			X (assessed by weekly surveys)	X (assessed by in person or phone visit)	X (assessed by biweekly surveys)
Adverse events				X
Healthcare usage				X	X

Sample size and interim analyses

Among patients with CDI within the previous 120 days and subsequently re-exposed to antibiotics, we expect the rate of CDI recurrence to be 30% (modeled 27.5–32.5%) based on prior studies of antibiotic re-exposure [5, 21, 23]. This estimate is higher than the typical recurrence rate of CDI (~ 25%) [1, 4, 5] because antibiotic re-exposure is an independent risk factor for rCDI and re-exposed patients are more likely to be older and multi-comorbid, which are additional risk factors for rCDI [21].

We used a robust mixture prior approach for sample size calculations [50], which enables the incorporation of prior evidence while maintaining conservative boundaries. The prior equally combines together both a vague and an informative prior. The vague prior is centered at OR = 1 with a 95% credible interval (95%CrI) of 0.125 to 8.0. The informative prior is derived from the 95% predictive interval (95%PI) of our Bayesian meta-analysis of the San-Juan et al. [28] and Keating et al. [27] trials (unpublished), with OR = 0.6 and 95%PI = 0.19–2.00. The vague component of the prior protects against overreliance on the informative component of the prior and ensures that, in the event of conflicting signals, SPORES-V’s results can supersede the informative prior.

The target sample size will be 500 patients with interim analyses at 125 and 250 patients. The pre-specified stopping boundaries for superiority (OR < 1) will be ≥ 99%, ≥ 97.5%, and ≥ 97.5% at 125, 250, and 500 patients recruited, respectively. Futility will be declared at any of the interim or final analyses if the probability of a risk difference ≤ 2.5% falls below 10%. Using these parameters and a 100,000-iteration Monte Carlo simulation, the average sample size of this design is 321 patients. The simulated type I error is 5.2%. The conditional power is 71.8% for an effect size matching the informative prior (OR = 0.60) and exceeds 80% for any absolute risk reduction of greater than 10%.

We estimate that over 1000 cases of CDI will be diagnosed at the participating sites annually (Table 1), re-exposure to systemic antibiotics will occur among 40% within 120 days [21], 20% ineligibility or death prior to eligibility [5], and 50% recruitment of eligible patients based on our recent CDI trial [44]. Therefore, we will ideally recruit ~ 160 patients per year once all sites are operational (Fig. 2).

Fig. 2.

Simulated study power as a function of risk difference with (blue) and without (grey) the informative prior

Statistical analysis

A modified intention-to-treat (mITT) analysis of patients who received ≥ 1 dose of study drug will be used for the primary outcome. A per-protocol analysis of patients who completed the course of study drug as prescribed, except when stopped due to recurrence, will also be conducted. The primary and secondary outcomes will be compared as a function of treatment assignment using Bayesian logistic regression, with a Bernoulli likelihood, and reported as an adjusted odds ratio (aOR) [51]. For the primary outcome, we will use Bayesian model averaging with the robust mixture prior [50]. This approach upweights the informative component of the prior when it aligns with the observed data and downweights it when there is discordance. The effective sample size of the prior under maximally informative conditions is 53 patients.

We will also conduct a secondary analysis treating rCDI and all-cause mortality as time-to-event variables using adjusted hazard ratios (aHR). All analyses will be adjusted for age and stratification factors. Analyses will be conducted by a statistician specializing in Bayesian statistics who is blinded to treatment assignment. Current recommendations for Bayesian workflow will be followed [52] and modeling choices will be reported according to the Bayesian Analysis Reporting Guidelines [35].

Subgroup analyses

Pre-specified subgroup analyses will be conducted based on (1) whether the qualifying episode was a first episode of CDI vs. a recurrence [23], (2) patients who received fidaxomicin versus vancomycin for the qualifying episode of CDI [25], (3) age (< 75 vs. ≥ 75 years), (4) biologic sex, (5) inpatient vs. outpatient status, (6) oral vs. intravenous systemic antibiotics, (7) time since the qualifying episode of CDI (≤ 60 vs. > 60 days), and (8) high- (defined as beta-lactam beta-lactamase inhibitors, third- or fourth-generation cephalosporins, carbapenems, fluroquinolones, and clindamycin) vs. low-risk systemic antibiotics for rCDI.

Missing data

We will consider two approaches for missing primary outcome data, with the final choice made with the biostatistician [53, 54]. First, we may exclude participants with missing data if < 3% of participants are missing data, noting potential bias and loss of power. Second, we may use multiple imputation based on age, sex, study arm, CDI episode, and comorbidities. Secondary outcomes will be analyzed using complete cases.

Study monitoring

The trial steering committee (TSC) will consist of Drs. McDonald, Lee, and Prosty along with other members to be named from other sites. The TSC will act as an executive body providing overall supervision of the trial and will meet regularly to review study progress, new publications in the area, as well as reports from the data safety and monitoring committee (DSMC). The DSMC will be independent of the study team and will consist of one expert consultant in infectious diseases, one biostatistician, and one clinical trialist. They will meet to review the preplanned interim analyses and reported adverse events from the trial to date and make recommendations to the TSC as appropriate.

Ethics and dissemination

This trial is registered on clinicaltrials.gov (NCT06979609). A no objection letter was obtained from Health Canada (Control number: 289540) and the protocol was approved by the McGill University Health Centre Research Ethics Board (2025–11089). Protocol amendments will be submitted for approval and subsequently reported in the final study publication as well as on clinicaltrials.gov. Results of this study, regardless of whether target enrollment is obtained, will be disseminated by publication. Contributors that meet ICJME criteria will be included as authors. Requests for anonymized datasets will be granted within reason.

Trial status

The trial began vanguard recruitment at the McGill University Health Centre site on October 23, 2025, under protocol version 1.4. Recruitment is expected to complete in 2028. Any amendments to the trial will be approved by Health Canada and the MUHC REB and communicated on clinicaltrials.gov.

Additional outcomes

Secondary studies on the gut microbiome, vancomycin-resistant Enterococcus (VRE) colonization, and C. difficile colonization will be conducted if funding is secured. Fecal samples will be obtained using Bunny Wipes on days 0 and 56, and at the time of rCDI [55]. The samples will be biobanked and the DNA will then be extracted. Shotgun metagenomic sequencing will then be performed to evaluate the taxonomic composition of the microbiome, which will be compared within participants at day 0 vs. 56 and at day 56 across treatment groups [10]. A validated PCR for the vanA/vanB genes will be performed to detect new VRE colonization (i.e., VRE detected at day 56 but not 0) [56]. C. difficile colonization status at days 0 and 56 will be determined by a validated PCR for the tcdB gene [57].

Discussion

Observational studies [25] and RCTs of primary and secondary vancomycin prophylaxis [26–28] support the potential role for vancomycin as secondary C. difficile prophylaxis during antibiotic re-exposure. SPORES-V will address the lack of high-quality evidence in this space.

This trial will leverage the established multicenter network, which includes both academic and community centers, used for the TAPER-V trial of a 28-day vancomycin pulse and taper vs. 14 days of vancomycin for a first episode or first recurrence of CDI [44]. The proposed sample size will greatly exceed prior RCTs of primary [26] and secondary [27, 28] vancomycin prophylaxis. The double-blind design will reduce the ascertainment bias, especially in sites using PCR-based diagnostic algorithms [45]. Further, the flexible stopping criteria enable enrollment to cease once there is sufficient signal of benefit or futility, which enhances the trial’s efficiency and equitability. Nevertheless, this trial will be subject to certain limitations. The primary outcome at day 56 may not capture later recurrences especially in patients who receive the maximum 35 days of prophylaxis. However, they will likely be captured by the secondary outcome at 120 days, which will also help assess whether prophylaxis prevents or merely delays rCDI. The use of PCRs for the diagnosis of C. difficile may lead to overdiagnosis given that, in isolation, PCRs do not differentiate between colonization and infection, but with blinding this will not be differential between the two arms and our trial uses strict clinical criteria for the diagnosis of C. difficile [45]. The use of off-study C. difficile-active antibiotics (i.e., metronidazole, fidaxomicin) will be discouraged but not prohibited, but their use is unlikely to be differential between arms. Data on their use will also be collected and reported. Patients could be re-exposed to systemic antibiotics for longer than the maximum duration of prophylaxis, 35 days. However, this is expected to be very uncommon and non-differential given that patients receiving prophylactic antibiotics or who are anticipated to require long durations of antibiotics (i.e., for endocarditis) are excluded.

If prophylaxis is shown to be efficacious then numerous additional questions will need to be explored in future studies. First, whether fidaxomicin might be more efficacious than vancomycin in the prophylaxis setting. Second, if prophylaxis can be foregone in patients who are not colonized with C. difficile (i.e., by PCR) at the time of antibiotic re-exposure or in those who receive low-risk antibiotics [58]. Third, the optimal dose and duration of prophylaxis and the most suitable timeframe for prophylaxis after CDI.

Conclusion

Use of secondary vancomycin prophylaxis for the prevention of rCDI is a common practice in some jurisdictions [32] supported by low-quality observational studies [23, 25] and, more recently, two underpowered RCTs [27, 28]. This phase III placebo-controlled trial of secondary vancomycin prophylaxis for the prevention of rCDI aims to provide high-quality evidence and may prove vancomycin to be an inexpensive and safe prophylaxis strategy for this prevalent and morbid disease.

Trial status

The trial began recruiting at the McGill University Health Centre on October 23, 2025, under protocol number 1.4. It is anticipated that recruitment will be completed in 2028.

Abbreviations

aHR

Adjusted hazard ratio

aOR

Adjusted odds ratio

AMMI

Association of Medical Microbiology and Infectious Disease

CDI

Clostridioides difficile Infection

CI

Confidence interval

Cdiff32

Clostridioides difficile Health-Related Quality of Life Questionnaire

DSMC

Data safety and monitoring committee

FMT

Fecal microbiota transplantation

GCP

Good Clinical Practice

IDSA-SHEA

Infectious Disease Society of America and Society for Healthcare Epidemiology of America

ITT

Intention-to-treat

mITT

Modified intention-to-treat

MUHC

McGill University Health Centre

OR

Odds ratio

PCR

Polymerase chain reaction

RCT

Randomized controlled trial

REB

Research Ethics Board

rCDI

Recurrent Clostridioides difficile infection

SPIRIT

Standard Protocol Items: Recommendations for Interventional Trials

SPORES-V

Secondary Prophylaxis of Recurrent Clostridioides difficile Infections During Systemic Antibiotics with Vancomycin

TSC

Trial steering committee

VRE

Vancomycin-resistant Enterococcus

Authors’ contributions

CP, EGM, and TCL conceived of the study and wrote the manuscript. JB was the lead trial statistician. SR is a patient partner. The remaining authors contributed to the editing of the protocol. All authors read and approved the final manuscript.

Funding

C. Prosty receives graduate student funding from the Canadian Institutes of Health Research.

Data availability

Authors C. Prosty, E. McDonald, T. Lee, and J. Brophy will have access to the final trial dataset.

Declarations

Ethics approval and consent to participate

MUHC REB 2025–11089. Written informed consent to participate will be obtained from all participants.

Consent for publication

Not applicable. Model consent forms will be provided upon request.

Competing interests

The authors declare no competing interests.