Clostridioides Difficile InfectionPhase 2/3SPORES-VNCT06979609
Secondary Prevention of Clostridioides Difficile Using Vancomycin
A Phase 2/3 study testing Oral Vancomycin Prophylaxis in people with Clostridioides Difficile Infection and Clostridioides Difficile Infection Recurrence, run by McGill University Health Centre/Research Institute of the McGill University Health Centre at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Clostridioides Difficile Infection, Clostridioides Difficile Infection Recurrence, Clostridoides Difficile Associated Disease
- What is being tested?
- Oral Vancomycin Prophylaxis
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 300 participants
- Where
- 1 siteCanada
- Study dates
- 1 Nov 2025to 1 Oct 2029
- Phase
- Phase 2/3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 hours with a duration >24 hours, endoscopic/histologic evidence of pseudomembranous colitis, or ileus.
- Treatment of the qualifying CDI episode with vancomycin or fidaxomicin for ≥10 days, and achievement of clinical cure (≤3 unformed stool per 24 hours in ≥2 days10).
- Receipt of ≤3 days of at least one oral or intravenous systemic antibiotic, for which therapy is planned for at least one additional consecutive day in duration.
- Clinical Exclusion Criteria
- ≥72 hours of off-study vancomycin prophylaxis for the current episode of antibiotic re-exposure.
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- ≤1 day elapsed since discontinuation of CDI treatment
- 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, REBYOTA, or another microbiome agent.
- Inability to take medications orally.
- Ileostomy, colostomy, or total colectomy with ileorectal anastomosis.
- Severe intolerance or allergy to oral vancomycin.
- Lack of achievement of clinical cure during the treatment of the qualifying CDI episode
- 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 who are anticipated to die within 8 weeks of enrollment from another illness.
- The qualifying antibiotic is non-systemic (i.e., topical) or is not considered a significant risk factor for CDI including: single-dose antibiotics, as well as macrolides, nitrofurantoin, intravenous vancomycin, metronidazole, tetracyclines, and oral fosfomycin. If two or more systemic antibiotics are given (i.e., ceftriaxone and azithromycin), as long as at least one of the systemic antibiotics does not meet exclusion criteria, then the patient will still be eligible.
- Concomitant receipt of rifaximin (e.g., for hepatic encephalopathy).
- Receipt of ≥2 courses of vancomycin prophylaxis since the qualifying episode of CDI or <2 weeks since the last course of vancomycin prophylaxis.
- Treating team declined participation.
- Administrative Exclusion Criteria
- Prior enrollment in this trial.
- Inability to consent and 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.
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
McGill University Health Centre
Montreal, Quebec, H4A3J1
Emily G. McDonald, MD MSc, 514 934-1934 ext. x53333, cdi@idtrials.ca
About this study
Official title: Secondary Prophylaxis of Recurrent Clostridioides Difficile Infections During Systemic Antibiotics With Vancomycin: A Randomized Controlled Trial
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:
- Does oral vancomycin prophylaxis prevent CDI recurrences in patients with recent CDI (within 120 days) and who are re-exposed to systemic antibiotics?
Read more
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 or over the phone follow-up at day 56
- Respond to weekly electronic questionnaires
Read the 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, the investigators 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.
- Conditions
- Clostridioides Difficile Infection, Clostridioides Difficile Infection Recurrence, Clostridoides Difficile Associated Disease
- Being tested
- Oral Vancomycin Prophylaxis, Placebo
- Keywords
- Clostridioides difficile, Clostridium difficile, Vancomycin, Prophylaxis, C. difficile, Recurrence, CDI
- Medical subject headings
- Clostridium Infections, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oral Vancomycin ProphylaxisDrug
125mg PO BID for the duration of antibiotic re-exposure + 125mg PO QD for 7 days
PlaceboDrug
2 capsules PO BID for the duration of antibiotic re-exposure + 1 capsule PO QD x 7 days
| Study group | Role | What they receive |
|---|---|---|
| Oral Vancomycin Prophylaxis | Experimental | Vancomycin 125mg PO BID for the duration of antibiotic re-exposure + 125mg PO QD for 7 days Receives: Drug: Oral Vancomycin Prophylaxis |
| Placebo | Placebo comparator | 2 capsules PO BID for the duration of antibiotic re-exposure + 1 capsule PO QD for 7 days Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
CDI Recurrence
Patients reporting diarrhea will be brought in for an in-person appointment that is standard of care for patients with potential rCDI and investigated as appropriate clinically without unblinding. Additionally, patients and/or their proxy will be instructed to contact the study team if they believe they are having a recurrence between contacts. Patients will be able to come be assessed for potential recurrence by infectious diseases physicians at each site (who may or may not be a part of the study) or could see their usual doctors. Recurrence will be assessed by clinical record review (chart, laboratory, pharmacy records) and any direct patient interview.
CDI recurrence will be defined by 1) three or more unformed stools in a 24-hour period, 2) a positive PCR for toxin gene or and/or 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 the NEJM fidaxomicin trial.
Measured: 56 Days
Secondary outcomes (5)
Late CDI Recurrence
As per the primary outcome.
Measured: 120 Days
All-Cause Mortality
Patients present for their day 56 in-person follow-up are considered alive. Those responding to weekly/bi-weekly surveys (text/email/phone) are considered alive at the response time. If a patient misses the day 56 follow-up, the investigators will review their hospital file for death. If unclear, the investigators will contact the patient or proxy by phone. If unreachable and unresponsive to surveys, the investigators will check obituaries.
After day 56, survey responses confirm vital status. If there is no response to the day 120 survey by day 125, the investigators will review the hospital file, check obituaries, and then attempt phone contact with the patient or proxy. If unsuccessful, the investigators will send a registered letter. Without a response, the patient will be recorded as lost to follow-up.
Measured: At 56 and 120 days
Discontinuation of the Study Drug Due to Adverse Event
During the in-person visit on Day 56 the investigators will inquire about adherence to the study drug and completion of the prescribed course. If the course was not completed, the investigators will inquire as to the reason why. Patients reporting cessation of the study drug due to an adverse event will be recorded as such.
Measured: 56 Days
Emergency Room Visits or Hospital Admissions
Within 120 days the investigators will look in the chart and the patient email/text surveys for the first episode of each of emergency room visit and/or hospital admission and record the date. Patient charts will also be flagged for immediate review should they visit the emergency room or be admitted to study centres. With explicit written patient consent, medical records from outside hospitals will be also requested for review if they report presenting elsewhere.
Measured: At 56 and 120 days
Adverse Events
Serious events will be reviewed and classified by the site PIs. Severity will be classified according to the Common Terminology Criteria for Adverse Events (CTCAE)49. The relationship between the event and study drug and whether or not the event is expected will be assessed from the product monograph (blinded to assignment).
Any events that are unexpected (in terms of severity or frequency), that can reasonably be attributed to the drug under study and that may expose other subjects to harm will be reported.
Measured: 56 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 May 2025
- Study start1 Nov 2025
- Primary completion1 Oct 2028 (estimated)
- Study completion1 Oct 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (20)Papers the sponsor has linked to this study.
- Other trials for Clostridioides Difficile InfectionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 300 participants (estimated)
Sponsor and investigators
- Lead sponsor
- McGill University Health Centre/Research Institute of the McGill University Health Centre
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Emily McDonald, McGill University Health Centre/Research Institute of the McGill University Health Centre
- Investigators
- Todd C. Lee, MD MPH, Principal investigator, McGill University Health Centre/Research Institute of the McGill University Health CentreConnor J. Prosty, MD, Principal investigator, McGill University Health Centre/Research Institute of the McGill University Health Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06979609
- Sponsor's protocol ID
- 2025-11089
- Other IDs
- 2025
- Acronym
- SPORES-V
- Status last verified
- Jun 2026
- First submitted
- 13 May 2025
- Last updated
- 24 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
van Prehn J, Reigadas E, Vogelzang EH, Bouza E, Hristea A, Guery B, Krutova M, Noren T, Allerberger F, Coia JE, Goorhuis A, van Rossen TM, Ooijevaar RE, Burns K, Scharvik Olesen BR, Tschudin-Sutter S, Wilcox MH, Vehreschild MJGT, Fitzpatrick F, Kuijper EJ; Guideline Committee of the European Study Group on Clostridioides difficile. European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin Microbiol Infect. 2021 Dec;27 Suppl 2:S1-S21. doi: 10.1016/j.cmi.2021.09.038. Epub 2021 Oct 20.
PubMed 34678515Johnson S, Lavergne V, Skinner AM, Gonzales-Luna AJ, Garey KW, Kelly CP, Wilcox MH. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis. 2021 Sep 7;73(5):e1029-e1044. doi: 10.1093/cid/ciab549.
PubMed 34164674McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66(7):987-994. doi: 10.1093/cid/ciy149.
PubMed 29562266Kelly CR, Fischer M, Allegretti JR, LaPlante K, Stewart DB, Limketkai BN, Stollman NH. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Am J Gastroenterol. 2021 Jun 1;116(6):1124-1147. doi: 10.14309/ajg.0000000000001278.
PubMed 34003176San-Juan R, Origuen J, Campion K, Fernandez-Ruiz M, Diaz-Pollan B, Callejas-Diaz A, Candela G, Orellana MA, Lora D, Llorente Munoz I, Garcia MT, Martinez-Una M, Ferrari JM, Aguado JM. Evaluation of the effectiveness and safety of oral vancomycin versus placebo in the prevention of recurrence of Clostridioides difficile infection in patients under systemic antibiotic therapy: a phase III, randomised, double-blind clinical trial. BMJ Open. 2023 Sep 13;13(9):e072121. doi: 10.1136/bmjopen-2023-072121.
PubMed 37709311Maraolo AE, Mazzitelli M, Zappulo E, Scotto R, Granata G, Andini R, Durante-Mangoni E, Petrosillo N, Gentile I. Oral Vancomycin Prophylaxis for Primary and Secondary Prevention of Clostridioides difficile Infection in Patients Treated with Systemic Antibiotic Therapy: A Systematic Review, Meta-Analysis and Trial Sequential Analysis. Antibiotics (Basel). 2022 Jan 30;11(2):183. doi: 10.3390/antibiotics11020183.
PubMed 35203786Johnson SW, Brown SV, Priest DH. Effectiveness of Oral Vancomycin for Prevention of Healthcare Facility-Onset Clostridioides difficile Infection in Targeted Patients During Systemic Antibiotic Exposure. Clin Infect Dis. 2020 Aug 22;71(5):1133-1139. doi: 10.1093/cid/ciz966.
PubMed 31560051McDonald EG, Prosty C, Hanula R, Bortolussi-Courval E, Albuquerque AM, Tong SYC, Hamilton F, Lee TC. Observational versus randomized controlled trials to inform antibiotic treatment durations: a narrative review. Clin Microbiol Infect. 2023 Feb;29(2):165-170. doi: 10.1016/j.cmi.2022.09.002. Epub 2022 Sep 13.
PubMed 36108947Connor KA, Conn KM. Analysis of the impact of secondary prophylaxis on Clostridioides difficile recurrence in critically ill adults. SAGE Open Med. 2020 Jun 12;8:2050312120930898. doi: 10.1177/2050312120930898. eCollection 2020.
PubMed 32587690Caroff DA, Menchaca JT, Zhang Z, Rhee C, Calderwood MS, Kubiak DW, Yokoe DS, Klompas M. Oral vancomycin prophylaxis during systemic antibiotic exposure to prevent Clostridiodes difficile infection relapses. Infect Control Hosp Epidemiol. 2019 Jun;40(6):662-667. doi: 10.1017/ice.2019.88. Epub 2019 Apr 29.
PubMed 31030679Najjar-Debbiny R, Barnett-Griness O, Arbel A, Cohen S, Weber G, Amar M, Yassin R, Greenfeld I, Shehadeh S, Saliba W. Secondary prophylaxis for Clostridioides difficile infection for patients on non-C. difficile antibiotics: a retrospective cohort study. Microbes Infect. 2024 Jul-Aug;26(5-6):105349. doi: 10.1016/j.micinf.2024.105349. Epub 2024 May 6.
PubMed 38719086Van Hise NW, Bryant AM, Hennessey EK, Crannage AJ, Khoury JA, Manian FA. Efficacy of Oral Vancomycin in Preventing Recurrent Clostridium difficile Infection in Patients Treated With Systemic Antimicrobial Agents. Clin Infect Dis. 2016 Sep 1;63(5):651-3. doi: 10.1093/cid/ciw401. Epub 2016 Jun 17.
PubMed 27318333Carignan A, Poulin S, Martin P, Labbe AC, Valiquette L, Al-Bachari H, Montpetit LP, Pepin J. Efficacy of Secondary Prophylaxis With Vancomycin for Preventing Recurrent Clostridium difficile Infections. Am J Gastroenterol. 2016 Dec;111(12):1834-1840. doi: 10.1038/ajg.2016.417. Epub 2016 Sep 13.
PubMed 27619835Abujamel T, Cadnum JL, Jury LA, Sunkesula VC, Kundrapu S, Jump RL, Stintzi AC, Donskey CJ. Defining the vulnerable period for re-establishment of Clostridium difficile colonization after treatment of C. difficile infection with oral vancomycin or metronidazole. PLoS One. 2013 Oct 2;8(10):e76269. doi: 10.1371/journal.pone.0076269. eCollection 2013.
PubMed 24098459Seekatz AM, Rao K, Santhosh K, Young VB; New Collective Author. Dynamics of the fecal microbiome in patients with recurrent and nonrecurrent Clostridium difficile infection. Genome Med. 2016 Apr 27;8(1):47. doi: 10.1186/s13073-016-0298-8.
PubMed 27121861