Secondary Prevention of Clostridioides Difficile Using Vancomycin

NCT06979609 | Recruiting Phase 2 DMC

• 1 other identifier: 2025-11089
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 1

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 or over the phone follow-up at day 56
• Respond to weekly electronic questionnaires

Conditions

Clostridioides Difficile Infection; Clostridioides Difficile Infection Recurrence; Clostridoides Difficile Associated Disease

Keywords

Clostridioides difficile; Clostridium difficile; Vancomycin; Prophylaxis; C. difficile; Recurrence; CDI

Outcome Measures

Primary Outcomes (1)

• 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.

  56 Days

Secondary Outcomes (5)

• Late CDI Recurrence

  120 Days

• All-Cause Mortality

  At 56 and 120 days

• Discontinuation of the Study Drug Due to Adverse Event

  56 Days

• Emergency Room Visits or Hospital Admissions

  At 56 and 120 days

• Adverse Events

  56 days

Study Arms (2)

Oral Vancomycin Prophylaxis

EXPERIMENTAL

Vancomycin 125mg PO BID for the duration of antibiotic re-exposure + 125mg PO QD for 7 days

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

Drug: Placebo

Interventions

Oral Vancomycin Prophylaxis DRUG

125mg PO BID for the duration of antibiotic re-exposure + 125mg PO QD for 7 days

Oral Vancomycin Prophylaxis

Placebo DRUG

2 capsules PO BID for the duration of antibiotic re-exposure + 1 capsule PO QD x 7 days

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• ≥72 hours of off-study vancomycin prophylaxis for the current episode of antibiotic re-exposure.
• ≤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.
• 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.
• Prior enrollment in this trial.

Sponsors & Collaborators

• McGill University Health Centre/Research Institute of the McGill University Health Centre: lead

Study Sites (1)

McGill University Health Centre

Montreal, Quebec, H4A3J1, Canada

RECRUITING

Related Publications (19)

• 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.

  PMID: 34678515 BACKGROUND

• Johnson 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.

  PMID: 34164674 BACKGROUND

• McDonald 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.

  PMID: 29562266 BACKGROUND

• Kelly 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.

  PMID: 34003176 BACKGROUND

• San-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.

  PMID: 37709311 BACKGROUND

• Maraolo 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.

  PMID: 35203786 BACKGROUND

• Johnson 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.

  PMID: 31560051 BACKGROUND

• McDonald 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.

  PMID: 36108947 BACKGROUND

• Connor 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.

  PMID: 32587690 BACKGROUND

• Caroff 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.

  PMID: 31030679 BACKGROUND

• Najjar-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.

  PMID: 38719086 BACKGROUND

• Van 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.

  PMID: 27318333 BACKGROUND

• Carignan 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.

  PMID: 27619835 BACKGROUND

• Abujamel 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.

  PMID: 24098459 BACKGROUND

• Seekatz 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.

  PMID: 27121861 BACKGROUND

• Sethi AK, Al-Nassir WN, Nerandzic MM, Bobulsky GS, Donskey CJ. Persistence of skin contamination and environmental shedding of Clostridium difficile during and after treatment of C. difficile infection. Infect Control Hosp Epidemiol. 2010 Jan;31(1):21-7. doi: 10.1086/649016.

  PMID: 19929371 BACKGROUND

• Kimura T, Snijder R, Sugitani T. Characterization and risk factors for recurrence of Clostridioides (Clostridium) difficile infection in Japan: A nationwide real-world analysis using a large hospital-based administrative dataset. J Infect Chemother. 2019 Aug;25(8):615-620. doi: 10.1016/j.jiac.2019.03.011. Epub 2019 Apr 12.

  PMID: 30987950 BACKGROUND

• Zilberberg MD, Reske K, Olsen M, Yan Y, Dubberke ER. Risk factors for recurrent Clostridium difficile infection (CDI) hospitalization among hospitalized patients with an initial CDI episode: a retrospective cohort study. BMC Infect Dis. 2014 Jun 4;14:306. doi: 10.1186/1471-2334-14-306.

  PMID: 24898123 BACKGROUND

• Deshpande A, Pasupuleti V, Thota P, Pant C, Rolston DD, Hernandez AV, Donskey CJ, Fraser TG. Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2015 Apr;36(4):452-60. doi: 10.1017/ice.2014.88. Epub 2015 Jan 28.

  PMID: 25626326 BACKGROUND

MeSH Terms

Conditions

Clostridium Infections; Recurrence

Condition Hierarchy (Ancestors)

Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Todd C. Lee, MD MPH

  McGill University Health Centre/Research Institute of the McGill University Health Centre

  PRINCIPAL INVESTIGATOR

• Connor J. Prosty, MD

  McGill University Health Centre/Research Institute of the McGill University Health Centre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Emily G. McDonald, MD MSc

CONTACT

514-934-1934; cdi@idtrials.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of General Internal Medicine

Study Record Dates

• First Submitted: May 13, 2025
• First Posted: May 20, 2025
• Study Start: November 1, 2025
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2029
• Last Updated: June 24, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)