Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection

NCT04138706 | Completed Phase 3 DMC

• 1 other identifier: MP-37-2020-5986
• Study Type: interventional
• Target: 263
• Locations: 1 country
• Sites: 12

Brief Summary

The first line therapy for an initial episode of CDI (Clostridium difficile infection) is 10-14 days of oral vancomycin which is now recommended over metronidazole in the 2018 guidelines from the Association of Medical Microbiologists and Infectious Diseases of Canada (AMMI). Although response rates for the treatment of a first episode of CDI now approach 90%, approximately 25% of patients who have a complete response will develop recurrence (rCDI) within 8 weeks. Doctors' ability to predict recurrence is evolving, but remains very limited. The investigators hypothesize that by extending initial vancomycin therapy with a 2-week tapering regimen this will reduce the risk of rCDI. Starting at the end of the initial 14 days of therapy, participants will be randomized to receive an additional 14-days of placebo or vancomycin taper (125 mg orally twice daily x 7 days followed by 125 mg orally once daily x 7 days). This taper was chosen as it represents two steps of a commonly used 4-week vancomycin taper. The investigators' proposal to evaluate the extension of initial treatment from 14 to 28 days with a tapering dose of vancomycin represents a practical clinical trial that capitalizes on oral vancomycin's safety profile, worldwide availability, and relatively low cost.

Conditions

Clostridium Difficile Infection

Outcome Measures

Primary Outcomes (1)

• CDI recurrence

  Patients will be contacted via text message, email, or phone call weekly until day 56 to determine if they have had a recurrence. After day 56 this will be bi-weekly until day 90. Recurrence will be assessed by clinical record review (chart, laboratory, pharmacy records) and direct patient interview. Blinded case summaries will be reviewed in duplicate with disagreement resolved by consensus. CDI recurrence will be defined by three or more diarrheal stools/24-hour period coupled with a positive PCR for toxin gene or and/or detection of toxin by EIA or CCA and administration of treatment. However, to avoid missing severe recurrences: for cases of ileus, toxic megacolon, or pseudomembranous colitis on colonoscopy the test result will be used in the absence of three or more stools.

  Within 56 days of initial vancomycin treatment start date

Secondary Outcomes (13)

• Early recurrence of CDI

  Up to day 38 following initial vancomycin start date

• Late CDI recurrence

  Up to 90 days following initial vancomycin treatment start date

• Use of fidaxomicin

  Within 90 days of initial vancomycin treatment start date

• Number of patients with colectomy

  Within 90 days of initial vancomycin treatment start date

• Number of patients with fecal microbiota transplantation

  Within 90 days of initial vancomycin treatment start date

Study Arms (2)

Control: Placebo

PLACEBO COMPARATOR

Following a 14-day initial vancomycin treatment (125mg QID x14 days), the participant will receive a placebo for an additional 14 days (twice a day x 7 days, then once a day for 7 days).

Drug: Placebos

Intervention: Extended vancomycin regimen

ACTIVE COMPARATOR

Following a 14-day initial vancomycin treatment (125mg QID x14 days), the participant will receive active vancomycin for an additional 14 days (125mg twice a day x 7 days, then 125mg once a day for 7 days).

Drug: Vancomycin

Interventions

Vancomycin DRUG

Extension of initial vancomycin regimen for the treatment of C. diff from 14 days to 28 days (i.e. an additional 14 days of vancomycin treatment)

Intervention: Extended vancomycin regimen

Placebos DRUG

Initial vancomycin treatment (x14 days) will be followed by 14 days of placebo.

Control: Placebo

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All consecutive adult patients (inpatients and outpatients) who have a treated first episode or first recurrence of CDI.
• CDI will be defined by a positive PCR for toxin gene and/or detection of toxin by EIA or CCA along with three or more episodes of diarrhea within 24 hours
• Patients with a positive test with less than three bowel movements may be included if they initially presented with ileus or if they had pseudomembranous colitis visualized on colonoscopy

You may not qualify if:

• Clinical:
• Toxic megacolon at presentation not resolved by day 10
• For the current episode of CDI: use of metronidazole monotherapy\*, fidaxomicin, fecal microbiota transplant or intravenous immunoglobulins
• \*Participants may be eligible if they are initially treated with metronidazole but switch to oral vancomycin within 3 days (i.e. maximum 3 days of metronidazole monotherapy).
• Previous or current colectomy
• Severe allergy/intolerance to oral vancomycin
• Patient is expected to die within 3 months from another disease or is expected to be admitted to a palliative care unit
• Failure to achieve clinical cure (as above) by day 10
• More than 2 episodes of C. difficile in the last 5 years.
• Documented history of sensorineural hearing loss (other than presbycusis and noise induced hearing loss). The following patients with documented previous subtypes of sensorineural hearing loss will be excluded from the trial: Menière's disease, multiple sclerosis affecting auditory nerves, otic syphilis, viral cochleitis, autoimmune disorders, previous drug induced hearing loss, and otherwise unexplained sudden sensorineural hearing loss (SSNHL)
• Known pregnancy or planning to become pregnant during the study period
• Women who are breast feeding
• Administrative:
• Expected transfer to a palliative care unit or non-study hospital;
• No provincial health insurance

Sponsors & Collaborators

• McGill University Health Centre/Research Institute of the McGill University Health Centre: lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (12)

Vancouver General Hospital

Vancouver, British Columbia, V5Z 1M9, Canada

Location

Health Sciences Centre - Eastern Health

St. John's, Newfoundland and Labrador, A1B 3V6, Canada

Location

Kingston Health Sciences Centre

Kingston, Ontario, K7L 2V7, Canada

Location

The Ottawa Hospital

Ottawa, Ontario, K1Y 4E9, Canada

Location

Michael Garron Hospital

Toronto, Ontario, M4C 3E7, Canada

Location

Sunnybrook Health Science Centre

Toronto, Ontario, M4N 3M5, Canada

Location

St. Michael's Hospital

Toronto, Ontario, M5B 1W8, Canada

Location

University Health Network

Toronto, Ontario, M5G 1L7, Canada

Location

St Joseph's Health Care

Toronto, Ontario, M6R 1B5, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

McGill University Health Centre (Royal Victoria Hospital)

Montreal, Quebec, H4A3J1, Canada

Location

Centre hospitalier universitaire de Sherbrooke

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Related Publications (11)

• Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015 Apr 16;372(16):1539-48. doi: 10.1056/NEJMra1403772. No abstract available.

  PMID: 25875259 BACKGROUND

• Lessa FC, Gould CV, McDonald LC. Current status of Clostridium difficile infection epidemiology. Clin Infect Dis. 2012 Aug;55 Suppl 2(Suppl 2):S65-70. doi: 10.1093/cid/cis319.

  PMID: 22752867 BACKGROUND

• Levy AR, Szabo SM, Lozano-Ortega G, Lloyd-Smith E, Leung V, Lawrence R, Romney MG. Incidence and Costs of Clostridium difficile Infections in Canada. Open Forum Infect Dis. 2015 Jun 3;2(3):ofv076. doi: 10.1093/ofid/ofv076. eCollection 2015 Sep.

  PMID: 26191534 BACKGROUND

• Dobson G, Hickey C, Trinder J. Clostridium difficile colitis causing toxic megacolon, severe sepsis and multiple organ dysfunction syndrome. Intensive Care Med. 2003 Jun;29(6):1030. doi: 10.1007/s00134-003-1754-7. Epub 2003 May 7. No abstract available.

  PMID: 12734650 BACKGROUND

• Mylonakis E, Ryan ET, Calderwood SB. Clostridium difficile--Associated diarrhea: A review. Arch Intern Med. 2001 Feb 26;161(4):525-33. doi: 10.1001/archinte.161.4.525.

  PMID: 11252111 BACKGROUND

• McDonald EG, Milligan J, Frenette C, Lee TC. Continuous Proton Pump Inhibitor Therapy and the Associated Risk of Recurrent Clostridium difficile Infection. JAMA Intern Med. 2015 May;175(5):784-91. doi: 10.1001/jamainternmed.2015.42.

  PMID: 25730198 BACKGROUND

• Sheitoyan-Pesant C, Abou Chakra CN, Pepin J, Marcil-Heguy A, Nault V, Valiquette L. Clinical and Healthcare Burden of Multiple Recurrences of Clostridium difficile Infection. Clin Infect Dis. 2016 Mar 1;62(5):574-580. doi: 10.1093/cid/civ958. Epub 2015 Nov 17.

  PMID: 26582748 BACKGROUND

• Rodrigues R, Barber GE, Ananthakrishnan AN. A Comprehensive Study of Costs Associated With Recurrent Clostridium difficile Infection. Infect Control Hosp Epidemiol. 2017 Feb;38(2):196-202. doi: 10.1017/ice.2016.246. Epub 2016 Nov 7.

  PMID: 27817758 BACKGROUND

• Olsen MA, Yan Y, Reske KA, Zilberberg MD, Dubberke ER. Recurrent Clostridium difficile infection is associated with increased mortality. Clin Microbiol Infect. 2015 Feb;21(2):164-70. doi: 10.1016/j.cmi.2014.08.017. Epub 2014 Oct 12.

  PMID: 25658560 BACKGROUND

• The Lancet. A new approach to treating infection. Lancet. 2018 Feb 24;391(10122):714. doi: 10.1016/S0140-6736(18)30320-9. No abstract available.

  PMID: 29486930 BACKGROUND

• McDonald EG, Butler-Laporte G, Brophy JM, Elsayed S, Frenette C, Huseen I, Loo VG, Moran K, Coburn B, Hota SS, Longtin Y, Kong LY, Muller MP, Steiner TS, Valiquette L, Daneman N, Daley P, Nott C, MacFadden DR, Kandel CE, Chen Y, Perez-Patrigeon S, Lee TC; TAPER-V Team. Initial Vancomycin Taper for the Prevention of Recurrent Clostridioides difficile Infection: A Randomized Clinical Trial. JAMA Netw Open. 2026 Feb 2;9(2):e2560495. doi: 10.1001/jamanetworkopen.2025.60495.

  PMID: 41758514 DERIVED

MeSH Terms

Conditions

Clostridium Infections

Interventions

Vancomycin

Condition Hierarchy (Ancestors)

Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Glycopeptides; Glycoconjugates; Carbohydrates; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Todd C Lee, MD, MPH

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

  PRINCIPAL INVESTIGATOR

• Emily G McDonald, MD MSc

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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blinded placebo-controlled randomized controlled trial: A double blind and placebo will be used because the knowledge of being on active drug might influence patient reporting on gastrointestinal symptoms or physician interpretation of such symptoms leading to asymmetrical workup of CDI recurrence and hence bias in the results. To avoid other sources of bias post-randomization, patients, research personnel, investigators, endpoint adjudicators, and study analysis will all remain blinded to the intervention status until completion of the analysis and reporting of results. Analysis will be performed by intention to treat.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine, McGill University; Consultant in Infectious Diseases and Internal Medicine

Study Record Dates

• First Submitted: October 22, 2019
• First Posted: October 24, 2019
• Study Start: November 19, 2020
• Primary Completion: October 4, 2024
• Study Completion: November 22, 2024
• Last Updated: December 10, 2025

Record last verified: 2025-12

Locations

CA (12)