Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection
Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection
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.
STUDY POPULATION

 This is a multi-centre study involving institutions in British Columbia, Ontario and Quebec.
 The study population will be drawn from patients cared for as inpatients or outpatients at
 the participating hospitals. Such patients will have a test positive for Clostridium
 difficile and will be receiving treatment. The trial will involve only adult patients 18
 years of age and older.

 Criteria for Recruitment

 The microbiology laboratory will notify the study team about a positive CDI test via
 telephone, email, or fax. The nature of recruitment will then depend on the inpatient status
 of the patient at the time of the test.

 Inpatients:

 Pre-existing approval for approaching patients for this study will be obtained from the
 relevant department heads. The study team will speak with a member of the inpatient treating
 team (resident physician or faculty physician as appropriate) to determine if the patient is
 appropriate for recruitment. If this seems to be the case, the patient's file will be rapidly
 screened to determine eligibility and if the patient is eligible they will be approached for
 consent.

 Outpatients:

 The physician who ordered the C. difficile test will be contracted to determine if the
 patient is appropriate for recruitment. At the invitation of this physician, the
 investigators will then contact the patient via telephone to evaluate suitability for
 inclusion and arrange an intake visit.

 RANDOMIZATION

 For patients who have enrolled in the study, randomization will occur centrally at McGill via
 an existing internet application (such as https://cloudtrials.mchi.mcgill.ca/) and will be
 performed by permuted block with randomized block sizes. This randomization will be
 stratified for first episode or first recurrence at study entry to ensure these factors are
 properly balanced.

 TRIAL SCHEDULE

 -  Day 1: Patient diagnosed with C. difficile -> Determine eligibility and obtain
 permission for approach

 -  Day 7-10 (Patient's C. difficile has improved and meets eligibility): Consent obtained;
 randomization; distribution of study drug for day 14 start -> Collection of
 demographics, storage of stool.

 -  Day 14-28 -> Receipt of study therapy

 -  Day 28: In person visit

 -  Day 56: In person visit -> Primary outcome determined, quality of life questionnaire

 -  Day 90: Study ends for the patient -> Secondary outcomes can be determined

 -  weekly until Day 56: Brief questionnaire -> By email/text/phone

 -  biweekly after Day 56: Brief questionnaire -> By email/text/phone

 -  Ad hoc: If patient has symptoms of recurrence of C. difficile -> Review by ID physician
 in clinic if possible, otherwise usual doctors or emergency room

 Patients will be able to come be assessed for potential relapse by infectious diseases
 physicians at each site (who may or may not be a part of the study) or could see their usual
 doctors.

 SAMPLE SIZE AND STATISTICAL METHODS

 The estimated number of CDI cases available has been based on fiscal year 2016 data: total of
 1770 per year.

 The risk of recurrence is estimated at 25%. The investigators aim to demonstrate that an
 initial tapering regimen is associated with an absolute decrease in the risk of relapse of at
 least 10% (number needed to treat of 10) which would be similar to than the effect seen
 within 40 days in the fidaxomicin trial. This estimate accounts for our longer period of
 follow up and will allow some flexibility in the actual recurrence rate found in our control
 arm. With 80% power and a type 1 error of 5%, this would require 276 patients to complete
 follow up in each arm (total 552).
Inclusion Criteria:

 -  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

 Exclusion Criteria:

 -  Clinical:

 1. Toxic megacolon at presentation not resolved by day 10

 2. For the current episode of CDI: use of fidaxomicin, fecal microbiota transplant
 or intravenous immunoglobulins

 3. Previous or current colectomy

 4. Severe allergy/intolerance to oral vancomycin

 5. Patient is expected to die within 3 months from another disease or is expected to
 be admitted to a palliative care unit

 6. Failure to achieve clinical cure (as above) by day 10

 7. More than 2 lifetime episodes of C. difficile.

 -  Administrative:

 1. Expected transfer to a palliative care unit or non-study hospital;

 2. No provincial health insurance

 3. Previously enrolled

 4. No reliable means of outpatient contact

 5. Incompetent without healthcare proxy

 6. Patient stated inability to come to follow up appointments.