Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection

Study Overview
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Brief Summary
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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.

Detailed Description
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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 and started on standard of care oral vancomycin treatment -> 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 15 start -> Collection of demographics, storage of stool. Day 15-28 -> Receipt of study therapy Day 28: In person or remote visit Day 56: In person or remote 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 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).

Official Title
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Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection

Conditions
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Clostridium Difficile Infection

Intervention / Treatment
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* Drug: Vancomycin
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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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: 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 Previously enrolled No reliable means of outpatient contact Incompetent without healthcare proxy Patient stated inability to come to follow up appointments.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control: Placebo<br>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<br>* Initial vancomycin treatment (x14 days) will be followed by 14 days of placebo.<br>|
| Active Comparator: Intervention: Extended vancomycin regimen<br>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<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Late CDI recurrence | same as primary outcome | 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 | 
| Number of patient deaths (All-cause death) | If a patient misses their day 28 or day 56 in-person follow up, we will initially review their hospital file to see if they have died. If this does not show death, we will contact the patient (or their proxy) by telephone to determine why they missed the follow up and reschedule it as required. If we cannot reach the patient or their proxy, and the patient has not been replying to the email/text/phone surveys we will search the obituaries. After day 56 we will use the survey responses as proof of life. If there is no response to the day 90 survey by day 95, we will first check the hospital file to see if they have died. Then, if vital status is not clear, we will search the obituaries. Then if vital status is still not clear, we will attempt to reach the patient by telephone. If we cannot reach the patient, we will record that patient as lost to follow up but include a sensitivity analysis including these patients as having died. | Within 90 days of initial vancomycin treatment start date | 
| C. diff associated quality of life | At day 56 patients will be asked to provide a measure of self-reported quality of life using the Cdiff32 score which was developed and validated to evaluate health-related quality of life in patients with C.difficile. Each item in the Cdiff32 Quality of Life Questionnaire is scored between 0 (worst quality of life) to 100 (best quality of life). | At day 56 after initial vancomycin treatment start date | 
| Emergency department visits | Within 90 days post enrolment we will access the medical record and we will also analyze patient emails/text surveys for all emergency department visits and will record the date of the first emergency department visit. Patient charts will also be flagged for immediate review should they visit the emergency room or be admitted to study centres to assess for the primary and other secondary outcomes. With explicit written patient consent, medical records from outside hospitals will be also requested for review if they report presenting elsewhere. | Within 90 days of initial vancomycin treatment start date | 
| Re-admission to hospital | Within 90 days post enrolment we will access the medical record and we will also analyze patient emails/text surveys for all hospital readmissions and will record the date of the first hospital readmission. Patient charts will also be flagged for immediate review should they be readmitted to study centres to assess for the primary and other secondary outcomes. With explicit written patient consent, medical records from outside hospitals will also be requested for review if they report presenting elsewhere. | Within 90 days of initial vancomycin treatment start date | 
| Discontinuation of study drug | At the day 28 visit we will inquire about adherence and the quantity of pills remaining. | At day 28 after initial vancomycin treatment start date | 
| Receipt of non-study antibiotics | Exposure to antibiotics for infections other than C. difficile may occur. We will ask patients to contact us if this occurs so that the appropriate data can be recorded to account for these effects outside of the study. | Within 90 days of initial vancomycin treatment start date | 
| Use of off-study vancomycin secondary prophylaxis up to day 90 | Exposure to antibiotics for other infections may lead to the receipt of vancomycin secondary prophylaxis in that context. We will ask patients to contact us if this occurs so that the appropriate data can be recorded to account for these effects outside of the study. If vancomycin secondary prophylaxis has occurred prior to day 28, the patient will stop the study drug to avoid excess vancomycin exposure and this will be recorded. | Within 90 days of initial vancomycin treatment start date | 
| Economic analysis | Economic analysis will be carried out from the perspective of the McGill University Health Centre (MUHC) following established guidelines and will be generalized to the rest of Canada. We will estimate the average cost per patient of using the interventions under study routinely in patients with C. difficile diarrhea. We will also gather information on the cost of health services use (hospitalizations and other interventions such as colectomy) following this intervention to determine the budget impact compared with routine practice. If the intervention proves efficacious, we will carry out a cost-benefit or cost-effectiveness analysis to determine the incremental cost per case of C. difficile diarrhea avoided. The base case will be the placebo group, to which the treatment will be compared. Further, we will carry out a cost utility analysis to report the incremental cost per unit increase in quality of life as measured by the Cdiff32 score. | Cost of health care utilization up to 90 days after initial vancomycin treatment start date | 
| Safety & tolerability of the vancomycin extension/taper treatment period | We will create a survey at day 28 asking participants to communicate any side effects from the study medication, with a section for detailing any adverse reactions. | Days 15-28 of vancomycin treatment |