Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection (TAPER-V)
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|ClinicalTrials.gov Identifier: NCT04138706|
Recruitment Status : Not yet recruiting
First Posted : October 24, 2019
Last Update Posted : March 19, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|Clostridium Difficile Infection||Drug: Vancomycin Drug: Placebos||Phase 4|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||552 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
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.
|Official Title:||Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection|
|Estimated Study Start Date :||April 2020|
|Estimated Primary Completion Date :||April 2022|
|Estimated Study Completion Date :||October 2022|
Placebo Comparator: Control: Placebo
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).
Initial vancomycin treatment (x14 days) will be followed by 14 days of placebo.
Active Comparator: Intervention: Extended vancomycin regimen
Following a 14-day initial vancomycin treatment (125mg QID x14 days), the participant will will receive active vancomycin for an additional 14 days (125mg twice a day x 7 days, then 125mg once a day for 7 days).
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)
- CDI recurrence [ Time Frame: Within 56 days of initial diagnosis ]
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.
- Late CDI recurrence [ Time Frame: Up to 90 days following initial CDI diagnosis ]same as primary outcome
- Number of patients with fecal microbiota transplantation [ Time Frame: Within 90 days of CDI diagnosis ]
- Use of fidaxomicin [ Time Frame: Within 90 days of CDI diagnosis ]
- Number of patients with colectomy [ Time Frame: Within 90 days of CDI diagnosis ]
- Number of patient deaths (All-cause death) [ Time Frame: Within 90 days of initial CDI diagnosis ]
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.
- C. diff associated quality of life [ Time Frame: At day 56 after initial CDI diagnosis ]
At study entry and 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).
- Emergency department visits [ Time Frame: Within 90 days of initial diagnosis ]Within 90 days post enrolment we will access the medical record and we 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.
- Re-admission to hospital [ Time Frame: Within 90 days of initial diagnosis ]Within 90 days post enrolment we will access the medical record and we 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 readmitted 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.
- Discontinuation of study drug or placebo [ Time Frame: At day 28 after initial CDI diagnosis ]At the day 28 in-person visit we will inquire about adherence and the quantity of pills remaining.
- Receipt of non-study antibiotics [ Time Frame: Within 90 days of initial CDI diagnosis ]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.
- Use of off-study vancomycin secondary prophylaxis up to day 28 [ Time Frame: Within 28 days of initial CDI diagnosis ]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.
- Use of vancomycin secondary prophylaxis between day 29 and 90 [ Time Frame: From day 29 to 90 after initial CDI diagnosis ]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 is happening so that the appropriate data can be recorded to account for these effects outside of the study.
- Economic analysis [ Time Frame: Cost of health care utilization up to 90 days after initial CDI diagnosis ]
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.
- Safety & tolerability of the vancomycin extension/taper treatment period [ Time Frame: Days 15-28 of vancomycin treatment ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04138706
|Contact: Todd C Lee, MD, MPHfirstname.lastname@example.org|
|Principal Investigator:||Todd C Lee, MD, MPH||McGill University Health Centre/Research Institute of the McGill University Health Centre|