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Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection (TAPER-V)

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ClinicalTrials.gov Identifier: NCT04138706
Recruitment Status : Recruiting
First Posted : October 24, 2019
Last Update Posted : June 18, 2021
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Todd C. Lee MD MPH FIDSA, McGill University Health Centre/Research Institute of the McGill University Health Centre

Tracking Information
First Submitted Date  ICMJE October 22, 2019
First Posted Date  ICMJE October 24, 2019
Last Update Posted Date June 18, 2021
Actual Study Start Date  ICMJE November 19, 2020
Estimated Primary Completion Date April 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2019)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 17, 2020)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2019)
  • Late CDI recurrence [ Time Frame: Up to 90 days following initial CDI diagnosis ]
    same as primary outcome
  • Fecal microbiota transplantation [ Time Frame: Within 90 days of CDI diagnosis ]
  • Use of fidaxomicin [ Time Frame: Within 90 days of CDI diagnosis ]
  • Colectomy [ Time Frame: Within 90 days of CDI diagnosis ]
  • 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.
  • All-cause mortality [ Time Frame: Within 90 days of initial diagnosis ]
  • Emergency department visits [ Time Frame: Within 90 days of initial diagnosis ]
  • Re-admission to hospital [ Time Frame: Within 90 days of initial diagnosis ]
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection
Official Title  ICMJE Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection
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.

Detailed Description

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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

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.

Primary Purpose: Prevention
Condition  ICMJE Clostridium Difficile Infection
Intervention  ICMJE
  • Drug: Vancomycin
    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)
  • Drug: Placebos
    Initial vancomycin treatment (x14 days) will be followed by 14 days of placebo.
Study Arms  ICMJE
  • 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).
    Intervention: Drug: Placebos
  • 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).
    Intervention: Drug: Vancomycin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 23, 2019)
552
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2022
Estimated Primary Completion Date April 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
    8. 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)
    9. Known pregnancy or planning to become pregnant during the study period
    10. Women who are breast feeding
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sarah Elsayed 5149341934 ext 23730 sarah.elsayed@idtrials.com
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04138706
Other Study ID Numbers  ICMJE MP-37-2020-5986
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Todd C. Lee MD MPH FIDSA, McGill University Health Centre/Research Institute of the McGill University Health Centre
Study Sponsor  ICMJE McGill University Health Centre/Research Institute of the McGill University Health Centre
Collaborators  ICMJE Canadian Institutes of Health Research (CIHR)
Investigators  ICMJE
Principal Investigator: 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
PRS Account McGill University Health Centre/Research Institute of the McGill University Health Centre
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP