Clinical trial NCT04138706: Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection
Official title: Initial Vancomycin Taper for the Prevention of Recurrent Clostridium Difficile Infection
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Clostridium Difficile Infection
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2019-10-24
Enrollment: 263
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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, Quebec and Newfoundland. 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
* 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).

Eligibility criteria: 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 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).
  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 episodes of C. difficile in the last 5 years.
  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.

Primary outcomes:
measure: CDI recurrence
timeFrame: Within 56 days of initial vancomycin treatment start date
Secondary outcomes:
measure: Early recurrence of CDI
timeFrame: Up to day 38 following initial vancomycin start date
measure: Late CDI recurrence
timeFrame: Up to 90 days following initial vancomycin treatment start date
measure: Use of fidaxomicin
timeFrame: Within 90 days of initial vancomycin treatment start date
measure: Number of patients with colectomy
timeFrame: Within 90 days of initial vancomycin treatment start date
measure: Number of patients with fecal microbiota transplantation
timeFrame: Within 90 days of initial vancomycin treatment start date
measure: Number of patient deaths (All-cause death)
timeFrame: Within 90 days of initial vancomycin treatment start date
measure: Emergency Department Visit or Readmission to Hospital
timeFrame: Within 90 days of initial vancomycin treatment start date
measure: C. diff associated quality of life
timeFrame: At day 56 after initial vancomycin treatment start date
measure: Discontinuation of study drug
timeFrame: At day 28 after initial vancomycin treatment start date
measure: Receipt of non-study antibiotics
timeFrame: Within 90 days of initial vancomycin treatment start date
measure: Use of off-study vancomycin secondary prophylaxis up to day 90
timeFrame: Within 90 days of initial vancomycin treatment start date
measure: Safety and tolerability of the vancomycin extension/taper treatment period
timeFrame: Days 15-28 of vancomycin treatment
measure: Economic analysis
timeFrame: Cost of health care utilization up to 90 days after initial vancomycin treatment start date
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Saint John's
country: Canada
facility: Health Sciences Centre - Eastern Health
state: Newfoundland and Labrador
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: Michael Garron Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Toronto
country: Canada
facility: St Joseph's Health Care
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre (Royal Victoria Hospital)
state: Quebec
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre hospitalier universitaire de Sherbrooke
state: Quebec
Study officials:
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Todd C Lee, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Emily G McDonald, MD MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.