Clinical trial NCT03802461: Effectiveness of Fecal Flora Alteration for Eradication of Carbapenemase-producing Enterobacteriaceae Colonization
Official title: Effectiveness of Fecal Flora Alteration for Eradication of Carbapenemase-producing Enterobacteriaceae Colonization Trial (EFFECT-CPE): a Multisite, Open-label, Randomized Controlled Feasibility Pilot Trial
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
PHASE3
Conditions: Infection
Keywords: Fecal Microbiota Transplantation
Gut Microbiome
Carbapenemase-producing Enterobacteriaceae (CPE)
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Sinai Health System, Ontario, Canada
name: University of Toronto, Ontario, Canada
name: The Toronto Invasive Bacterial Diseases Network, Ontario, Canada
name: Public Health Ontario Laboratories, Ontario, Canada
First posted: 2019-01-14
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Asymptomatic adult patients intestinally colonized with CPE will either randomized to receive fecal microbiota transplantation (intervention) or standard of care (no intervention).
Primary purpose: TREATMENT

Brief summary: Carbapenemase-producing Enterobacteriaceae (CPE) are bacteria carried in the gastrointestinal tract that are resistant to carbapenems, antibiotics of last resort. CPE infections result in death in 25-50% of cases. Fecal microbiota transplantation (FMT) is the transfer of stool from a healthy donor to a recipient to alter the composition of gut microbes. Early studies support its use for eliminating CPE carriage but definitive studies are lacking. The investigators propose a feasibility pilot for a multicenter, non-blinded randomized trial comparing the effectiveness of FMT with no intervention (standard of care) in eliminating intestinal carriage of CPE. Forty patients with CPE will be randomly assigned to receive FMT by enema or no intervention. Feasibility will be demonstrated by the ability to recruit and retain 40 patients over 12 months, and to provide FMT made at a central site to at least one off-site hospital. The primary clinical endpoint for the full trial is CPE intestinal carriage 3 months after the intervention. Secondary endpoints include: CPE carriage at 1, 6 and 12 months; time to decolonization of CPE; safety; CPE infections over 12 months; and, intestinal carriage of other antibiotic-resistant organisms. Data on the clinical outcomes will be collected but not analyzed in this feasibility study.

Detailed description: This is a multisite, open-label randomized controlled internal pilot trial designed to assess the feasibility of a larger trial aimed at determining the effectiveness of fecal microbiota transplantation (FMT) by enema in short and long term intestinal decolonization of carbapenemase-producing Enterobacteriaceae (CPE). Forty (40) asymptomatic adult patients intestinally colonized with CPE will be allocated in a 1:1 ratio to receive a bowel preparation followed by FMT by enema route, versus standard of care (no intervention). FMT will be provided by the University of Toronto Microbiota Therapeutics Outcomes Program (MTOP), using standardized operating procedures for recruiting and screening FMT donors, manufacturing FMT and administering FMT by enema. The feasibility outcomes are: successful randomization of 40 patients within 12 months, retention of \>90% (36/40) of patients up to 6 months, and provision of FMT at a non-primary study site in at least one patient. Data on the clinical and exploratory outcomes will be collected but not analyzed in this pilot study. The primary clinical outcome is incidence of intestinal decolonization of CPE at 3 months. Secondary clinical outcomes include: time to decolonization of CPE; incidence of CPE clinical infections up to 12 months post-intervention; incidence of intestinal decolonization of CPE and other antibiotic-resistant organisms (extended spectrum beta-lactamase Enterobacteriaceae - ESBLs and vancomycin-resistant Enterococci - VRE) at 1, 3, 6 and 12 months post-intervention; and, safety profile. As an exploratory outcome, changes in fecal microbiome composition will be examined before and after intervention. This study leverages existing support, research infrastructures and expertise - including the Toronto Invasive Bacterial Diseases Network (TIBDN), Toronto Antimicrobial Resistance Research Network (TARRN), and the University of Toronto Microbiota Therapeutics Outcomes Program (MTOP) - to optimize feasibility regarding patient recruitment and FMT administration.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years
2. ≥ 1 rectal swab, groin, stool, or urine specimen positive for a CPE within the past 1 month.

   • Presence of CPE will be confirmed at baseline through collection of pooled groin/rectal swab and urine specimen.
3. Women of childbearing age must be using at least one reliable form of birth control.
4. Must be able to provide informed consent.

Exclusion Criteria:

1. Active infection with CPE at the time of assessment.
2. Pregnancy, planned pregnancy or breastfeeding.
3. Current admission to intensive care unit.
4. Significantly immunocompromised patients .

   * neutropenia (ANC \< 1)
   * ongoing use of systemic corticosteroids \> 30 mg/day
   * ongoing use of biologic therapy
   * undergoing chemotherapy, received chemotherapy ≤ 30 days from baseline visit, or expected to undergo chemotherapy in the upcoming 12 months
   * active hematologic malignancy
   * solid organ transplant recipient
   * hematopoetic stem cell transplant recipient
   * HIV positive patients with cluster differentiation 4 (CD4) cell count \< 350
5. Patients with ascites or receiving peritoneal dialysis.
6. History of inflammatory bowel disease (Crohn's or Ulcerative colitis).
7. Chronic diarrhea or active colitis for any reason.
8. Ileus or active gastrointestinal motility disorder at baseline.
9. History of total colectomy.
10. Severe, irreversible bleeding disorder.
11. History of anaphylactic or anaphylactoid allergic reaction to any foods.
12. Anticipated life expectancy less than 6 months.
13. Unable to tolerate enema.
14. Participant is not a Canadian citizen or permanent resident, and not expected to remain in Toronto region for 12 months.
15. Any reason in the view of the investigator.

Primary outcomes:
measure: Incidence of intestinal colonization of patients with CPE 3 months after intervention.
timeFrame: 3 months
measure: Randomization rate in study
timeFrame: 12 months
measure: Proportion of patients retained in study for up to 6 months
timeFrame: 6 months
Secondary outcomes:
measure: Incidence of CPE decolonization in FMT-treatment and non-treatment groups at 1, 6 and 12 months.
timeFrame: 1, 6, and 12 months
measure: Time to CPE decolonization in FMT-treatment and non-treatment groups.
timeFrame: 1, 3, 6, and 12 months
measure: Incidence of CPE clinical infection in FMT treatment and non-treatment groups over 12 months.
timeFrame: 1, 3, 6, and 12 months
measure: Incidence of extended spectrum beta-lactamase organisms (ESBL) and vancomycin-resistant Enterococci (VRE) intestinal colonization at 0, 1, 3, 6 and 12 months in FMT treatment and non-treatment groups.
timeFrame: 1, 3, 6, and 12 months
measure: Incidence of solicited and unsolicited adverse and serious adverse events in both groups
timeFrame: 3 months
measure: Number of patients with all-cause mortality at 30 days post-randomization
timeFrame: 1 month
Other outcomes:
measure: Changes in composition and diversity of fecal bacterial phyla (as measured by 16s ribosomal ribonucleic acid sequencing) in both intervention groups
timeFrame: 12 months
Locations:
city: Brampton
country: Canada
facility: William Osler Health System
state: Ontario
city: Burlington
country: Canada
facility: Joseph Brant Hospital
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health
state: Ontario
city: Richmond Hill
country: Canada
facility: MacKenzie Health
state: Ontario
city: Scarborough
country: Canada
facility: The Scarborough Hospital
state: Ontario
city: Toronto
country: Canada
facility: North York General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Michael Garron Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences 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: Public Health Ontario Laboratories
state: Ontario
city: Toronto
country: Canada
facility: Sinai Health System
state: Ontario
city: Toronto
country: Canada
facility: St. Joseph Health Centre
state: Ontario
Study officials:
affiliation: Infectious Diseases Physician, University Health Network
name: Susy S. Hota, MD MSc FRCPC
role: PRINCIPAL_INVESTIGATOR
affiliation: Microbiologist & Infectious Disease Physician, Sinai Health System
name: Susan M. Poutanen, MD MPH FRCPC
role: PRINCIPAL_INVESTIGATOR
References: