Effectiveness of Fecal Flora Alteration for Eradication of Carbapenemase-producing Enterobacteriaceae Colonization (EFFECT-CPE)

Effectiveness of Fecal Flora Alteration for Eradication of Carbapenemase-producing Enterobacteriaceae Colonization Trial (EFFECT-CPE): a Multisite, Open-label, Randomized Controlled Feasibility Pilot Trial

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.

Study Overview

• Status: Suspended
• Conditions: Infection
• Intervention / Treatment: Biological: Fecal Microbiota Transplantation (FMT)

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.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • William Osler Health System
    • Burlington, Ontario, Canada, L7S 1W7
      • Joseph Brant Hospital
    • Oshawa, Ontario, Canada, L1G 2B9
      • Lakeridge Health
    • Richmond Hill, Ontario, Canada, L4C 4Z3
      • Mackenzie Health
    • Scarborough, Ontario, Canada, M1P 2T7
      • The Scarborough Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5B 1W8
      • St Michael's Hospital
    • Toronto, Ontario, Canada, M2K 1E1
      • North York General Hospital
    • Toronto, Ontario, Canada, M4C 3E7
      • Michael Garron Hospital
    • Toronto, Ontario, Canada, M5G 1X5
      • Sinai Health System
    • Toronto, Ontario, Canada, M5B 1W8
      • University Health Network
    • Toronto, Ontario, Canada, M5G 1M1
      • Public Health Ontario Laboratories
    • Toronto, Ontario, Canada, M6R 1B5
      • St. Joseph Health Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fecal Microbiota Transplantation (FMT); Bowel lavage preparation followed by FMT administered by enema, given on 3 occasions. Fecal filtrate for FMT will be prepared from 50 g of healthy donor stool, homogenized, and diluted in 300 mL sterile normal saline.	Biological: Fecal Microbiota Transplantation (FMT); Feces from healthy donor
No Intervention: Standard of Care; Patients in this arm will not receive intervention and will be on standard of care .

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of intestinal colonization of patients with CPE 3 months after intervention.	Incidence of CPE colonization in FMT arm vs control arm at 3 months	3 months
Randomization rate in study	Completion of randomization of 40 study participants during the study period will be used to indicate feasibility of the study.	12 months
Proportion of patients retained in study for up to 6 months	A retention of 90% of patients up to 6 months in the study will be used to indicate feasibility.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of CPE decolonization in FMT-treatment and non-treatment groups at 1, 6 and 12 months.	As above	1, 6, and 12 months
Time to CPE decolonization in FMT-treatment and non-treatment groups.	As above	1, 3, 6, and 12 months
Incidence of CPE clinical infection in FMT treatment and non-treatment groups over 12 months.	As above	1, 3, 6, and 12 months
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.	Changes in colonization status of other antimicrobial resistant organisms over the study period	1, 3, 6, and 12 months
Incidence of solicited and unsolicited adverse and serious adverse events in both groups	Participants will be asked to report adverse and serious adverse events will be throughout the study period and will be asked specifically about adverse events during study visits	3 months
Number of patients with all-cause mortality at 30 days post-randomization	As above	1 month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in composition and diversity of fecal bacterial phyla (as measured by 16s ribosomal ribonucleic acid sequencing) in both intervention groups	As above	12 months

Collaborators and Investigators

• Sponsor: Susy Hota
• Collaborators: Sinai Health System, Ontario, Canada; University of Toronto, Ontario, Canada; The Toronto Invasive Bacterial Diseases Network, Ontario, Canada; Public Health Ontario Laboratories, Ontario, Canada
• Investigators: Principal Investigator: Susy S. Hota, MD MSc FRCPC, Infectious Diseases Physician, University Health Network; Principal Investigator: Susan M. Poutanen, MD MPH FRCPC, Microbiologist & Infectious Disease Physician, Sinai Health System

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2019
• Primary Completion (Anticipated): December 15, 2023
• Study Completion (Anticipated): March 20, 2024

Study Registration Dates

• First Submitted: November 8, 2018
• First Submitted That Met QC Criteria: January 10, 2019
• First Posted (Actual): January 14, 2019

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: November 1, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Fecal Microbiota Transplantation; Gut Microbiome; Carbapenemase-producing Enterobacteriaceae (CPE)
• Other Study ID Numbers: 18-5177

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No