Antimicrobial Resistant Organism Decolonization After Microbiome Perturbation (ARO-DECAMP)

Antimicrobial Resistant Organism Decolonization After Microbiome Perturbation (ARO-DECAMP): a Multi-centre, Randomized, Placebo-controlled Feasibility Pilot Trial

ARO-DECAMP is a multi-centre, placebo-controlled, pilot and feasibility randomized controlled trial for the microbial consortium Microbial Ecosystem Therapeutic-2. Non-intensive care unit patients ≥ 18 years old diagnosed with a bloodstream infection and receiving treatment for an antibiotic resistant organism will be included. Participants will be randomized to receive either MET-2 or placebo for 10 days. Recruitment rate and study intervention adherence will be evaluated for feasibility. Participants will be followed for 180 days, and biological samples will be collected periodically for clinical, ecological, and biomarker outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Microbial Colonization; Antibiotic Resistant Infection; Gram-negative Bacteremia
• Intervention / Treatment: Drug: MET-2; Drug: Placebo

Detailed Description

Reconstituting the perturbed microbiome is a novel therapeutic modality with the potential to decrease ARO colonization and infection and combat AMR without additional pressure for selection of further antimicrobial resistance. No trial has yet assessed the potential of a therapeutic microbial consortium for ARO decolonization and infection prevention after antibiotic treatment.

The investigational product, Microbial Ecosystem Therapeutic-2 (MET-2), is a defined microbial community derived from healthy donor stool. MET capsules are orally administered mixtures of bacterial strains cultured from the stool of a healthy donor. This study is designed to determine if a trial of administration of MET-2 after antibiotic treatment for bloodstream infections is feasible. Stool and plasma biomarkers to assess the effects of the intervention will also be evaluated.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bryan Coburn, MD, PhD; Phone Number: 416-634-7457; Email: bryan.coburn@uhn.ca
• Study Contact Backup: Name: Noelle Yee; Phone Number: 416-302-5715; Email: noelle.yee@uhn.ca

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4E9
      • The Ottawa Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5G 1L7
      • University Health Network
    • Toronto, Ontario, Canada, M6G 1X5
      • Sinai Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult (≥18 years old) inpatient not admitted to the ICU or equivalent (step-up and step-down units are eligible)

2. Positive blood culture with an ARO:

   • AmpC beta-lactamase producing species: Enterobacter cloacae, Citrobacter spp., Klebsiella aerogenes, Serratia spp., Morganella morganii, Hafnia alvei OR
   • ESBL-producing gram-negative bacilli
3. Currently receiving treatment for the bloodstream infection

Exclusion Criteria:

1. Inability to swallow oral MET-2 or placebo capsule
2. Recipient of small bowel transplant
3. Inflammatory bowel disease, short bowel syndrome, diverting/non-diverting ileo/colostomy
4. Use of >3 days over-the-counter or prescription probiotics (not including food additives) within 10 days of enrolment
5. Receipt of fecal microbiota transplant (FMT) within 3 months of enrolment
6. Absolute neutrophil count <0.5x109/L
7. Death expected within 72 hours of enrolment
8. Planned continuation of non-prophylaxis antimicrobial therapy active against the bloodstream isolate for >42 days
9. Known pregnancy, planning to become pregnant during the study period, or breastfeeding
10. Any other reason in view of the site investigator or treating team

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MET-2; Participants randomized to the intervention will receive MET-2 daily for 10 days. MET-2 capsules are administered orally at 0.5 g per capsule, containing 3.1 x 10^5-10^11 colony forming units (CFU). An initial loading dose of 10 MET-2 capsules/day will be taken for 2 days (5 grams total). For the following 8 days, participants will take a maintenance dose of 3 MET-2 capsules/day (1.5 grams total).	Drug: MET-2; Microbial Ecosystem Therapeutics (MET) is a defined microbial community derived from healthy donor stool. MET capsules are orally administered mixtures of pure cultures of human-derived bacterial strains.
Placebo Comparator: Placebo; Participants randomized to the placebo will receive microcrystalline cellulose in a capsule, identical in appearance to MET-2 but not containing live bacteria. Participants will take the placebo in the same dosing schedule as the MET-2 arm: 10 capsules daily for 2 days, followed by 3 capsules daily for 8 days.	Drug: Placebo; Microcrystalline Cellulose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate overall and by study site	Defined by the numbers of eligible, consented, and randomized patients	1.5 years
Adherence to MET-2/placebo for the treatment duration	Defined as >80% of loading dose (16/20 pills) + >75% of daily doses (18/24 pills) for the maintenance period, as determined by returned unused capsules	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in microbiome composition after intervention	Assessment of gut microbiome composition in pre- and post-randomization stool samples using bacterial culture and culture-independent (sequencing) assays.	180 days
Number of biomarker samples collected, by sample type and timepoint	Successful adherence to biomarker sample collection is defined as >80% of participants having samples suitable for analysis at 30 days post-intervention	30 days
Concentration of potential biomarkers in pre- and post-randomization blood and urine samples	Microbial-derived metabolites (short chain fatty acids and bile acids in blood, and 3-indoxyl sulfate in urine), markers of intestinal permeability (soluble CD14, LPS, LPS-binding protein, ZO-1, intestinal fatty acid protein), immune cell profiles (CD8 T lymphocytes, CD4 T lymphocytes, T regulatory cells, B lymphocytes, Th17 cells, Th1 cells).	180 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Frequency and grade	180 days
90- and 180-day infection rate	Infection will be defined as either isolation of a pathogenic species from any sterile site OR the initiation of a therapeutic course of antimicrobials with or without isolation of a pathogenic species from a sterile or non-sterile site	180 days
ARO colonization by culture at 30 and 90 days post-intervention	Defined as any positive result for ARO from any site	90 days
Determine 90- and 180-day recurrence/re-infection rates (with the same organism) in each treatment arm		180 days
AMR gene complement by sequencing at 30 and 90 days post-intervention		90 days
90- and 180-day all-cause mortality		180 days
ICU and hospital lengths of stay		180 days
C. difficile carriage at days 30 and 90		90 days

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Investigators: Principal Investigator: Bryan Coburn, MD, PhD, University Health Network, Toronto

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2024
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): February 1, 2026

Study Registration Dates

• First Submitted: December 21, 2023
• First Submitted That Met QC Criteria: January 9, 2024
• First Posted (Estimated): January 19, 2024

Study Record Updates

• Last Update Posted (Estimated): January 19, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Infection; Microbiome; Bacteremia; Microbiota; Antibiotic; Antibiotic resistance; Decolonization; Microbial consortia
• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Infections; Communicable Diseases; Bacteremia
• Other Study ID Numbers: 23-5419

Drug and device information, study documents

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