Study Design
This is a placebo-controlled, pilot and feasibility randomized control trial in 4 hospitals in Ontario, Canada. Research coordinators will screen all non-Intensive Care Unit (ICU) hospitalized patients with a diagnosis of BSI with qualifying organisms that are being treated with antibiotics. The study intervention will start at least 2 and no more than 3 full calendar days following completion of antibiotics (i.e., with a minimum 2-day and maximum 3-day antibiotic-free period prior to initiation of the investigational agent). Participants will be randomized to oral MET-2 or placebo through central randomization to ensure allocation concealment. The placebo is identical in appearance to MET-2.
Antimicrobial Resistant Organism Decolonization After Microbiome Perturbation (ARO-DECAMP) is an investigator-initiated study sponsored by the University Health Network. The trial is funded by the Canadian Institutes of Health Research (CIHR). NuBiyota, the manufacturer of MET-2, is providing MET-2 and placebo in-kind. None of these groups played a role in the design, conduct, analysis, interpretation, or writing of this protocol.
Eligibility Criteria
Inclusion criteria:
- Adult (>18 years old) inpatient not admitted to the ICU or equivalent at the time of screening (step-up and step-down units are eligible)
- Positive blood culture with one of the following organisms:
- AmpC beta-lactamase producing species: Enterobacter cloacae, Citrobacter spp., Klebsiella aerogenes, Serratia spp., Morganella morganii, Hafnia alvei
- Extended-spectrum beta-lactamase-producing Gram-negative bacilli
- Receiving treatment (or intent to initiate treatment) for the bloodstream infection at the time of screening
Exclusion criteria:
- Inability to swallow oral MET-2 or placebo capsule
- Recipient of small bowel transplant
- Inflammatory bowel disease, short bowel syndrome, diverting/non-diverting ileo/colostomy
- Use of >3 days over-the-counter or prescription probiotics (not including food additives) in the 10 days prior to enrolment
- Receipt of FMT within 3 months of enrolment
- Absolute neutrophil count <0.5x109/L
- Death expected within 72 hours of enrolment
- Planned continuation of non-prophylaxis antimicrobial therapy active against the bloodstream isolate for >42 days
- Known pregnancy, planning to become pregnant during the study period, or breastfeeding
- Any other reason in view of the site investigator or treating team
Trial Interventions
Participants randomized to the intervention will consume the investigational drug, MET-2, once daily for 10 days. MET-2 capsules are administered orally at 0.5 g per capsule, containing 3.1 x 105-1011 colony forming units (CFUs). An initial loading dose of 10 MET-2 capsules/day will be taken for 2 days (5 grams total). This is expected to deliver a therapeutic dose of MET-2 in the range of 106-1012 CFU. For the following 8 days, participants will take a maintenance dose of 3 MET-2 capsules/day (1.5 grams total) (24).
Participants randomized to the placebo will receive microcrystalline cellulose in a capsule, identical in appearance to MET-2 but not containing live bacteria. The placebo is also prepared by the MET-2 manufacturer. Participants will take the placebo in the same dosing schedule as MET-2: 10 capsules daily for 2 days, followed by 3 capsules daily for 8 days.
Primary Feasibility Outcomes
The two primary feasibility outcomes are:
- Recruitment rate of eligible patients into the study. This is determined by the numbers of eligible, consented, and randomized patients overall and by study site per month. Successful recruitment is defined as >85 patients over an 18-month period.
- Adherence to MET-2 or placebo for the treatment duration. Successful adherence is defined as >80% of the prescribed interventional loading dose (16/20 pills) and >75% of daily doses (18/24 pills) for the maintenance period. This is determined by returned unused capsules and records of missed doses (in the medical chart or patient study drug diary).
Secondary Feasibility Outcomes
The secondary feasibility outcomes will aim to evaluate study generalizability and sample collection feasibility, and to establish biomarker pilot data to inform a definitive trial. These will include descriptive microbiologic and demographic features of the study population, adherence to biomarker sample collection (successful adherence is defined as >80% of participants having samples suitable for analysis at 30 days post-intervention), and descriptive distribution of microbiologic, ecological and biomarker values in pre- and post-randomization stool, blood, and urine samples.
Safety and Clinical Outcomes
Safety and clinical outcomes recorded will include:
- Adverse event (AE) frequency, grade, and attribution to study product in each treatment arm, and the rate of discontinuance due to AEs;
- Infection rate at 90- and 180-days post-intervention. Infection is 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. Available data for >80% and >60% of study participants at 90 and 180 days, respectively, will constitute successful data collection;
- ARO colonization by culture at 30- and 90-days post-intervention, defined as any positive result for AROs from any site;
- Recurrence and re-infection rates (with the same organism) at 90- and 180-days post-intervention in each treatment arm;
- AMR gene complement by sequencing at 30- and 90-days post-intervention;
- All-cause mortality at 90- and 180-day;
- ICU and hospital lengths of stay;
- C. difficile carriage at days 30 and 90.
Follow-up
The total time in the study for each participant is approximately 6 months. Table 1 details the Schedule of Assessments.
Table 1: Schedule of Assessments
|
Screening
|
Baseline
|
Intervention
|
Follow-Up
|
|
Antibiotic period
|
Antibiotic washout period
(48-72 hours)
|
Day 1-2
|
Day 3-10
|
Day
30
(+ 3)
|
Day
90
(+ 7)
|
Day
180
(+ 7)
|
Eligibility screening
|
X
|
|
|
|
|
|
|
Informed consent
|
X
|
|
|
|
|
|
|
Randomization
|
|
X
|
|
|
|
|
|
MET-2 or Placebo
|
|
|
Loading dose of 10 capsules/day
|
Maintenance dose of 3 capsules/day
|
|
|
|
Stool collection
|
|
X
|
|
|
X
|
X
|
|
Rectal swab collection
|
|
X
|
|
|
X
|
X
|
X*
|
Blood collection
|
|
X
|
|
|
X
|
X
|
|
Urine collection
|
|
X
|
|
|
X
|
X
|
|
AE documentation
|
|
|
|
|
X
|
X
|
X
|
Collect data per case report form
|
X
|
X
|
|
|
X
|
X
|
X
|
*optional
Sample size and recruitment
With an anticipated rate of 85% adherence to treatment allocation, a sample size of 100 individuals (randomized 1:1) is required to provide an estimate of adherence within error margin of ±7% with 95% confidence. The data we obtain on recruitment, willingness to participate, and adherence to the study procedures will directly inform the estimates of attrition and recruitment needed to calculate the appropriate sample size and study duration of a definitive, separate trial.
Statistical analysis
Analysis will be performed at the end of the trial. No interim or subgroup analyses will be performed on collected data due to the short duration of the trial and sample size.
For primary feasibility outcomes, recruitment rates will be described overall and per site as per month recruitment, and adherence to the intervention and biomarker sample collection will be described as proportions.
Descriptive baseline characteristics in the secondary feasibility outcomes will be defined as medians/ranges (for continuous variables such as age) or proportions (for categorical variables). Adherence to biomarker sample collection will be described as rates per individual and per timepoint. Biomarker values will be reported as means (with standard deviations) with logarithmic transformation when appropriate.
The safety and clinical outcomes reporting will vary by outcome. AEs will be reported as frequency/grade. Infection and all-cause mortality will be reported for each timepoint as frequencies. ARO and C. difficile carriage will be reported as proportions. AMR gene complement will be assessed by sequencing and reported as AMR gene richness and relative abundance both overall and by mechanism and resistance by drug class.
Comparisons between categorical variables will be assessed using tests of proportion (e.g., Chi-Square), and continuous variables will be assessed using comparisons of means or non-parametrically when appropriate.
Any deviation from this statistics section of the protocol along with the accounting for missing, unused, and spurious data will be described in the final report.
Data management and monitoring
The Data and Safety Monitoring Board (DSMB) will provide independent review of study reports, procedures, indicators of trial management, and emerging safety and AE data. After the first 10 and 25 participants have reached Day 30 and after the first 50 participants have reached Day 90, the DSMB will review all available data and decide if the study has any safety concerns. The DSMB will meet on an ad hoc basis in the case of any unexpected serious safety issue or unexpected death. Recommendations made by the DSMB to alter the conduct of the study for the protection of the safety of study participants will be forwarded to the sponsor for review and for a final decision. The sponsor or its designee will notify investigative sites and regulatory authorities, as appropriate, of DSMB recommendations. All unexpected AEs and serious AEs will be reported to the Research Ethics Board. Serious and unexpected adverse drug reactions will be reported to Health Canada.