Ignite Creation Date:
2024-05-06 @ 6:49 PM
Last Modification Date:
2024-10-26 @ 2:55 PM
Study NCT ID:
NCT05791396
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-03-30
First Post:
2023-03-16
Brief Title:
FMT to Eradicate Intestinal Colonization by Carbapenem-resistant Enterobacteriaceae
Sponsor:
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Organization:
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Study Overview
Official Title:
Efficacy and Mechanisms of Fecal Microbiota Transplantation to Eradicate Intestinal Colonization by Carbapenem-resistant Enterobacteriaceae
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
FMT_CRE
Brief Summary:
Antibiotic resistance AR is a critical public health threat and one of the greatest challenges of the 21st century In an estimate of 2019 nearly 700000 infections and 33000 attributable deaths from multi-drug-resistant bacteria MDRB have occurred in Europe in 2015 The gastrointestinal tract is a large reservoir for MDRB and the gut microbiota can harbor a collection of AR genes called gut resistome Preliminary nonrandomized evidence suggests that fecal microbiota transplant FMT could be a promising treatment option to eradicate MDRB but established evidence as well as mechanisms that underpin this therapeutic pathway are still unavailable Leveraging our expertise in FMT OU1 microbiome OU2 and MDRB OU3 we aim to evaluate the efficacy of FMT from donors with limited presence of AR genes in eradicating intestinal MDRB through a randomized controlled trial and identifying microbial features that are associated with clinical efficacy and clearance of AR genes
Detailed Description:
Antibiotic resistance AR is a critical public health threat and one of the greatest challenges of the 21st century In an estimate of 2019 nearly 700000 infections and 33000 attributable deaths from multi-drug-resistant bacteria MDRB have occurred in Europe in 2015 Despite specific interventions including antibiotic stewardship measures and AR surveillance programs this burden has nearly doubled since 2007 and is highest for infections caused by intestinal bacteria The gastrointestinal tract is a large reservoir for MDRB and the gut microbiota can harbor a collection of AR genes called gut resistome There is increasing evidence that healthy gut microbiota can prevent the colonization of MDRB through mechanisms of colonization resistance including competition production of antimicrobial peptides immune regulation However this protective mechanism can be impaired by therapies that alter gut microbiota eg antibiotics The restoration of healthy gut microbiota by fecal microbiota transplantation FMT may lead to the eradication of antibiotic-resistant bacteria After becoming a standard treatment for Clostridioides difficile infection FMT has been investigated in several disorders and preliminary nonrandomized reports suggest that it could be a promising treatment option to eradicate MDRB but established evidence as well as mechanisms that underpin this therapeutic pathway are still unavailable We hypothesize that 1 FMT from donors with limited presence of AR genes can be more effective than placebo in eradicating intestinal MDRB focusing on carbapenem-resistant Enterobacteriaceae and 2 microbial features of donors and patients can be reproducibly associated with clinical efficacy and clearance of AR genes Our results will pave the way for the development of effective targeted microbiome-based therapies against MDRB alleviating the burden of AR with considerable benefits for healthcare systems
The extended aims of this study are
To identify FMT donors with limited presence of AR genes and store feces for FMT
To assess the efficacy of FMT in eradicating intestinal MDRB carbapenem-resistant Enterobacteriaceae and collect stool samples for multi-omics analysis
To characterize the fecal microbiome bacteriome virome mycobiome resistome of donors and patients before and after FMT to associate microbial profiles with clearance of AR genes and clinical efficacy and identify the microbial features that influence it
The investigators will carry out a single-centre placebo-controlled double blind randomised clinical trial of donor FMT vs placebo FMT in carriers of CRE Patients will be recruited among those referred to the infectious disease outpatient clinic of the Fondazione Policlinico Universitario A Gemelli Patients with all inclusion criteria and none of the exclusion criteria detailed in the specific section of this website will be considered for this study
Before randomisation demographic data will be collected by the infectious disease staff Moreover patients will repeat rectal swab and stool culture
Additionally patients will be requested to give stool samples to be collected in a sterile sealed container and stored at -80C for metagenomic assessment of gut microbiome and meta-transcriptome assessment by the microbiology staff
After baseline assessments patients will be randomly assigned to one of the following treatment arms
Donor FMT D-FMT
Placebo FMT P-FMT Patients in both groups will undergo a single FMT procedure by colonoscopy Each patient in the donor FMT group will receive faeces from one single donor Placebo FMT will be made of 250 mL water
Donors will be recruited among healthy individuals following international guidelines and according the new recommendation imposed by the reorganisation of faecal microbiota transplant during the COVID-19 pandemic Only donors with a history of limited antibiotic usage 5 antibiotic courses shorter than 10 days will be chosen for resistome analysis and only the three donors with the lowest rate of AR genes will be finally enrolled Each donor will be asked to donate frequently 7 aliquotsdonor and in a limited timeframe 3 months to minimize the risk of changes in intestinal AR genes Selected donors will be excluded if they will undergo antibiotic therapies within the donating period
Thirty-six patients with intestinal colonization by CRE will be enrolled based on sample size calculation Informed consent will be collected from all patients At baseline stool samples will be collected for multi-omics analysis Patients will be then randomized to colonoscopic FMT or placebo and will be followed up at week 1 4 and 12 after treatments At each visit they will undergo a clinical visit and a rectal swab for CRE and stool samples will be collected and stored for multi-omics analysis
Study Outcomes are detailed in the specific section of this website
Statistical analysis will be performed both on an intention-to-treat and per-protocol basis Differences among groups will be assessed with a two-tailed Wilcoxon-rank sum test for continuous data and with Fishers exact probability test using two- tailed P-values for categorical data
For microbiome analysis statistical differences between group means will be calculated using a two-tailed Wilcoxon-Rank Sum Test through the R statistical software package R Core Team Vienna Austria
Machine learning models will be used to identify and reproducibly characterize responder and nonresponder profiles In particular in a Python 39 environment using scikit-learn ver 0221 two unsupervised ML algorithm namely K-means and Agglomerative Hierarchical Clustering will be used for creating patient clusters based on baseline microbiome features in order to assess whether ML may identify distinct microbiome profiles associated with clinical response and changes in AR levels
The extended aims of this study are
To identify FMT donors with limited presence of AR genes and store feces for FMT
To assess the efficacy of FMT in eradicating intestinal MDRB carbapenem-resistant Enterobacteriaceae and collect stool samples for multi-omics analysis
To characterize the fecal microbiome bacteriome virome mycobiome resistome of donors and patients before and after FMT to associate microbial profiles with clearance of AR genes and clinical efficacy and identify the microbial features that influence it
The investigators will carry out a single-centre placebo-controlled double blind randomised clinical trial of donor FMT vs placebo FMT in carriers of CRE Patients will be recruited among those referred to the infectious disease outpatient clinic of the Fondazione Policlinico Universitario A Gemelli Patients with all inclusion criteria and none of the exclusion criteria detailed in the specific section of this website will be considered for this study
Before randomisation demographic data will be collected by the infectious disease staff Moreover patients will repeat rectal swab and stool culture
Additionally patients will be requested to give stool samples to be collected in a sterile sealed container and stored at -80C for metagenomic assessment of gut microbiome and meta-transcriptome assessment by the microbiology staff
After baseline assessments patients will be randomly assigned to one of the following treatment arms
Donor FMT D-FMT
Placebo FMT P-FMT Patients in both groups will undergo a single FMT procedure by colonoscopy Each patient in the donor FMT group will receive faeces from one single donor Placebo FMT will be made of 250 mL water
Donors will be recruited among healthy individuals following international guidelines and according the new recommendation imposed by the reorganisation of faecal microbiota transplant during the COVID-19 pandemic Only donors with a history of limited antibiotic usage 5 antibiotic courses shorter than 10 days will be chosen for resistome analysis and only the three donors with the lowest rate of AR genes will be finally enrolled Each donor will be asked to donate frequently 7 aliquotsdonor and in a limited timeframe 3 months to minimize the risk of changes in intestinal AR genes Selected donors will be excluded if they will undergo antibiotic therapies within the donating period
Thirty-six patients with intestinal colonization by CRE will be enrolled based on sample size calculation Informed consent will be collected from all patients At baseline stool samples will be collected for multi-omics analysis Patients will be then randomized to colonoscopic FMT or placebo and will be followed up at week 1 4 and 12 after treatments At each visit they will undergo a clinical visit and a rectal swab for CRE and stool samples will be collected and stored for multi-omics analysis
Study Outcomes are detailed in the specific section of this website
Statistical analysis will be performed both on an intention-to-treat and per-protocol basis Differences among groups will be assessed with a two-tailed Wilcoxon-rank sum test for continuous data and with Fishers exact probability test using two- tailed P-values for categorical data
For microbiome analysis statistical differences between group means will be calculated using a two-tailed Wilcoxon-Rank Sum Test through the R statistical software package R Core Team Vienna Austria
Machine learning models will be used to identify and reproducibly characterize responder and nonresponder profiles In particular in a Python 39 environment using scikit-learn ver 0221 two unsupervised ML algorithm namely K-means and Agglomerative Hierarchical Clustering will be used for creating patient clusters based on baseline microbiome features in order to assess whether ML may identify distinct microbiome profiles associated with clinical response and changes in AR levels
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None