FMT for the Decolonization of Carbapenem-resistant Enterobacteriaceae (FMT-CRE)
Primary Purpose
Enterobacteriaceae Infections, Multi-antibiotic Resistance
Status
Unknown status
Phase
Phase 1
Locations
Italy
Study Type
Interventional
Intervention
Donor FMT
Placebo FMT
Sponsored by
About this trial
This is an interventional treatment trial for Enterobacteriaceae Infections focused on measuring Fecal microbiota transplantation, Enterobacteriaceae, Multi-drug resistant bacteria
Eligibility Criteria
Inclusion criteria
- 18 years old or older
- Current evidence of gut colonisation (diagnosed with rectal swab) by CRE
- Ability to give their consent to be included in the study.
Exclusion criteria
- Another known gastrointestinal infection apart from C. difficile infection
- Known active gastrointestinal disorders (e.g. infectious gastroenteritis, coeliac disease, inflammatory bowel disease, irritable bowel syndrome, chronic pancreatitis, biliary salt diarrhoea)
- Previous colorectal surgery or cutaneous stoma
- Food allergies
- Current or recent (<2 weeks) therapy with drugs that could possibly alter gut microbiota (e.g. antimicrobials, probiotics, proton pump inhibitors, immunosuppressants, metformin)
- Decompensated heart failure or heart disease with ejection fraction lower than 30%
- Severe respiratory insufficiency
- Psychiatric disorders
- Pregnancy
- Unable to give informed consent
Sites / Locations
- Digestive Disease Center, Fondazione Policlinico Univesitario A. Gemelli IRCCSRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Donor FMT
Placebo FMT
Arm Description
Patients enrolled in this arm will receive donor FMT
Patients enrolled in this arm will receive placebo FMT (that will be made of water)
Outcomes
Primary Outcome Measures
Number of participants who will obtain an eradication of CRE carriage after treatments
The investigators will evaluate the number of participants who will obtain eradication of CRE carriage after treatments, at 4 weeks-follow-up, evaluated through rectal swab for CRE
Secondary Outcome Measures
Number of participants who will obtain an eradication of CRE carriage after treatments
The investigators will evaluate the number of participants who will obtain eradication of CRE carriage after treatments, at 1,2 and 12 weeks-follow-up, evaluated through rectal swab for CRE
Number of participants with significant increase in alpha-diversity and beta-diversity of their gut microbiota after treatments
Throughout the study period (12 weeks) the investigators will evaluate the number of participants with significant increase in alpha-diversity (assessed by Shannon index) and beta-diversity (assessed by Bray-Curtis dissimilarity) of their gut microbiota after treatments, compared with baseline
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
The number of participants with treatment-related adverse events (assessed by CTCAE v4.0) will be recorded throughout the study period (12 weeks)
Full Information
NCT ID
NCT04759001
First Posted
February 13, 2021
Last Updated
August 16, 2021
Sponsor
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
1. Study Identification
Unique Protocol Identification Number
NCT04759001
Brief Title
FMT for the Decolonization of Carbapenem-resistant Enterobacteriaceae
Acronym
FMT-CRE
Official Title
Faecal Microbiota Transplantation to Eradicate Gut Colonisation From Carbapenem-resistant Enterobacteriaceae: a Randomised Controlled Trial
Study Type
Interventional
2. Study Status
Record Verification Date
August 2021
Overall Recruitment Status
Unknown status
Study Start Date
February 18, 2021 (Actual)
Primary Completion Date
February 18, 2023 (Anticipated)
Study Completion Date
February 18, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Rates of antimicrobial resistance are increasing worldwide. There is increasing evidence that physiological gut microbiota is a large reservoir of antibiotic-resistance genes. Healthy gut microbiota is known to prevent the colonization of the gastrointestinal tract by pathogens, the so-called mechanism of colonization resistance, but this protective mechanism can be altered by therapies that impair gut microbiota, including antibiotics or chemotherapeutics, with consequent colonisation of gut pathogens, including multi-drug resistant bacteria (MDRB). MDRB carriers represent an epidemiological threat to other hospitalized patients and to the whole community, but are also at risk of developing clinical consequences of this colonization, including bloodstream infections from these pathogens. Fecal microbiota transplantation (FMT) has shown high efficacy in the eradication of recurrent C. difficile infection, and initial evidence suggests that this procedure could be useful in eradicating also MDRB, mainly carbapenem-resistant Enterobacteriaceae.
However, current evidence is mostly limited to case reports and case series, and to a single randomised trial, which was stopped early and did not draw clear conclusion. In a systematic review of 21 studies and 192 patients, eradication rates ranged from 0% to 100%, and authors concluded that larger, well designed randomised controlled trials are needed to further explore this therapy.
The aim of this study is to investigate the efficacy of FMT, compared with placebo FMT, in eradicating gut colonisation from MDRB, focusing on CRE. The investigators will randomize patients colonized by CRE (diagnosed by rectal swab) to FMT from healthy donors or placebo, by colonoscopy. Then, patients will be followed up, rectal swabs will be repeated, and stool samples for culture and microbiome analysis will be collected, up to 3 months after FMT.
Detailed Description
Rates of antimicrobial resistance are increasing worldwide. There is increasing evidence that physiological gut microbiota is a large reservoir of antibiotic-resistance genes. Healthy gut microbiota is known to prevent the colonization of the gastrointestinal tract by pathogens, the so-called mechanism of colonization resistance, but this protective mechanism can be altered by therapies that impair gut microbiota, including antibiotics or chemotherapeutics, with consequent colonisation of gut pathogens, including multi-drug resistant bacteria (MDRB). MDRB carriers represent an epidemiological threat to other hospitalized patients and to the whole community, but are also at risk of developing clinical consequences of this colonization, including bloodstream infections from these pathogens. Fecal microbiota transplantation (FMT) has shown high efficacy in the eradication of recurrent C. difficile infection, and initial evidence suggests that this procedure could be useful in eradicating also MDRB, mainly carbapenem-resistant Enterobacteriaceae.
However, current evidence is mostly limited to case reports and case series, and to a single randomised trial, which was stopped early and did not draw clear conclusion. In a systematic review of 21 studies and 192 patients, eradication rates ranged from 0% to 100%, and authors concluded that larger, well designed randomised controlled trials are needed to further explore this therapy.
The extended aims of this study are:
To compare the efficacy of donor FMT and placebo FMT in eradicating gut colonisation from CRE
To compare the efficacy of donor FMT and placebo FMT in preventing clinical manifestations of gut colonisation from CRE
To investigate changes in gut microbiome after treatments
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 -80°C 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. The selection of stool donors will be performed by the gastroenterology staff following protocols previously recommended by international guidelines and according the new recommendation imposed by the reorganisation of faecal microbiota transplant during the COVID-19 pandemic (Ianiro et al. - Gut 2020) The assignment of faecal infusates from healthy donors to patients will be done randomly, without any specific recipient-donor match, as this is not recommended by international guidelines All faecal infusates will be manufactured in the microbiology unit of our hospital. Only frozen faeces will be used. Preparation of frozen faeces will follow protocols from international guidelines.
Follow-up visits will be performed by physicians from the gastroenterology and the infectious disease unit. All patients will be followed up for 3 months after the end of treatments. Follow-up visits will be scheduled at week 1, week 2, week 4, and week 12, after the end of treatments, respectively. At each visit the following assessments will be performed: 1) rectal swab for MDRB; 2) collection of stool samples for stool culture ; 3) collection of stool samples for microbiome analysis; 4) record of adverse events. Unscheduled follow-up visits will be offered if requested by the patients.
Study Outcomes are detailed in the specific section of this website.
The 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 Fisher's exact probability test (using two-tailed P-values) for categorical data. Differences in cure percentages will be determined with Fisher's exact test (with two-tailed P values). 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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Enterobacteriaceae Infections, Multi-antibiotic Resistance
Keywords
Fecal microbiota transplantation, Enterobacteriaceae, Multi-drug resistant bacteria
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Randomized controlled trial
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
To mask treatments to physicisans and recipients, both FMT bottles and syringes will be covered with dark-coloured paper before the infusion, and the patients will be unable to see the endoscopic display during the procedure. Moreover, the physicians who will evsaluate patients at follow-up will not aware of the treatment being administered.
Allocation
Randomized
Enrollment
52 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Donor FMT
Arm Type
Experimental
Arm Description
Patients enrolled in this arm will receive donor FMT
Arm Title
Placebo FMT
Arm Type
Placebo Comparator
Arm Description
Patients enrolled in this arm will receive placebo FMT (that will be made of water)
Intervention Type
Biological
Intervention Name(s)
Donor FMT
Intervention Description
This intervention is represented by the administration, in the recipients' gut, of donor microbiota through FMT
Intervention Type
Other
Intervention Name(s)
Placebo FMT
Intervention Description
This intervention is represented by the administration, in the recipients' gut, of a placebo through FMT
Primary Outcome Measure Information:
Title
Number of participants who will obtain an eradication of CRE carriage after treatments
Description
The investigators will evaluate the number of participants who will obtain eradication of CRE carriage after treatments, at 4 weeks-follow-up, evaluated through rectal swab for CRE
Time Frame
4 weeks
Secondary Outcome Measure Information:
Title
Number of participants who will obtain an eradication of CRE carriage after treatments
Description
The investigators will evaluate the number of participants who will obtain eradication of CRE carriage after treatments, at 1,2 and 12 weeks-follow-up, evaluated through rectal swab for CRE
Time Frame
12 weeks
Title
Number of participants with significant increase in alpha-diversity and beta-diversity of their gut microbiota after treatments
Description
Throughout the study period (12 weeks) the investigators will evaluate the number of participants with significant increase in alpha-diversity (assessed by Shannon index) and beta-diversity (assessed by Bray-Curtis dissimilarity) of their gut microbiota after treatments, compared with baseline
Time Frame
12 weeks
Title
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Description
The number of participants with treatment-related adverse events (assessed by CTCAE v4.0) will be recorded throughout the study period (12 weeks)
Time Frame
12 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria
18 years old or older
Current evidence of gut colonisation (diagnosed with rectal swab) by CRE
Ability to give their consent to be included in the study.
Exclusion criteria
Another known gastrointestinal infection apart from C. difficile infection
Known active gastrointestinal disorders (e.g. infectious gastroenteritis, coeliac disease, inflammatory bowel disease, irritable bowel syndrome, chronic pancreatitis, biliary salt diarrhoea)
Previous colorectal surgery or cutaneous stoma
Food allergies
Current or recent (<2 weeks) therapy with drugs that could possibly alter gut microbiota (e.g. antimicrobials, probiotics, proton pump inhibitors, immunosuppressants, metformin)
Decompensated heart failure or heart disease with ejection fraction lower than 30%
Severe respiratory insufficiency
Psychiatric disorders
Pregnancy
Unable to give informed consent
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gianluca Ianiro
Phone
3381929859
Email
gianluca.ianiro@hotmail.it
First Name & Middle Initial & Last Name or Official Title & Degree
Serena Porcari
Email
porcariserena89@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gianluca Ianiro
Organizational Affiliation
Fondazione Policlinico Gemelli IRCCS
Official's Role
Principal Investigator
Facility Information:
Facility Name
Digestive Disease Center, Fondazione Policlinico Univesitario A. Gemelli IRCCS
City
Rome
ZIP/Postal Code
00168
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gianluca Ianiro, MD
Phone
0630156265
Email
gianluca.ianiro@hotmail.it
First Name & Middle Initial & Last Name & Degree
Serena Porcari, MD
Email
porcariserena89@gmail.com
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data will be available to other researchers
IPD Sharing Time Frame
data will be available after the completion of the study, for 5 years
IPD Sharing Access Criteria
Data will be given upon reasonable request to the PI
Citations:
PubMed Identifier
18291338
Citation
Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis. 2008 Mar;8(3):159-66. doi: 10.1016/S1473-3099(08)70041-0.
Results Reference
background
PubMed Identifier
30616014
Citation
Huttner BD, de Lastours V, Wassenberg M, Maharshak N, Mauris A, Galperine T, Zanichelli V, Kapel N, Bellanger A, Olearo F, Duval X, Armand-Lefevre L, Carmeli Y, Bonten M, Fantin B, Harbarth S; R-Gnosis WP3 study group. A 5-day course of oral antibiotics followed by faecal transplantation to eradicate carriage of multidrug-resistant Enterobacteriaceae: a randomized clinical trial. Clin Microbiol Infect. 2019 Jul;25(7):830-838. doi: 10.1016/j.cmi.2018.12.009. Epub 2019 Jan 4.
Results Reference
background
PubMed Identifier
31563878
Citation
Cammarota G, Ianiro G, Kelly CR, Mullish BH, Allegretti JR, Kassam Z, Putignani L, Fischer M, Keller JJ, Costello SP, Sokol H, Kump P, Satokari R, Kahn SA, Kao D, Arkkila P, Kuijper EJ, Vehreschild MJG, Pintus C, Lopetuso L, Masucci L, Scaldaferri F, Terveer EM, Nieuwdorp M, Lopez-Sanroman A, Kupcinskas J, Hart A, Tilg H, Gasbarrini A. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019 Dec;68(12):2111-2121. doi: 10.1136/gutjnl-2019-319548. Epub 2019 Sep 28.
Results Reference
background
PubMed Identifier
32620549
Citation
Ianiro G, Mullish BH, Kelly CR, Kassam Z, Kuijper EJ, Ng SC, Iqbal TH, Allegretti JR, Bibbo S, Sokol H, Zhang F, Fischer M, Costello SP, Keller JJ, Masucci L, van Prehn J, Quaranta G, Quraishi MN, Segal J, Kao D, Satokari R, Sanguinetti M, Tilg H, Gasbarrini A, Cammarota G. Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic. Gut. 2020 Sep;69(9):1555-1563. doi: 10.1136/gutjnl-2020-321829. Epub 2020 Jul 3.
Results Reference
background
PubMed Identifier
30986562
Citation
Saha S, Tariq R, Tosh PK, Pardi DS, Khanna S. Faecal microbiota transplantation for eradicating carriage of multidrug-resistant organisms: a systematic review. Clin Microbiol Infect. 2019 Aug;25(8):958-963. doi: 10.1016/j.cmi.2019.04.006. Epub 2019 Apr 12.
Results Reference
background
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FMT for the Decolonization of Carbapenem-resistant Enterobacteriaceae
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