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| ID | Type | Description | Link |
|---|---|---|---|
| 2014-003727-22 | EudraCT Number |
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| Name | Class |
|---|---|
| European Commission | OTHER |
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This investigator initiated,international, multicenter open-label, randomized controlled trial aims to assess whether a 5 day course of oral nonabsorbable antibiotics (colistin sulfate 2 million IU per os 4x/day and neomycin sulfate 500 mg (salt) per os 4x/day ) followed by fecal microbiota transplantation (administered either via nasogastric administration or via capsules) is effective at eradicating intestinal carriage of beta-lactamase producing Enterobacteriaceae (ESBL-E) and carbapenemase producing Enterobacteriaceae (CPE). compared to no intervention (current standard of care) in adult non-immunosuppressed patients .
In recent years a certain family of bacteria (Enterobacteriaceae) that colonizes the human gastrointestinal tract but can also cause severe infections has increasingly become resistant to antibiotics by acquiring enzymes that can inactivate a wide array of these valuable drugs. Depending on the class of beta-lactam antibiotics that these enzymes can inactivate, these bacteria are either designated as extended spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) or carbapenemase producing Enterobacteriaceae (CPE).
The R-GNOSIS project which is financed by the European Commission combines five separate international clinical studies (work packages 2 to 6) that examine intervention strategies to reduce carriage, infection and spread of these bacteria. This study (work package 3 of R-GNOSIS) will be conducted in 4 centers in 3 European countries (Switzerland, France, The Netherlands) and Israel. The study will examine whether it is possible to eradicate intestinal carriage with ESBL-E and CPE by administering a 5 day course of oral nonabsorbable antibiotics (colistin sulfate and neomycin sulfate) followed by administration of "healthy" stool flora obtained from a healthy volunteer donor ("fecal microbiota transplantation" or FMT). The "healthy" stool flora for this procedure will be obtained from carefully selected healthy volunteers that have been tested for a wide variety of infectious diseases and do not show any risk factors or risky behavior for transmittable diseases. Once the fecal material has been processed it will be frozen at -80°C for up to six months until administration to patients (via capsules or via a nasogastric tube). FMT has been successfully used to treat recurrent infections with a specific pathogen (Clostridium difficile) and has proven safe and effective for this indication but has never been studied with the aim of eradicating multidrug-resistant organisms.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| colistin + neomycin followed by FMT | Active Comparator | CAPSULE APPROACH: Treatment days 1-5
Treatment days 7 and 8: -15 capsules of capsulized Fecal microbiota transplantation (FMT) per os per day NASOGASTRIC TUBE APPROACH: Treatment days 1-5
Treatment day 6 and 7: - Omeprazole 20 mg per os 1 dose on the evening of day 6 and on the morning of day 7 Treatment day 7: - Infusion of 80 ml of a standardized stool suspension through a nasogastric tube - Fecal microbiota transplantation (FMT) |
|
| No intervention | No Intervention | Control arm without any intervention |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Colistin | Drug |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Intestinal carriage of ESBL-E / CRE | Intestinal carriage of ESBL-E / CRE (absence / presence by stool culture of any ESBL-E and / or CRE with enrichment independent of type of carriage at baseline) 35 to 48 days after randomization | 35 to 48 days after randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Intestinal carriage of ESBL-E / CRE | Intestinal ESBL-E or CRE carriage (detected / not detected) by stool culture during the other follow-up visits | 6 months after randomization |
| Occurrence of any adverse drug reaction |
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Inclusion Criteria:
Exclusion Criteria:
Pregnancy or planned pregnancy
Breastfeeding
Difficult / impossible follow-up
Allergy or other contraindication to one of the study drugs
Recurrent aspirations / chronic dysphagia
Resistance to colistin (defined as MIC> 2 mg/l) of any of the ESBL-E or CPE strains isolated at baseline
Estimated life expectancy < 6 months
Treatment with any systemic antibiotic on the day of inclusion
Severe immunodeficiency
Current hospitalization in an Intensive Care Unit
Estimated glomerular filtration rate (CKD-EPI) < 15 ml/min/1.73m2
Severe food allergy (anaphylaxis, urticaria)
Unavailability of compatible FMT preparation (with regard to donor / recipient cytomegalovirus, Epstein-Barr virus and toxoplasma serology)
Anatomic contraindication to the placement of a nasogastric tube (only if FMT application via nasogastric tube)
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| Name | Affiliation | Role |
|---|---|---|
| Stephan J Harbarth, MD, MS | Geneva University Hospitals and University of Geneva | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon | Clichy | 92110 | France | |||
| Sourasky Medical Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23719234 | Background | Huttner B, Haustein T, Uckay I, Renzi G, Stewardson A, Schaerrer D, Agostinho A, Andremont A, Schrenzel J, Pittet D, Harbarth S. Decolonization of intestinal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae with oral colistin and neomycin: a randomized, double-blind, placebo-controlled trial. J Antimicrob Chemother. 2013 Oct;68(10):2375-82. doi: 10.1093/jac/dkt174. Epub 2013 May 29. | |
| 25322359 |
| Label | URL |
|---|---|
| Official website of the R-GNOSIS project | View source |
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| ID | Term |
|---|---|
| D003091 | Colistin |
| D009355 | Neomycin |
| D000069467 | Fecal Microbiota Transplantation |
| D009853 | Omeprazole |
| ID | Term |
|---|---|
| D011113 | Polymyxins |
| D010456 | Peptides, Cyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
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| Neomycin | Drug |
|
|
| Fecal microbiota transplantation (FMT) | Drug | FMT consist in the administration of fecal material obtained from healthy donors that has been diluted, homogenized, filtered and reconcentrated. In this study the processed fecal material will be frozen at -80°C after processing and will be administered to patients for up to six months after freezing via a nasogastric tube or via capsules. |
|
|
| Omeprazole | Drug | Administered to inhibit gastric acid secretion before FMT administration if FMT administered via nasogastric tube approach (not used for capsule approach). |
|
|
| 6 months |
| Occurrence of any adverse event | 6 months |
| Occurrence of any serious adverse event | 6 months |
| Occurrence of any gastrointestinal adverse event | 6 months |
| Isolation of any not intrinsically colistin resistant strain of Enterobacteriaceae during follow-up (MIC> 2mg/l) | 6 months |
| Comparison between treatment groups of the change (relative to baseline) in the proportion of bacterial taxa and antibiotic resistance genes over time | 6 months |
| Comparison of the global microbiota composition and diversity between the groups with FMT from the same donor and the groups with FMT from different donors | 6 months |
| Assess the stability of the microbiome of donor stools after 3 months of frozen storage | Aliquots from a random sample of donations will also be taken for metagenomic analysis performed after 3 months of storage at -80°C to assess the long-term impact of freezing on the microbiome | 3 months of freezing (donor stools) |
| Assess the stability of the microbiome of donor stools after 6 months of frozen storage | Aliquots from a random sample of donations will also be taken for metagenomic analysis performed after 6 months of storage at -80°C to assess the long-term impact of freezing on the microbiome | 6 months of freezing (donor stools) |
| Assess the stability of the microbiome of donor stools after 12 months of frozen storage | Aliquots from a random sample of donations will also be taken for metagenomic analysis performed after 12 months of storage at -80°C to assess the long-term impact of freezing on the microbiome | 12 months of freezing (donor stools) |
| Assess the stability of the microbiome of donor stools after 18 months of frozen storage | Aliquots from a random sample of donations will also be taken for metagenomic analysis performed after 18 months of storage at -80°C to assess the long-term impact of freezing on the microbiome | 18 months of freezing (donor stools) |
| Assess the stability of the microbiome of donor stools after 24months of frozen storage | Aliquots from a random sample of donations will also be taken for metagenomic analysis performed after 24 months of storage at -80°C to assess the long-term impact of freezing on the microbiome | 24 months of freezing (donor stools) |
| ESBL-E and CRE infections per 100 patient months at risk (first infection with either) | 6 months |
| Use of any antibiotics active against all of the colonizing ESBL-E / CRE strains | 6 months |
| Use of any antibiotics active against at least one of the colonizing ESBL-E / CRE strains | 6 months |
| Tel Aviv |
| Israel |
| Universitair Medisch Centrum Utrecht, | Utrecht | Netherlands |
| Geneva University Hospitals | Geneva | Switzerland |
| Background |
| Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014 Nov 5;312(17):1772-8. doi: 10.1001/jama.2014.13875. |
| 31954100 | Derived | de Lastours V, Poirel L, Huttner B, Harbarth S, Denamur E, Nordmann P. Emergence of colistin-resistant Gram-negative Enterobacterales in the gut of patients receiving oral colistin and neomycin decontamination. J Infect. 2020 May;80(5):578-606. doi: 10.1016/j.jinf.2020.01.003. Epub 2020 Jan 15. No abstract available. |
| 30616014 | Derived | 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. |
| D055666 |
| Lipopeptides |
| D008055 | Lipids |
| D023181 | Antimicrobial Cationic Peptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000089882 | Antimicrobial Peptides |
| D052899 | Pore Forming Cytotoxic Proteins |
| D008565 | Membrane Proteins |
| D011506 | Proteins |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
| D053799 | 2-Pyridinylmethylsulfinylbenzimidazoles |
| D013454 | Sulfoxides |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001562 | Benzimidazoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |