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Eradication of Antibiotic-resistant Bacteria Through Antibiotics and Fecal Bacteriotherapy (R-GNOSIS WP3)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2017 by University Hospital, Geneva
Sponsor:
Collaborator:
European Commission
Information provided by (Responsible Party):
Stephen Harbarth, University Hospital, Geneva
ClinicalTrials.gov Identifier:
NCT02472600
First received: June 4, 2015
Last updated: April 28, 2017
Last verified: April 2017
  Purpose
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 .

Condition Intervention Phase
Intestinal Colonization With Multidrug-resistant Bacteria
Drug: Colistin
Drug: Neomycin
Drug: Fecal microbiota transplantation (FMT)
Drug: Omeprazole
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Randomized Controlled Multicenter Trial of a Five Day Course of Oral Colistin and Neomycin Followed by Restoration of the Gut Microbiota Using Fecal Transplantation to Eradicate Intestinal Carriage of Extended Spectrum Beta-lactamase or Carbapenemase-producing Enterobacteriaceae in High-risk Patients

Resource links provided by NLM:


Further study details as provided by University Hospital, Geneva:

Primary Outcome Measures:
  • Intestinal carriage of ESBL-E / CRE [ Time Frame: 35 to 48 days after randomization ]
    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


Secondary Outcome Measures:
  • Intestinal carriage of ESBL-E / CRE [ Time Frame: 6 months after randomization ]
    Intestinal ESBL-E or CRE carriage (detected / not detected) by stool culture during the other follow-up visits

  • Occurrence of any adverse drug reaction [ Time Frame: 6 months ]
  • Occurrence of any adverse event [ Time Frame: 6 months ]
  • Occurrence of any serious adverse event [ Time Frame: 6 months ]
  • Occurrence of any gastrointestinal adverse event [ Time Frame: 6 months ]
  • Isolation of any not intrinsically colistin resistant strain of Enterobacteriaceae during follow-up (MIC> 2mg/l) [ Time Frame: 6 months ]
  • Comparison between treatment groups of the change (relative to baseline) in the proportion of bacterial taxa and antibiotic resistance genes over time [ Time Frame: 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 [ Time Frame: 6 months ]
  • Assess the stability of the microbiome of donor stools after 3 months of frozen storage [ Time Frame: 3 months of freezing (donor stools) ]
    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

  • Assess the stability of the microbiome of donor stools after 6 months of frozen storage [ Time Frame: 6 months of freezing (donor stools) ]
    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

  • Assess the stability of the microbiome of donor stools after 12 months of frozen storage [ Time Frame: 12 months of freezing (donor stools) ]
    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

  • Assess the stability of the microbiome of donor stools after 18 months of frozen storage [ Time Frame: 18 months of freezing (donor stools) ]
    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

  • Assess the stability of the microbiome of donor stools after 24months of frozen storage [ Time Frame: 24 months of freezing (donor stools) ]
    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

  • ESBL-E and CRE infections per 100 patient months at risk (first infection with either) [ Time Frame: 6 months ]
  • Use of any antibiotics active against all of the colonizing ESBL-E / CRE strains [ Time Frame: 6 months ]
  • Use of any antibiotics active against at least one of the colonizing ESBL-E / CRE strains [ Time Frame: 6 months ]

Estimated Enrollment: 64
Study Start Date: February 2016
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: colistin + neomycin followed by FMT

CAPSULE APPROACH:

Treatment days 1-5

  • Colistin sulphate 2 million IU per os 4x/day (for 5 days)
  • Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days) Treatment day 6: no treatment

Treatment days 7 and 8:

-15 capsules of capsulized Fecal microbiota transplantation (FMT) per os per day

NASOGASTRIC TUBE APPROACH:

Treatment days 1-5

  • Colistin sulphate 2 million IU per os 4x/day (for 5 days)
  • Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days)

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)

Drug: Colistin
Other Names:
  • Polymyxin E
  • Diarönt® mono
  • A07AA10
Drug: Neomycin
Other Names:
  • Neomycin Sulfate X-Gen
  • A01AB08
Drug: Fecal microbiota transplantation (FMT)
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.
Other Names:
  • Fecal bacteriotherapy
  • Feces transplantation
Drug: Omeprazole
Administered to inhibit gastric acid secretion before FMT administration if FMT administered via nasogastric tube approach (not used for capsule approach).
Other Name: A02BC01
No Intervention: No intervention
Control arm without any intervention

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients (>= 18 years at date of inclusion)
  • Ability to provide informed consent
  • Documented intestinal carriage of ESBL-E and / or CPE by stool culture at baseline (visit 0)
  • IF COLONIZED WITH ESBL-E ONLY (WITHOUT CPE): At least one episode of symptomatic infection with ESBL-E requiring systemic antibiotic therapy within the last 180 days before date of inclusion (based on the last day of antibiotic therapy for that infection)

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

    • Systemic chemotherapy ≤30 days from baseline or planned chemotherapy within the next 6 months
    • Human Immunodeficiency Virus (HIV) with CD4 count < 250/mcl
    • Prolonged use of steroids (prednisone equivalent ≥ 60 mg per day for >= 30 days) or other immunosuppressive medications
    • neutropenia with absolute neutrophil count <1000/μL,
    • Solid organ transplant
    • Hematopoeitic stem cell transplant recipients
    • Other causes of 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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02472600

Contacts
Contact: Stephan J Harbarth, MD, MS +41 79 55 33 633 stephan.harbarth@hcuge.ch
Contact: Benedikt D Huttner, MD, MS +41 79 55 33 399 benedikt.huttner@hcuge.ch

Locations
France
Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon Recruiting
Clichy, France, 92110
Contact: Bruno Fantin, MD       bruno.fantin@bjn.aphp.fr   
Contact: Victoire de Lastours, MD    +33 (1) 71 11 46 20    victoire.de-lastours@aphp.fr   
Israel
Sourasky Medical Center Recruiting
Tel Aviv, Israel
Contact: Yehuda Carmeli       yehudac@tlvmc.gov.il   
Netherlands
Universitair Medisch Centrum Utrecht, Recruiting
Utrecht, Netherlands
Contact: Marc Bonten       M.J.M.Bonten@umcutrecht.nl   
Switzerland
Geneva University Hospitals Recruiting
Geneva, Switzerland
Contact: Stephan Harbarth, MD, MS       stephan.harbarth@hcuge.ch   
Sponsors and Collaborators
Stephen Harbarth
European Commission
Investigators
Principal Investigator: Stephan J Harbarth, MD, MS Geneva University Hospitals and University of Geneva
  More Information

Additional Information:
Publications:
Responsible Party: Stephen Harbarth, Professor, University Hospital, Geneva
ClinicalTrials.gov Identifier: NCT02472600     History of Changes
Other Study ID Numbers: 13-266
2014-003727-22 ( EudraCT Number )
Study First Received: June 4, 2015
Last Updated: April 28, 2017

Keywords provided by University Hospital, Geneva:
extended spectrum beta-lactamase producing enterobacteriaceae
carbapenemase producing enterobacteriaceae
multidrug resistant bacteria

Additional relevant MeSH terms:
Omeprazole
Neomycin
Colistin
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors

ClinicalTrials.gov processed this record on May 25, 2017