E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients colonized with MDR-GNB (multi-drug resistant Gram Negative bacteria ) |
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E.1.1.1 | Medical condition in easily understood language |
Patients colonized with MDR-GNB (multi-drug resistant Gram Negative bacteria ) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028152 |
E.1.2 | Term | Multi-antibiotic resistance |
E.1.2 | System Organ Class | 100000004862 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this two-arm placebo-controlled randomized trial in subjects carrying ESBL-E or CRE in their stool, as determined by culture methods, is to assess whether FMT with frozen capsules from healthy donors is effective for decolonization at 30±10 days post-randomization. |
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E.2.2 | Secondary objectives of the trial |
To determine whether FMT with frozen capsules from healthy donors is effective for the:
• Decolonization of MDR-GNB carriers at 90±30 days post-randomization
• Decolonization of MDR-GNB carriers at 30±10 days and 90± 30 days post-randomization
• Prevention of MDR-GNB infections
• Reduction of duration of MDR-GNB carriage
• Reduction of duration of isolation precautions and hospital stay
• Reduction of the relative abundance of resistant strains over the total Enterobacteriaceae
• Reduction of antibiotic consumption
• To assess the safety and tolerability of FMT
• Assess the changes in the microbiota of subjects undergoing FMT
• To assess the link between successful decolonization and microbiota profiles prior to FMT and/or microbiota profiles of the donors
• To assess factors associated with failure (no decolonization) |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Ancillary genomic studies will include genomic characterization of the MDR-GNB (this part of the work will not be financed by the PHRC but will be the subject of a separate financing).
The objective will be (i) to characterize in detail de MDR-GNB and determine whether the type of MDR-GNB or the mechanisms of resistance involved may be associated with a successful outcome and (ii) determine the intra-patient clonality of the strains in order to assess whether the strains identified during the follow-up period were similar to the strains identified at inclusion; and (iii) an interpatient, global clonality analysis will also be performed in order to assess the possible diffusion of clones among patients. |
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E.3 | Principal inclusion criteria |
a) Donors:
- Healthy subjects ≥18 years and < 50 years
- Subjects acceptable for stool donation according to the published recommendations for clinical and microbiological screening of the subject and of the stool of the Agence nationale de sécurité du médicament et des produits de santé (ANSM) in 2016.
- Written informed consent
b) Patients:
- ≥18 years and <105 years
- Colonized with a carbapenem-resistant Enterobacteriaceae (CRE) at inclusion on stool culture, or colonized with ESBL-E at inclusion on stool culture AND having suffered from an infection with an ESBL-E in the previous 12 months
- Capable of taking oral capsules (n=25 two days in a row) with no dysphagia or swallowing disorders.
- Written informed consent
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E.4 | Principal exclusion criteria |
a) Donors:
- Any history of, or current proctologic disease, or any acute condition, which in the investigator’s judgment could harm the volunteer and / or compromise or limit the evaluation of the protocol or data analysis (cf. protocole).
- Non-affiliation to a social security scheme (AME excepted)
b) Patients:
- Antibiotic treatment on the day of inclusion except for long term antibiotic prophylaxis (for at least 3 months/year)
- Patients hospitalized in the intensive care unit
- Pregnancy or breastfeeding during the study (see definitions in annex 5)
- Women of childbearing potential who are unwilling or unable to use an acceptable method of birth control [such as oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (condoms)] to avoid pregnancy for the entire study
- Patient under legal guardianship
- Participation in another trial
- Non-affiliation to a social security scheme (AME excepted)
NB. If an antibiotic treatment can be anticipated (for ex. prophylaxis treatment for surgery, or expected neutropenia) inclusion should be delayed to limit the use of antibiotics just after FMT. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects not carrying MDR-GNB (neither ESBL-E nor CRE) at day 30 (±10 days) after randomization as determined by culture methods. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Prevention of infections:
• Occurrence of a clinical infection with ESBL-E or CRE, between inclusion and day 90
• Number of days of use of systemic antibiotics between inclusion and day 90
• Number of days of isolation precautions during the hospital stay
• Length of stay in hospital
Safety: Occurrence of any adverse event or severe adverse event
Microbiology:
• Proportion of subjects not carrying MDR-GNB (neither ESBL-E nor CRE) at day 90 after randomization
• Relative abundance of resistant strains over the total Enterobacteriaceae (expressed as a ratio)
• Concentration (expressed in colony-forming units per gram of feces) of resistant strains
• Characteristics of ESBL-E/CPE strains (species identification, resistance mechanisms)
• 16S microbiome analysis, analysis in terms of diversity and operational taxonomic unit (OTU) presence:
o Intra-subject comparison of the microbiome before and after intervention (relative to baseline)
o Inter-subjects comparison between donors and patients, donors and receivers, and patients with and without a successful outcome. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |