| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| severe infections due to extended-spectrum beta-lactamase–producing Gram-negative Enterobacteriaceae |
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| E.1.1.1 | Medical condition in easily understood language |
| severe infections due to extended-spectrum beta-lactamase–producing Gram-negative Enterobacteriaceae |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| 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 the study is to demonstrate that among patients hospitalized in ICU with ESBL-producing Enterobacteriaceae severe infection (i.e. sepsis or septic shock), a treatment with a carbapenem-sparing agent (piperacillin/tazobactam or temocillin) is non-inferior to a carbapenem in terms of mortality. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to compare carbapemen-sparing agents (piperacillin/tazobactam or temocillin) to carbapenem in terms of relapse/recurrence of ESBL infection, secondary nosocomial infection, antibiotic allergy and adverse events, antibiotic consumption, ICU and hospital length of stay and organ failure kinetics.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients ≥ 18-year-old
2. Hospitalized in the ICU
3. Severe infection, eg sepsis or septic shock (according to the Sepsis-3 definition)
a. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, characterized by an increase of Sequential Organ Failure Assessment (SOFA) score of 2 points or more. This increase in 2 points will be calculated the day infection is diagnosed (day of positive culture serving as reference for the infection) as compared to the day before infection onset.
b. Septic shock is defined as sepsis and persisting hypotension requiring vasopressors to maintain mean arterial pressure ≥65 mmHg and having a serum lactate level >2 mmol/l despite adequate volume resuscitation.
This criterion (sepsis or septic shock) has to be fulfilled within a time frame of +/- 24 hours from the day of infection diagnosis (i.e. the day of positive bacteriological sample).
4. Pathogen responsible for infection is an ESBL-producing Enterobacteriaceae susceptible to meropenem and either to piperacillin/tazobactam (minimum inhibitory concentration <8 mg/L) or to temocillin (minimum inhibitory concentration ≤8 mg/L)
5. Informed consent from a legal representative/family member/close relative. According to the specifications of emergency inclusion, randomization without the close relative or surrogate consent could be performed. Close relative/surrogate/family consent will be asked as soon as possible. The patient will be asked to give his/her consent for the continuation of the trial when his/her condition will allow
6. Affiliation to social security (AME excluded)
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| E.4 | Principal exclusion criteria |
1. Pregnancy or breastfeeding
2. Known allergy to beta-lactam
3. Patient with severe neutropenia, as defined by absolute neutrophil count <0.5x109/L
4. Infection requiring prolonged antimicrobial treatment (endocarditis; mediastinitis; osteomyelitis/septic arthritis; undrainable/undrained abscess; unremovable/unremoved prosthetic-associated infection)
5. Moribund, defined by a SAPS II score at inclusion >75
6. Decision of withholding/withdrawing care
7. Patient with concomitant infection requiring antibiotics with activity against Gram-negative bacilli
8. Participation in another interventional study or being in the exclusion period at the end of a previous study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be mortality at 30 days from the date of randomization. Vital status will be assessed at day 30 post randomization either by visit if the patient is still in the hospital, or by phone is the patient is discharged from the hospital. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 30 days from the date of randomization. |
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| E.5.2 | Secondary end point(s) |
- 90-day mortality rate. Vital status at day 90 will be assessed either by visit if the patient is still in the hospital, or by phone is the patient is discharged from the hospital.
- Relapse rates of ESBL infection at day 30. Relapse of ESBL-producing Enterobacteriaceae infection is defined as new infection after randomization (whatever the site) due to ESBL-producing Enterobacteriaceae, either the same strain responsible for first episode, or a different one. The total number of relapse will be taken into account until day 30 post randomization.
- Clinical failure rate at day 30. A clinical failure will be defined by a relapse of ESBL infection or death between randomization and day 30.
- Rate of antibiotic allergy at day 30. Antibiotic allergy is defined as anaphylactic reaction (such as but not limited to skin rash, fever, eosinophilia, acute renal failure, hepatic).
- Rate of adverse events at day 30, defined as the proportion of patient with at least one adverse events occurring from randomization to day 30. Adverse event, severe adverse event will be described by intensity and frequency.
- ICU length of stay, measured by the number of days in the ICU since randomization.
- Hospital length of stay, measured by the number of days in the hospital since randomization.
- ICU- free days at day 30, measured as the number of day alive and outside the ICU from randomization to day 30 post-randomization. Patients dying before day 30 will have zero ICU-free days.
- Hospital-free days at day 30, measured as the number of day alive and outside the hospital from randomization to day 30 post-randomization. Patients dying before day 30 will have zero hospital-free days.
- Antibiotic-free days at day 30, measured as the number of day alive and without antibiotics from randomization to day 30 post-randomization. Patients dying before day 30 will have zero antibiotic-free days.
- Kinetics of organ failure from randomization to day 30 post-randomization, assessed by the sequential organ failure assessment (SOFA) score and its components [28]. This score will be calculated at randomisation, and days 3, 5, 7, 14 and 30 post-randomization.
- Rate of faecal colonization with carbapenem-resistant Gram-negative bacilli at randomization, at end of treatment, at ICU discharge (or at day 90 if patients still hospitalized in ICU), measured by the presence in the stools of carbapenems-resistant organisms
- Rate of Clostridium difficile infection at day 90. Clostridium difficile infection is defined as diarrhea, ileus or toxic megacolon with Clostridium difficile toxin in stools [29]
- Rate of secondary nosocomial infection at day 90. Secondary nosocomial infection is defined as any infection (including but not limited to nosocomial pneumonia, catheter-related bloodstream infection, urinary tract infection, surgical site infection…) occurring from randomization to day 90.
- Proportion of patients in whom duration of antimicrobial treatment of the index episode (the episode that led to inclusion in the study) exceed the recommended duration (See 4.2.1). For example, a patient has been included in the protocol for ventilator-associated pneumonia, for which recommendation is to stop antibiotics after 7-8 days. If the duration of treatment for this patient is 9 days, this patient will be considered as not following the guidelines.
- Proportion of patients who change their treatment before the recommended duration (see summary of guidelines) without relapse (= cross-over). For example a patient has been included in the protocol for ventilator-associated pneumonia, for which recommendation is to stop antibiotics after 7-8 days. This patient is randomized in the experimental arm and he receives piperacillin/tazobactam, but the investigator decides to change and to give a carbapenems to the patient before day 7-8.
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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) | No |
| 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 | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 30 |
| 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 | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 39 |
| E.8.9.1 | In the Member State concerned days | |
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