E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
adult inpatients ≥18 years with clinically-significant infections as defined below caused by carbapenem-resistant and colistin-susceptible Gram-negative bacteria: Acinetobacter sp., P. aeruginosa or any Enterobacteriaceae (including but not limited to K. pneumoniae, E. coli and Enterobacter sp.). |
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E.1.1.1 | Medical condition in easily understood language |
adult inpatients ≥18 years with clinically-significant infections as defined below caused by carbapenem-resistant and colistin-susceptible Gram-negative bacteria. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Microbiological Phenomena [G06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10004047 |
E.1.2 | Term | Bacterial infections NEC |
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 |
Clinical success, defined as a composite of all of the following, all measured at 14 days: • Patient alive • Systolic blood pressure >90 mmHg without need for vasopressor support • Stable or improved SOFA score, define as: o for baseline SOFA ≥ 3: a decrease of at least 30%; o for baseline SOFA <3: stable or decreased SOFA score • For patients with HAP/ VAP, PaO2/FiO2 ratio stable or improved • For patients with bacteremia, no growth of the initial isolate in blood cultures taken on day 14 if patient still febrile
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E.2.2 | Secondary objectives of the trial |
• 14 and 28-day all-cause mortality • Clinical success, as defined above, but any modification to the antibiotic treatment not permitted by protocol will also be considered as failure. This will include any change or addition of antibiotics not permitted by study protocol. Early discontinuation of antibiotic treatment will not be considered as failure. • Time to defervescence, defined as time to reach a temperature of <38°C with no recurrence for 3 days • Time to weaning from mechanical ventilation in VAP for patients weaned alive • Time to hospital discharge for patient discharged alive • Change in functional capacity from baseline before infection onset to discharge from hospital. Function capacity will be classified into 3 grades: I. Independent II. Need for assistance for activities of daily living
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
We will include adult inpatients ≥18 years with clinically-significant infections as defined below caused by carbapenem-resistant and colistin-susceptible Gram-negative bacteria: Acinetobacter sp., P. aeruginosa or any Enterobacteriaceae (including but not limited to K. pneumoniae, E. coli and Enterobacter sp.). Patient recruitment will occur only after microbiological documentation and susceptibility testing. All efforts should be made to recruit patients as soon as possible after isolate identification. |
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E.4 | Principal exclusion criteria |
Patient recruitment will occur only after microbiological documentation and susceptibility testing. All efforts should be made to recruit patients as soon as possible after isolate identification.
• Previous inclusion in the trial. Patients will be included in the RCT only once for the first identified episode of infection • Colistin administered >96 hours prior to randomization • Pregnant women • Epilepsy or prior seizures • Known allergy to colistin or a carbapenem
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E.5 End points |
E.5.1 | Primary end point(s) |
Clinical success, defined as a composite of all of the following, all measured at 14 days: • Patient alive • Systolic blood pressure >90 mmHg without need for vasopressor support • Stable or improved SOFA score, define as: o for baseline SOFA ≥ 3: a decrease of at least 30%; o for baseline SOFA <3: stable or decreased SOFA score • For patients with HAP/ VAP, PaO2/FiO2 ratio stable or improved • For patients with bacteremia, no growth of the initial isolate in blood cultures taken on day 14 if patient still febrile |
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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) |
• 14 and 28-day all-cause mortality • Clinical success, as defined above, but any modification to the antibiotic treatment not permitted by protocol will also be considered as failure. This will include any change or addition of antibiotics not permitted by study protocol. Early discontinuation of antibiotic treatment will not be considered as failure. • Time to defervescence, defined as time to reach a temperature of <38°C with no recurrence for 3 days • Time to weaning from mechanical ventilation in VAP for patients weaned alive • Time to hospital discharge for patient discharged alive • Change in functional capacity from baseline before infection onset to discharge from hospital. Function capacity will be classified into 3 grades: I. Independent II. Need for assistance for activities of daily living |
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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 | Yes |
E.6.5 | Efficacy | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |