E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
INFECTIONS DUE TO CARBAPENEM RESISTENT GRAM NEGATIVE BACTERIA |
INFEZIONE DA BATTERI GRAM NEGATIVI RESISTENTI AI CARBAPENEMICI |
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E.1.1.1 | Medical condition in easily understood language |
INFECTIONS DUE TO CARBAPENEM RESISTENT GRAM NEGATIVE BACTERIA |
INFEZIONE DA BATTERI GRAM NEGATIVI RESISTENTI AI CARBAPENEMICI |
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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 | 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 |
Miglioramento clinico a 14 giorni, definito come:
• paziente in vita E
• pressione arteriosa sistolica > 90 mmHg, senza necessità di sostegno farmacologico tramite vasopressore E
• punteggio SOFA stabile o in miglioramento, definito come segue: per SOFA al baseline ≥ 3 una riduzione di almeno il 30%; per SOFA al baseline <3 punteggio stabile o ridotto; E
• per i pazienti con HAP / VAP, rapporto PaO2/FiO2 stabile o in miglioramento; OPPURE
• per i pazienti con batteriemia, emocolture negative per il batterio target a 14 giorni, nel caso in cui il paziente sia ancora febbrile. |
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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 |
• mortalità (qualsiasi causa) a 14 e 28 giorni;
• successo clinico come definito precedentemente, ma senza alcuna modifiche di trattamento. In questo caso, l’aggiunta di antibiotici non consentiti dal protocollo di studio verrà considerata come fallimento clinico. Invece, l’interruzione precoce di terapia non verrà considerata fallimento;
• tempo di defervescenza, definito come il tempo per raggiungere una temperatura <38 ° C senza recidiva per 3 giorni consecutivi; |
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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. Patients will be included within 96 hours of the time the index culture was taken, regardless of the antibiotic treatment administered during this time period. |
Pazienti adulti (≥ 18 anni) con infezioni clinicamente significative, in base alle definizioni di seguito riportate, causate da batteri gram-negativi (Acinetobacter sp, P. aeruginosa o qualsiasi Enterobacteriaceae) carbapenemico-resistenti (CR) e colistina-sensibili. L'arruolamento dei pazienti avrà luogo solo dopo la conferma dell’isolamento tramite esami microbiologici e test di sensibilità, che dovrà avvenire entro 96 ore dalla raccolta del campione, e indipendentemente dal trattamento antibiotico somministrato durante questo periodo di tempo. |
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E.4 | Principal exclusion criteria |
• Previous inclusion in the trial. Patients will be included in the RCT only once for the first identified episode of infection
• Pregnant women
• Epilepsy or prior seizures
• Known allergy to colistin or a carbapenem |
• inclusione precedente: i pazienti saranno inclusi nello studio una sola volta corrispondente al primo episodio di infezione identificato;
• stato di gravidanza;
• storia di epilessia o convulsioni;
• allergia nota a colistina o carbapenemici; |
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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 |
Miglioramento clinico a 14 giorni, definito come:
• paziente in vita E
• pressione arteriosa sistolica > 90 mmHg, senza necessità di sostegno farmacologico tramite vasopressore E
• punteggio SOFA stabile o in miglioramento, definito come segue: per SOFA al baseline ≥ 3 una riduzione di almeno il 30%; per SOFA al baseline <3 punteggio stabile o ridotto; E
• per i pazienti con HAP / VAP, rapporto PaO2/FiO2 stabile o in miglioramento; OPPURE
• per i pazienti con batteriemia, emocolture negative per il batterio target a 14 giorni, nel caso in cui il paziente sia ancora febbrile. |
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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 |
mortalità (qualsiasi causa) a 14 e 28 giorni;
• successo clinico come definito precedentemente, ma senza alcuna modifiche di trattamento. In questo caso, l’aggiunta di antibiotici non consentiti dal protocollo di studio verrà considerata come fallimento clinico. Invece, l’interruzione precoce di terapia non verrà considerata fallimento;
• tempo di defervescenza, definito come il tempo per raggiungere una temperatura <38 ° C senza recidiva per 3 giorni consecutivi; |
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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 | Yes |
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 | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |