| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| late onset sepsis in the neonate and infant up to 90 days of age |
| sepsi tardiva nel neonato e lattante fino ai 90 giorni di età |
|
| E.1.1.1 | Medical condition in easily understood language |
| sepsis in neonates and infants up to 90 days of age |
|
| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053840 |
| E.1.2 | Term | Bacterial sepsis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 |
| To compare the efficacy at TOC visit of meropenem to the standard of care in the treatment of clinical or confirmed LOS in infants ≤ 90 days of postnatal age. |
| Mettere a confronto l’efficacia del Meropenem con quella della terapia standard nel trattamento della sepsi tardiva clinica o confermata, in neonati e bambini di età inferiore ai 90 giorni di vita postnatale (inclusi), durante la visita del test di cura (test of cure visit, TOC). |
|
| E.2.2 | Secondary objectives of the trial |
| • To compare the safety profile of meropenem to SOC. • To compare the efficacy at TOC visit of meropenem to SOC in confirmed sepsis. • To compare the response to meropenem and SOC on day 3 of antibacterial therapy. • To compare the efficacy at TOC visit of meropenem to SOC ignoring the change of antibiotics for safety reasons. • To compare the efficacy at TOC visit of meropenem to SOC by SOC regimen. • To compare survival at Day 28 in the meropenem arm and SOC arm. • To evaluate new infections and relapses that occur between TOC and FU visits in participants with a favourable outcome at TOC visit. • To define the organisms causing LOS. • To study antibacterial susceptibility of LOS-causing organisms and to describe clinical and microbiological responses according to this. • To compare gut colonization by resistant organisms after treatment with meropenem or SOC. |
| • Comparare il profilo di sicurezza del Meropenem con quello della terapia standard; • Comparare l’efficacia del Meropenem con quella della terapia standard nei casi di sepsi confermata, durante la visita del test di cura; • Comparare la risposta al Meropenem con quella alla terapia standard nel terzo giorno di terapia antibiotica; • Comparare l’efficacia del Meropenem con quella della terapia standard durante la visita del test di cura, non considerando i casi con sostituzione dell’antibiotico/degli antibiotici per motivi di sicurezza; • Comparare l’efficacia del Meropenem con quella della terapia standard, stratificata per regimi di terapia standard, durante la visita del test di cura; • Comparare la sopravvivenza nel braccio Meropenem con quella nel braccio terapia standard durante la visita di follow up (FU) (visita a 28 giorni); • Comparare le nuove infezioni e le ricadute. |
|
| 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 |
PHARMACOGENETIC STUDY:
Version 3 Date 2014/03/31
Title: Genetic determinants of suscebtibility to sepsis and to differential responses to Meropenem
Objectives:Find genetic determinants of suscebtibility to sepsis and to differential responses to Meropenem
|
STUDIO DI FARMACOGENETICA:
Versione 3 data: 31/03/2014
Titolo:Fattori genetici della suscittibilità alla sepsi
Obiettivi:Trovare fattori genetici che influiscono sulla suscettibilità alla sepsi e alla risposta agli antibiotici
|
|
| E.3 | Principal inclusion criteria |
| • Informed consent form signed by the parents/carers • Chronological age below 90 days inclusive • Chronological age greater or equal to 72 hours of life at beginning of LOS • Clinical or confirmed sepsis* |
| • Consenso informato firmato dai genitori/tutori; • Età cronologica < 90 giorni • Età cronologica > a 72 ore di vita al momento dell’insorgenza della sepsi tardiva; • Sepsi clinica o confermata. |
|
| E.4 | Principal exclusion criteria |
| • Administration of any systemic antibiotics for more than 24 hours prior to the randomisation, unless the change is driven by the lack of efficacy of the former regimen; • Severe congenital malformations if the infant is not expected to survive for more than 3 months; • Other situations where the treating physician considers a different antibiotic regimen necessary; • Known intolerance or contraindication to study medication; • Participation in any other clinical study of investigational drugs; • Renal failure (as defined by Akcan-Arikan et al., 2007) and requirement of haemofiltration or peritoneal dialysis; • Confirmed sepsis with microorganisms known to be resistant to study therapies. |
| • Somministrazione di qualsiasi terapia antibiotica sistemica, per più di 24 ore prima della somministrazione del farmaco in studio, eccetto il caso in cui il cambiamento della terapia sia dovuto a mancanza di efficacia del precedente regime terapeutico; • Malformazioni congenite severe, se la previsione di vita non è superiore a 3 mesi; • Altre situazioni in cui il Medico Curante ritenga necessario un diverso regime di terapia antibiotica; • Intolleranza nota o controindicazioni ai farmaci in studio; • Partecipazione a qualsiasi altro studio clinico con farmaci sperimentali; • Insufficienza renale (come definita da Akcan-Arikan et al., 2007) e necessità di emofiltrazione o dialisi peritoneale; • Sepsi confermata, causata da microrganismi resistenti alle terapie oggetto dello studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the outcome at the TOC visit performed 2 days after completion of an 11 ± 3 days full course of antibiotic treatment. A favourable outcome or a success is met when an infant fulfils all the following criteria: • Is alive • Has resolution or significant improvement (as defined in appendix B) of all abnormalities that defined LOS at entry and has no new clinical or laboratory abnormalities requiring a new course of antibiotic therapy • Has microbiological eradication either confirmed (absence of original baseline pathogen from appropriately obtained follow up specimen: CSF or blood or other sterile body fluids) or presumed (no source specimen but patient is assessed as clinically cured), and no new pathogens identified In the case of CoNS, two positive blood cultures collected more than 1 hour apart and within 24 hours of each other to confirm this is demeed to be a significant bacteremia in patients with BW >1000g. In patients with BW <1000g every effort should be made to obtain two blood cultures. However, one positive culture might be considered confirmative if there are other clinical signs and laboratory markers suggestive of neonatal sepsis (see inclusion criteria) • Has completed the 11 ± 3 days course of the regimen allocated at randomisation with no modification |
| • Outcome favorevole durante la visita del test di cura eseguita 2 giorni dopo il completamento della terapia (completion of therapy, COT) definito come sopravvivenza con risoluzione o miglioramento di tutti i parametri alterati che avevano caratterizzato la sepsi tardiva all’esordio, con eradicazione microbiologica e senza modifiche della terapia assegnata al momento della randomizzazione. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 2 days after completion of therapy |
| 2 giorni dopo il completamento della terapia |
|
| E.5.2 | Secondary end point(s) |
| • The description of all adverse events experienced by infants receiving meropenem or comparator agents - Clinical and biological adverse events will be recorded until FU visit and graded according to the need for a specific medical intervention (see page 40) - Auditory function parameters by brain-stem auditory evoked potentials will be assessed in all participants dosed with the trial drugs between EOAT and FU visit inclusive - Neurological evaluation by cerebral ultrasound (and if persistently abnormal, by magnetic resonance imaging (MRI) or computed tomography (CT) will be undertaken at any time between EOAT and the FU visit • Clinical, biological and microbiological response at Day 3, EOT, EOAT and COT • Survival at Day 28 • Time to NICU discharge • The organisms causing LOS in infants ≤ 90 days of age • The presence of antibiotic resistant bacteria at enrolment, EOT, and prior to NICU discharge (FU or before) following meropenem or SOC therapies • PK of meropenem (for details see § 8.3.7.1 on Pharmacokinetics) • Genetic parameters that can affect response to therapy |
| • Descrizione di tutti gli eventi avversi clinici e bioumorali verificatisi nei bambini trattati con Meropenem rispetto a quelli insorti nei bambini trattati con la terapia standard; • Risposta clinica e bioumorale in tutti i pazienti e nel sottogruppo con colture eseguite all’esordio risultate positive: al giorno 3, al completamento della terapia, alla fine della terapia (End Of Therapy, EOT) e alla fine della terapia assegnata (End Of Allocated Therapy, EOAT) • Sopravvivenza a 28 giorni; • Nuove infezioni o ricadute di sepsi tardiva manifestatesi tra la visita del test di cura e la visita di follow up, nei soggetti con outcome favorevole durante la visita del test di cura. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Within day 28 from enrolment. |
| Fino al giorno 28 dall’entrata nello studio di ogni singolo paziente |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 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 | 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 | 23 |
| 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
|
| Last Patient - Last Follow-up visit |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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