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    Summary
    EudraCT Number:2017-002110-32
    Sponsor's Protocol Code Number:10-0065
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-07
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-002110-32
    A.3Full title of the trial
    DMID Protocol Number: 10-0065
    OVERCOME Trial: Randomized Controlled Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli
    Sperimentazione OVERCOME: Sperimentazione randomizzata e controllata per il trattamento dei
    bacilli Gram-negativi estensivamente resistenti ai farmaci
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized treatment with either Colistin/Meropenem or Colistin/Placebo
    for extremely drug resistant Gram-negative Bacilli
    Trattamento randomizzato con Colistimettato/Meropenem o Colistimetato/Placebo per bacilli Gram-negativi estensivamente resistenti ai farmaci
    A.3.2Name or abbreviated title of the trial where available
    OVERCOME
    OVERCOME
    A.4.1Sponsor's protocol code number10-0065
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01597973
    A.5.3WHO Universal Trial Reference Number (UTRN)U0000-0000-0000
    A.5.4Other Identifiers
    Name:-Number:-
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTHE REGENTS OF THE UNIVERSITY OF MICHIGAN
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUniversit¿ del Michigan
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD Italy
    B.5.2Functional name of contact point-
    B.5.3 Address:
    B.5.3.1Street Addressvia San Bovio, 3 - San Felice
    B.5.3.2Town/ citySegrate (MI)
    B.5.3.3Post code20090
    B.5.3.4CountryItaly
    B.5.4Telephone number003902210811
    B.5.5Fax number00390221081228
    B.5.6E-mailDL_RegulatoryItaly@ppdi.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MEROPENEM HOSPIRA - 1 G POLVERE PER SOLUZIONE INIETTABILE O PER INFUSIONE 1 FLACONCINO IN VETRO
    D.2.1.1.2Name of the Marketing Authorisation holderHOSPIRA ITALIA S.R.L.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMeropenem
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMEROPENEM
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name COLISTIMETATO XELLIA - 1 MILIONE U.I. POLVERE PER SOLUZIONE INIETTABILE O PER INFUSIONE 10 FLACONCINI IN VETRO
    D.2.1.1.2Name of the Marketing Authorisation holderXELLIA PHARMACEUTICALS APS
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameColistimetato
    D.3.2Product code -
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCOLISTIMETATO SODICO
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameColistimethate sodium (Colistin)
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Blood stream Infection (BSI) and/or pneumonia due to extensively drug-resistant Gram-negative bacilli (XDR-GNB) including XDR-AB, CRE and XDR-PA
    Infezione del sangue e/o polmonite dovute a bacilli Gram-negativi estensivamente resistenti (XDR-GNB) compresi XDR-AB, CRE e XDR-PA
    E.1.1.1Medical condition in easily understood language
    Blood stream infection and/or pneumonia
    Infezione del sangue e/o polmonite
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10064977
    E.1.2Term Acinetobacter bacteremia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10004031
    E.1.2Term Bacterial infection due to other gram-negative organisms
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10054280
    E.1.2Term Escherichia coli bacteraemia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10021860
    E.1.2Term Infection Pseudomonas aeruginosa
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10023456
    E.1.2Term Klebsiella pneumonia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10035701
    E.1.2Term Pneumonia gram-negative bacterial NOS
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10051190
    E.1.2Term Pneumonia Pseudomonas aeruginosa
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10054218
    E.1.2Term Enterobacter pneumonia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10035679
    E.1.2Term Pneumonia due to Escherichia coli (E. Coli)
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10058884
    E.1.2Term Enterobacter bacteremia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10058883
    E.1.2Term Klebsiella bacteremia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Determine whether the treatment regimen of colistin combined with a carbapenem (imipenem or meropenem) is associated with a decreased
    risk for all-cause mortality during the 30 day post-enrollment period compared to colistin alone for subjects with bloodstream infection (BSI)
    and/or pneumonia due to extensively drug-resistant Gram-negative bacilli (XDR-GNB).
    Determinare se il regime di trattamento con colistina in combinazione con un carbapenemico (imipenem o meropenem) ¿ associato a una diminuzione del rischio di mortalit¿ per tutte le cause durante il periodo post-arruolamento di 30 giorni rispetto a colistina in monoterapia, per i soggetti con infezione del sangue (BSI) e/o polmonite causate da bacilli Gram-negativi estensivamente resistenti ai farmaci (XDR-GNB).
    E.2.2Secondary objectives of the trial
    Determine what treatment regimen (colistin monotherapy or colistin combined a carbapenem (imipenem or meropenem) is more likely to
    reduce the frequency of emergence of colistin resistance among XDRGNB isolates during therapy
    Determinare quale regime di trattamento (colistina in monoterapia o colistina in combinazione con un carbapenemico (imipenem o meropenem) ha pi¿ probabilit¿ di ridurre la frequenza dell'insorgenza di resistenza alla colistina tra gli isolati di XDR-GNB durante la terapia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Hospitalized Adults (> 18 years to 95 years of age), at one of the study sites.
    • Diagnosis of BSI and/or pneumonia (refer to Section 5.2.3 for definitions), due to a preliminary result of gram-negative non-lactose fermenter that is oxidase negative; ; or E. coli, Klebsiella spp. or Enterobacter spp. that are suspected to be CRE based on a screening test result (meropenem, imipenem, doripenem or ertapenem MIC>1 ug/ml); or result of a rapid molecular test performed indicating presence of A. baumannii, E. coli, Klebsiella spp., Enterobacter spp. or P. aeruginosa; or a final result of XDR-A. baumannii; carbapenem-resistant Enterobacteriaceae; or XDR- P. aeruginosa (refer to List of Abbreviations and Definition Section for pathogen definitions) and/or patients with suspected BSI and/or pneumonia and who have had a prior history (within last 6 months) of XDR-GNB that was susceptible to colistin.
    o If final results do not indicate that the pathogen is an XDR-GNB, according to study definitions, and alternative treatment options are identified, the patient would be eligible for the study if the patient is allergic to non-carbapenem beta-lactam treatment options. Patients are also eligible for inclusion if they have pneumonia or BSI due to Pseudomonas aeruginosa that, while “susceptible” to a beta-lactam option by current in vitro breakpoint definitions, the isolate is not considered to be treatable by the prescribing physician due to inability to achieve adequate clinical efficacy and/or pharmacokinetic/pharmacodynamic targets using standard approved dosages of these beta-lactam antimicrobials. For the purposes of this study, patients would be eligible if they have an infection due to a strain of Pseudomonas aeruginosa with a cefepime MIC of 8 mcg/ml; or imipenem/meropenem/doripenem MIC of 2 mcg/mL or aztreonam MIC of 8mcg/mL; where the treating physician does not feel that treatment with these agents would be adequate or optimal to treat this type of Pseudomonas aeruginosa strain. Recent literature suggests that current CLSI breakpoints may not be appropriate126,127.
    o In addition, if the pathogen is A. baumannii that is susceptible to ampicillin/sulbactam and the treating physician feels that ampicillin/sulbactam is not appropriate therapy, then the patient would be eligible for the trial, as the role and optimal dose of ampicillin/sulbactam remains uncertain for the treatment of invasive A. baumannii infections. Patients are also eligible at sites where the clinical microbiology laboratory does not differentiate between A. baumannii and non-baumannii Acinetobacter, because it is assumed that all XDR Acinetobacter are XDR A. baumannii.
    o Patients can also be included if they have isolates that are susceptible to ceftolazane-tazobactam and/or ceftazidime-avibactam and/or antimicrobials approved by the FDA after 1/1/2017.
    • Patients with polymicrobial respiratory or blood infections, including XDR-GNB and one or more pathogens, will be included in the study, as long as the XDR-GNB is determined to be a true pathogen (AB, CRE or PA). Other pathogens will be treated with antimicrobial agents as determined by the treating physician.
    • If more than one XDR-GNB study pathogens is identified as a study pathogen causing BSI and/or pneumonia, then the first study pathogen recovered will be considered as the primary study pathogen. If more than one study pathogen is recovered from the same culture, then the infection will be categorized as being caused by multiple study pathogens.
    • Patients with a life expectancy of > 24 hours
    • Signed written informed consent and HIPAA Authorization (if applicable) form
    ¿ For Israel ICF exception refer to SOP #7 in the MOP.
    • Adulti ricoverati in ospedale (da > 18 anni a 95 anni di età), presso uno dei centri dello studio.
    • Diagnosi di BSI e/o polmonite (fare riferimento alla sezione 5.2.3 del protocollo per le definizioni), dovuta a un risultato preliminare di Gram-negativi non fermentanti il lattosio, ossidasi-negativi; o E. coli, Klebsiella spp. o Enterobacter spp. che si sospetta siano CRE sulla base del risultato del test di screening (meropenem, imipenem, doripenem o ertapenem con MIC>1 µg/ml); o risultato di un test molecolare rapido eseguito che indica la presenza di A. baumannii, E. coli, Klebsiella spp., Enterobacter spp. o P. aeruginosa; o un risultato finale di A. baumannii XDR; Enterobacteriaceae resistenti ai carbapenemi; o P. aeruginosa XDR; (fare riferimento alla sezione del protocollo Elenco delle abbreviazioni e delle definizioni per le definizioni dei patogeni) e/o pazienti che presentano sospetto di BSI e/o polmonite e anamnesi precedente (entro gli ultimi 6 mesi) di XDR-GNB sensibile alla colistina.
    o Nel caso in cui i risultati finali non indichino che il patogeno è un XDR-GNB, secondo le definizioni dello studio e vengano identificate opzioni di trattamento alternativo, il paziente sarà considerato eleggibile per lo studio se questi è allergico alle opzioni di trattamento con antibiotici beta-lattamici non carbapenemici. I pazienti sono inoltre eleggibili per l'inclusione se presentano polmonite o BSI causate da Pseudomonas aeruginosa il cui isolato, pur essendo sensibile all'opzione con beta-lattamici secondo le definizioni di breakpoint in vitro attuali, non è considerato trattabile dal medico responsabile a causa dell'impossibilità di raggiungere un'adeguata efficacia clinica e/o i target di farmacocinetica/farmacodinamica utilizzando dosaggi standard approvati di questi antimicrobici beta-lattamici. Per gli scopi di questo studio, i pazienti saranno considerati eleggibili se presentano un'infezione causata da un ceppo di Pseudomonas aeruginosa con cefepima con MIC di 8 mcg/ml; oppure imipenem/meropenem/doripenem con MIC di 2 mcg/ml o aztreonam con MIC di 8 mcg/ml; nel caso in cui il medico responsabile non ritenga che il trattamento con tali agenti sia adeguato o ottimale per trattare questo tipo di ceppo di Pseudomonas aeruginosa. La letteratura recente suggerisce che i breakpoint del CLSI attuali potrebbero non essere appropriati126,127.
    o Inoltre, se il patogeno è A. baumannii che è sensibile a ampicillina/sulbactam e il medico responsabile ritiene che ampicillina/sulbactam non sia la terapia appropriata, il paziente sarà eleggibile per la sperimentazione, in quanto il ruolo e la dose ottimale di ampicillina/sulbactam rimane incerta per il trattamento delle infezioni invasive da A. baumannii. I pazienti sono inoltre eleggibili presso i centri in cui il laboratorio di microbiologia clinica non effettua distinzione tra A. baumannii e Acinetobacter non-baumannii, poiché si presume che tutti gli Acinetobacter XDR siano A. baumannii XDR.
    o I pazienti possono inoltre essere inclusi se presentano isolati sensibili a ceftolazane-tazobactam e/o ceftazidima-avibactam e/o antimicrobici approvati dalla FDA dopo l'1/1/2017.
    • I pazienti affetti da infezioni polimicrobiche respiratorie o del sangue, che includono XDR-GNB e uno o più patogeni, saranno inclusi nello studio, purché si determini che XDR-GNB è un vero patogeno (AB, CRE o PA). Altri patogeni saranno trattati con agenti antimicrobici come determinato dal medico responsabile del trattamento.
    • Se più di uno dei patogeni XDR-GNB in studio è identificato come patogeno in studio causa di BSI e/o polmonite, il primo patogeno in studio individuato sarà considerato come il patogeno in studio primario. Se più di un patogeno in studio viene individuato nella stessa coltura, l'infezione sarà classificata come causata da più patogeni in studio.
    • Pazienti con aspettativa di vita di > 24 ore
    • Firma del consenso informato scritto e del modulo di autorizzazione HIPAA (se applicabile)
    ¿ Per l'eccezione del modulo di consenso informato per Israele, fare riferimento alla SOP n. 7 nel MOP.
    E.4Principal exclusion criteria
    • Female patients who are pregnant
    • Female patients who are nursing
    • Patients who are prisoners
    • Patients who are less than 18 years of age or greater than or equal to 96 years of age
    • Patients with neutropenia (WBC<500 cells/mm3)
    • The presence of any of the following known clinical syndromes involving XDR-GNB as a study pathogen which necessitate durations of antimicrobial therapies greater than 14 days: endocarditis, osteomyelitis, prosthetic joint infections, meningitis and/or other central nervous system infections.
    • Patients receiving valproic acid (with or without a known seizure disorder).
    • Patients who received 72 hours or more of polymyxin treatment (excluding inhaled and topical formulations) within 96 hours of enrollment.
    • Patients who have end-stage renal disease requiring hemodialysis are not excluded from the study but will be excluded from evaluation pertaining to nephrotoxicity in the per protocol population.
    • Patients with known Type 1 or other severe drug allergy to either of the study drugs or to ß-lactams.
    o If patients with ß-lactam allergy have previously received carbapenems safely then they would not be excluded.

    No exclusions were made based upon gender or demographic preferences. Children <18 years of age were excluded from the study as they have not frequently developed infections due to XDR-GNB at study hospitals and the PK/PD of study drugs would have been different in this population.
    • Pazienti di sesso femminile in stato di gravidanza
    • Pazienti di sesso femminile che allattano al seno
    • Pazienti detenuti in carcere
    • Pazienti con età inferiore a 18 anni o superiore o pari a 96 anni
    • Pazienti con neutropenia (WBC<500 cellule/mm3)
    • La presenza di una qualsiasi delle seguenti note sindromi cliniche che coinvolgono XDR-GNB come patogeno in studio e necessitano di terapie antimicrobiche di durata superiore a 14 giorni: endocardite, osteomielite, infezione delle protesi articolari, meningite e/o altre infezioni del sistema nervoso centrale.
    • Pazienti trattati con acido valproico (con o senza disturbo convulsivo noto).
    • Pazienti che hanno ricevuto 72 ore o più di trattamento con polimixina (escluse formulazioni per inalazione e topiche) entro 96 ore dall'arruolamento.
    • I pazienti con malattia renale in stadio terminale che richiede emodialisi non sono esclusi dallo studio ma saranno esclusi dalla valutazione relativa alla nefrotossicità nella popolazione per-protocol.
    • I pazienti affetti da nota allergia ai farmaci di tipo 1 o altra allergia grave a uno dei farmaci in studio o ai beta-lattamici.
    o Se i pazienti affetti da allergia a beta-lattamici hanno precedentemente ricevuto carbapenemi in modo sicuro, non saranno esclusi.

    Non sono state effettuate esclusioni sulla base di sesso o preferenze di carattere demografico. I bambini di età <18 anni sono stati esclusi dallo studio poiché non sviluppano spesso infezioni causate da XDR-GNB presso gli ospedali dello studio e la PK/PD dei farmaci in studio sarebbe stata diversa in tale popolazione.
    E.5 End points
    E.5.1Primary end point(s)
    All-cause mortality 28-30 days after study enrollment
    Mortalità per tutte le cause 28-30 giorni dopo l'arruolamento nello studio
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 28
    Giorno 28
    E.5.2Secondary end point(s)
    Clinical failure at the end of therapy as defined by the following:
    ¿ Clinical failure
    ¿ BSI:
    ¿ One or more positive blood cultures (of the study pathogen) obtained after day 5 of enrollment
    ¿ Death after 48 hours of enrollment but prior to End of Treatment
    (EOT)
    ¿ Clinical instability or clinical worsening during the trial requiring rescue antimicrobial drug therapy for treatment of the study pathogen
    ¿ Pneumonia:
    ¿ Death after 48 hours of enrollment but prior to End of Treatment (EOT)
    ¿ Lack of improvement in PaO2/FiO2 at End of Treatment (EOT)
    ¿ Clinical instability or clinical worsening during the trial requiring rescue antimicrobial drug therapy for treatment of the study pathogen
    Insuccesso clinico al termine della terapia definito come segue:
    Insuccesso clinico
    ¿ BSI:
    ¿ Una o pi¿ colture ematiche positive (dei patogeni in studio) ottenuta/e dopo il giorno 5 di arruolamento
    ¿ Decesso dopo 48 ore dall'arruolamento ma prima della Fine del trattamento (EOT)
    ¿ Instabilit¿ clinica o peggioramento clinico durante la sperimentazione che richiedono terapia antimicrobica farmacologica di emergenza per il trattamento del patogeno in studio
    ¿ Polmonite:
    ¿ Decesso dopo 48 ore dall'arruolamento ma prima della Fine del trattamento (EOT)
    ¿ Assenza di miglioramento nella PaO2/FiO2 alla Fine del trattamento (EOT)
    ¿ Instabilit¿ clinica o peggioramento clinico durante la sperimentazione che richiedono terapia antimicrobica farmacologica di emergenza per il trattamento del patogeno in studio
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of therapy
    Fine terapia
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Israel
    Bulgaria
    Greece
    Italy
    E.8.7Trial 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
    Once the enrollment goal of 444 subjects has been met.
    Una volta raggiunto il target di 444 soggetti arruolati
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 149
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 295
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects may be enrolled in the research if permitted if consent is obtained from the Legally Authorized Representative (LAR).
    I soggetti potranno essere arruolati se il consenso verr¿ fornito da un Legale Rappresentante autorizzato.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 444
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Nessuno
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-02-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-11
    P. End of Trial
    P.End of Trial StatusOngoing
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