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    Summary
    EudraCT Number:2012-004006-96
    Sponsor's Protocol Code Number:D4281C00001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-01-11
    Trial results View 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 number2012-004006-96
    A.3Full title of the trial
    A Phase III, Randomized, Multicentre, Double-blind, Double-dummy, Parallel-group Comparative Study to Determine the Efficacy, Safety And Tolerability of Ceftazidime-Avibactam Versus Meropenem in the Treatment of Nosocomial Pneumonia Including Ventilator-Associated Pneumonia in Hospitalized Adults
    Studio comparativo di fase III, randomizzato, multicentrico, doppio cieco, doubble-dummy, a gruppi paralleli, per determinare l'efficacia, la sicurezza e la tollerabilita' di Ceftazimide-Avibactam (CAZ-AVI) rispetto a Meropenem nel trattamento di pazienti adulti ospedalizzati con polmonite nosocomiale inclusa polmonite associata a ventilazione meccanica (VAP).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study comparing Ceftazidime-Avibactam versus Meropenem in hospitalized adults with nosocomial pneumonia
    Studio di confronto dell'assocazione ceftazidima-Avibactam verso Meropenem in adulti ospedalizzati con polmonite nosocomiale.
    A.3.2Name or abbreviated title of the trial where available
    REPROVE (CAZ-AVI)
    CAZ-AVI
    A.4.1Sponsor's protocol code numberD4281C00001
    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 SponsorASTRAZENECA
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstrazeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstrazeneca
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street Address....
    B.5.3.2Town/ city.....
    B.5.3.3Post code......
    B.5.3.4CountryUnited States
    B.5.4Telephone number.....
    B.5.5Fax number.......
    B.5.6E-mailinformation.center@astrazeneca.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 No
    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 nameceftazidime avibactam
    D.3.2Product code CAZ-AVI
    D.3.4Pharmaceutical form Powder for solution for infusion
    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 INNCEFTAZIDIME PENTAHYDRATE
    D.3.9.1CAS number 78439-06-2
    D.3.9.4EV Substance CodeSUB01134MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2000
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAVIBACTAM
    D.3.9.1CAS number 1192500-31-4
    D.3.9.2Current sponsor codeAVIBACTAM
    D.3.9.3Other descriptive nameAVIBACTAM
    D.3.9.4EV Substance CodeSUB72111
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 RoleComparator
    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 Meronem
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Powder for solution for infusion
    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 TRIHYDRATE
    D.3.9.1CAS number 119478-56-7
    D.3.9.2Current sponsor codeMEROPENEM
    D.3.9.4EV Substance CodeSUB21617
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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.8.3Pharmaceutical form of the placeboSolution for infusion
    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
    nosocomial pneumonia (NP), ventilator-associated pneumonia (VAP)
    polmonite nocosomiale (NP) inclusa polmonite associata a ventilazione meccanica (VAP)
    E.1.1.1Medical condition in easily understood language
    lung infection
    Infezione Polmonare
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the non-inferiority of ceftazidime-avibactam compared to meropenem with respect to clinical cure at the test of cure visit in patients in the clinically modified intent-to-treat population and patients in the clinically evaluable population
    • Valutare la non-inferiorità della associazione ceftazidime- avibactam (CAZ-AVI) verso meropenem rispetto alla guarigione clinica valutata mediante verifica della negativizzazione della coltura batterica (visita al 21 ° giorno dalla randomizzazione) nei pazienti inseriti nella intent-to-treat clinicamente modificata (cMITT) e nella totalità dei pazienti clinicamente valutabili (CE).
    E.2.2Secondary objectives of the trial
    To determine the efficacy of CAZ-AVI compared to meropenem with respect to the clinical cure at end of treatment in the clinically modified intent-to-treat, clinically evaluable, microbiologically modified intent-totreat, microbiologically evaluable and extended microbiologically evaluable populations and at test of cure in the microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable populations.
    • Determinare l'efficacia di CAZ-AVI verso meropenem per quanto riguarda la guarigione clinica a fine trattamento (EoT) nei pazienti inseriti nella intent-to-treat clinicamente modificata (cMITT), nella totalità dei pazienti clinicamente valutabili (CE), nei pazienti inseriti nella intent-to-treat microbiologicamente modificata (mMITT), nei pazienti microbiologicamente valutabili (ME) e nella popolazione estesa di pazienti microbiologicamente valutabili (extended-ME) & alla visita di valutazione della guarigione clinica (ToC) nei pazienti inseriti nella intent-to-treat microbiologicamente modificata (mMITT), nei pazienti microbiologicamente valutabili (ME) e nella popolazione estesa di pazienti microbiologicamente valutabili (extended-ME)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • 18 to 90 years of age inclusive • Females can participate if surgically sterile or completed menopause; if able to have children, must have negative serum pregnancy test, agree not to attempt pregnancy and use acceptable contraception while receiving study therapy and for 1 week after • Onset of symptoms ≥48 hours after admission or <7 days after discharge from an inpatient acute or chronic care facility • New or worsening infiltrate on chest X-ray obtained within 48 hours prior to randomization • At least 1 of the following systemic signs: - Fever (temperature >38°C) or hypothermia (rectal/core temperature <35°C) - White blood cell count >10,000 cells/mm3, or White blood cell count<4500 cells/mm3, or >15% band forms
    • Adulti tra i 18 e i 90 anni di età.
    • Le pazienti di sesso femminile possono partecipare allo studio se chirurgicamente sterili o se in menopausa completa; se potenzialmente fertili devono avere il test di gravidanza sierico negativo, essere d’accordo a non pianificare gravidanze e utilizzare un metodo contraccettivo accettabile per tutto il periodo di trattamento con il farmaco di studio e per la settimana successiva.
    • Insorgenza dei sintomi oltre le 48 ore dal ricovero o entro 7 giorni dalla dimissione dalla struttura ospedaliera.
    • Nuovo infiltrato o infiltrato in peggioramento ai raggi X al torace entro 48 ore dalla randomizzazione
    • Almeno una delle seguenti manifestazioni sistemiche:
    - Febbre (temperatura &gt; 38°C) o ipotermia (temperatura rettale/centrale &lt;35 °C)
    - Conta dei globuli bianchi (WBC) &gt; 10000 cellule/mm3 o conta WBC &lt; 4500 cellule/mm3 o &gt;15% cellule a banda
    E.4Principal exclusion criteria
    • Pulmonary disease that precludes evaluation of therapeutic response (including, but not limited to, lung cancer, active tuberculosis, cystic fibrosis, granulomatous disease, fungal pulmonary infection or recent pulmonary embolism). • Patients with lung abscess, pleural empyema or post obstructive pneumonia. • Patients with an estimated creatinine clearance <16ml/min by Cockcroft Gault formula or patients expected to require haemodialysis or other renal support while on study therapy. • Acute hepatitis in the prior 6 months, cirrhosis, acute hepatic failure or acute decompensation of chronic hepatic failure. • Patients receiving hemodialysis or peritoneal dialysis.
    • Patologie polmonari che precludono la valutazione della risposta terapeutica (inclusi, ma non solo, tumore polmonare, tubercolosi attiva, fibrosi cistica, malattia granulomatosa, infezione polmonare fungina o recente embolia polmonare)
    • Pazienti con ascessi polmonari, empiema pleurico o polmonite post ostruttiva.
    • Pazienti con una clearance della creatinina stimata &lt;16 ml/min secondo la formula di Cockcroft Gault o pazienti per i quali si prevede una necessaria emodialisi o altri supporti renali durante il trattamento di studio.
    • Epatite acuta nei 6 mesi precedenti, cirrosi, insufficienza epatica acuta o scompenso acuto da insufficienza epatica cronica.
    • Pazienti in emodialisi o dialisi peritoneale.
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients with clinical cure in the clinically modified intent-to-treat and clinically evaluable analysis sets (co-primary analyses)
    . La percentuale di pazienti con guarigione clinica nella popolazione di pazienti cMITT e CE (analisi co-primaria).
    E.5.1.1Timepoint(s) of evaluation of this end point
    at test of cure visit
    alla Visita ''Test of Cure''
    E.5.2Secondary end point(s)
    • The proportion of patients with clinical cure in the microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable analysis sets • The proportion of patients with clinical cure in clinically modified intent-to-treat, clinically evaluable, microbiologically modified intent-to-treat, microbiologically evaluable, extended microbiologically evaluable analysis sets • The proportion of patients with a favorable per-patient microbiologic response in microbiologically modified intent-to-treat, microbiologically evaluable, extended microbiologically evaluable analysis sets • The proportion of favorable per-pathogen microbiologic responses in microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable analysis sets • The proportion of favorable per-pathogen microbiologic responses by minimum inhibitory concentration categories in microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable analysis sets • The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime in clinically evaluable, clinically modified intent to-treat, microbiologically evaluable analysis sets • Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime in microbiologically modified intent-to-treat, microbiologically evaluable, extended microbiologically evaluable analysis sets • The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime in microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable analysis sets • The proportion of patients with death due to any cause (all-cause mortality) in the clinically evaluable, clinically modified intent-to-treat and microbiologically modified intent-to-treat analysis sets
     La percentuale di pazienti con guarigione clinica nella popolazione di pazienti mMITT, ME e extended ME.  La percentuale di pazienti con guarigione clinica nella popolazione di pazienti cMITT e CE mMITT, ME ed extended ME  La percentuale di pazienti con una risposta microbiologica per-paziente favorevole in pazienti mMITT, ME ed extended-ME (derivata da risposta microbiologica per patogeno).  La percentuale di pazienti con una risposta microbiologica per-patogeno favorevole in pazienti mMITT, ME ed extended-ME  La percentuale di risposte microbiologiche per-patogeno favorevole in pazienti mMITT, ME ed extended-ME  La percentuale di risposte microbiologiche per-patogeno favorevole alla minima concentrazione inibente (minimum inhibitory concentration (MIC)) nelle popolazioni di pazienti mMITT, ME e extended-ME  La percentuale di pazienti con giuarigione clinica nei pazienti con patogeni resistenti alla ceftazidima nelle popolazioni CE, cMITT e ME  La percentuale di pazienti con risposta microbiologica per-paziente favorevole nei pazienti con patogeni resistenti alla ceftazidima nelle popolazioni mMITT, ME e extended ME (derivata da risposta microbiologica per patogeno)  La percentuale di risposte microbiologiche per-patogeno favorevole nei pazienti con patogeni resistenti alla ceftazidima nelle popolazioni mMITT, ME e extended ME  La percentuale di pazienti morti per qualsiasi causa (all cause mortality) nella popolazione CE, cMITT e mMITT
    E.5.2.1Timepoint(s) of evaluation of this end point
    at end of treatment visit and test of cure visit
    alla visita di fine trattamento e alla visita ''Test of Cure''
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Microbiology cultures
    Colture microbiologiche
    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 Yes
    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 No
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA81
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Brazil
    Chile
    China
    India
    Japan
    Mexico
    Peru
    Russian Federation
    South Africa
    Turkey
    Ukraine
    Vietnam
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months38
    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.1.1Number of subjects for this age range: 0
    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: 961
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 553
    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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients may require intubation with subsequent sedation and
    therefore not capable of providing consent.
    I pazienti possono necessitare di intubazione con sedazione e quindi possono non essere in grado di fornire il consenso.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 479
    F.4.2.2In the whole clinical trial 1494
    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)
    NA
    NA
    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 Decision2013-02-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-03-12
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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