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    Summary
    EudraCT Number:2012-000726-21
    Sponsor's Protocol Code Number:D4280C00006
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-02-26
    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 number2012-000726-21
    A.3Full title of the trial
    An Open-Label, Randomized, Multicenter, Phase III Study of Ceftazidime Avibactam (CAZ-AVI, formerly CAZ104) and Best Available Therapy for the Treatment of Infections Due to Ceftazidime Resistant Gram Negative Pathogens
    Uno studio di fase III multicentrico, randomizzato e in aperto su ceftazidima avibactam (CAZ-AVI, in precedenza CAZ104) e sulla migliore terapia disponibile per il trattamento di infezioni dovute a patogeni gram-negativi resistenti a ceftazidima.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ceftazidime-Avibactam for the treatment of infections due to Ceftazidime Resistant Pathogens
    Ceftazidima avibactam nel trattamento di infezioni dovute a patogeni ceftazidima resistenti.
    A.4.1Sponsor's protocol code numberD4280C00006
    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 AB
    B.1.3.4CountrySweden
    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 Centre
    B.5.3 Address:
    B.5.3.1Street AddressRoom Tatnall Bldg, 1800 Concord Pike, PO Box 15437
    B.5.3.2Town/ cityWilmington
    B.5.3.3Post codeDE 19850-5437
    B.5.3.4CountryUnited States
    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 concentrate 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 1192491-61-4
    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 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 Metronidazole
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter Healthcare Ltd
    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.3.1Product namemetronidazole
    D.3.4Pharmaceutical form Solution for injection/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 INNMETRONIDAZOLE
    D.3.9.1CAS number 443-48-1
    D.3.9.4EV Substance CodeSUB08922MIG
    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: 3
    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 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/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.3.9.4EV Substance CodeSUB21617
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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: 4
    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 Colomycin Injection
    D.2.1.1.2Name of the Marketing Authorisation holderForest Laboratories UK Limited
    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.3.1Product nameColomycin
    D.3.4Pharmaceutical form Powder for solution for injection/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 INNCOLISTIMETHATE SODIUM
    D.3.9.1CAS number 8068-28-8
    D.3.9.4EV Substance CodeSUB06801MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number2000000
    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: 5
    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 Tygacil
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nametigecycline
    D.3.4Pharmaceutical form Powder for solution for injection/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 INNTIGECYCLINE
    D.3.9.1CAS number 220620-09-7
    D.3.9.4EV Substance CodeSUB16467MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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: 6
    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 Imipenem/Cilastatin 500 mg/500 mg
    D.2.1.1.2Name of the Marketing Authorisation holderHospira UK Limited
    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.3.1Product nameImipenem/Cilistatin
    D.3.4Pharmaceutical form Powder for solution for injection/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 INNIMIPENEM MONOHYDRATE
    D.3.9.1CAS number 74431-23-5
    D.3.9.4EV Substance CodeSUB21472
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number530
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCILASTATIN SODIUM
    D.3.9.1CAS number 81129-83-1
    D.3.9.4EV Substance CodeSUB01295MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number530
    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: 7
    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 Doribax
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 namedoripenem
    D.3.4Pharmaceutical form Powder for solution for injection/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 INNDORIPENEM
    D.3.9.1CAS number 148016-81-3
    D.3.9.4EV Substance CodeSUB22196
    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.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    cUTI, Complicated Urinary Tract Infection, cIAI, Complicated intra-abdominal infection
    cUTI infezioni complicate del tratto urinario; cIAI, infezioni complicate intraddominali.
    E.1.1.1Medical condition in easily understood language
    Urinary Tract Infection, abdominal infection
    Infezioni complicate del tratto urinario; infezioni complicate intraddominali.
    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 14.1
    E.1.2Level LLT
    E.1.2Classification code 10046574
    E.1.2Term Urinary tract infection NOS
    E.1.2System Organ Class 100000004862
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10056570
    E.1.2Term Intra-abdominal infection
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To estimate the per-patient clinical response to ceftazidime-avibactam and best available therapy at TOC in the treatment of selected serious infections caused by ceftazidime-resistant Gram negative pathogens.
    • Valutare la risposta clinica per paziente alla ceftazidima avibactam (CAZ-AVI, già CAZ104) e la migliore terapia disponibile (BAT) alla Prova di cura (TOC) nel trattamento di una selezione di gravi infezioni dovute a patogeni gram-negativi resistenti a ceftazidima
    E.2.2Secondary objectives of the trial
    •To further evaluate the clinical response to CAZ-AVI and BAT at different visits and in patient subgroups (including entry diagnosis, pathogen, resistance mechanism, and previously failed treatment class)
    •To estimate the microbiological response to CAZ-AVI and BAT in the treatment of selected serious infections caused by ceftazidime-resistant Gram-negative pathogens
    •To evaluate the reasons for treatment change and/or discontinuation for CAZ-AVI and BAT
    •To estimate the 28-day, all-cause mortality among patients treated with CAZ-AVI and BAT
    •To evaluate the safety and tolerability profile of CAZ-AVI and BAT for the treatment of selected serious infections caused by ceftazidime-resistant Gram-negative pathogens
    •To evaluate the pharmacokinetics (PK) of the individual components of CAZ-AVI in this population with selected serious infections, and to characterize the relationship between the PK and clinical and microbiological response for CAZ-AVI
    •Valutare ulteriormente la risposta clinica a CAZ-AVI e BAT in occasione di visite differenti e in diversi sottogruppi di pazienti (compresi diagnosi di ingresso, patogeno, meccanismo di resistenza e classe del precedente trattamento senza esito positivo)
    •Valutare la risposta microbiologica a CAZ-AVI e BAT nel trattamento di una selezione di infezioni gravi causate da patogeni gram-negativi resistenti a ceftazidima
    •Valutare i motivi per il cambio e/o l'interruzione del trattamento per CAZ-AVI e BAT
    •Valutare la mortalità a 28 giorni dovuta a qualsiasi causa tra i pazienti trattati con CAZ-AVI e BAT
    •Valutare la tollerabilità e la sicurezza di CAZ-AVI e BAT per il trattamento di una selezione di infezioni gravi causate da patogeni gram-negativi resistenti a ceftazidima
    •Valutare la farmacocinetica (PK) dei singoli componenti di CAZ-AVI in questa popolazione con selezione di infezioni gravi e caratterizzare il rapporto tra PK e risposta clinica e microbiologica per CAZ-AVI
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.≥18 and ≤90 years of age
    2.Female patients can participate if they are surgically sterile or completed menopause or females capable of having children and agree not to attempt pregnancy while receiving IV study therapy and for a period of 28 days after last infusion
    3.Patient has a ceftazidime-resistant Gram negative pathogen that was isolated from an appropriate culture within 5 days prior to study entry (ie, the study-qualifying culture), which was determined to be the causative agent of the entry infection
    1) L'età dei pazienti deve essere ≥ 18 e < 90 anni.
    2) le pazienti femmine possono partecipare devono soddisfare i criteri elencati di seguito se sono state sterilizzate chirurgicamente o si trovano in post-menopausa o se potenzialmente fertili acconsentono a usare metodi contraccettivi, durante il trattamento e per almeno 28 giorni dopo l’ultima infusione della terapia sperimentale.
    3) Il paziente presenta un agente patogeno Gram-negativo ceftazidima-resistente, isolato da una coltura appropriata nei 5 giorni precedenti l’ingresso nello studio (cioè la coltura di qualifica per lo studio) e identificato quale agente che causa l’infezione di ammissione.
    E.4Principal exclusion criteria
    1.Patient has an APACHE II score >30
    2.Patient has an infection due to Gram negative pathogen that is unlikely to respond to CAZ-AVI treatment (eg, Acinetobacter spp., Stenotrophomonas spp.)
    3.Patient is receiving hemodialysis or peritoneal dialysis or had a renal transplant
    4.Patient is immunocompromised
    5.Patient has a rapidly progressive or terminal illness with a high risk of mortality due to any cause, including acute hepatic failure, respiratory failure or severe septic shock
    1. Il paziente ha un punteggio APACHE II >30
    2. Il paziente presenta un’infezione causata da agente batterico Gram-negativo, che con tutta probabilità non risponderà al trattamento CAZ-AVI (cioè Acinetobacter e sottospecie, Stenotrophomonas e sottospecie)
    3. Il paziente viene sottoposto a emodialisi o dialisi peritoneale o trapianto renale
    4. Il paziente è immunocompromesso.
    5. Il paziente ha una patologia in rapida progressione o terminale, comprese insufficienza epatica acuta o insufficienza respiratoria con elevato rischio di mortalità per altre cause
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients with clinical cure at the Test of Cure visit in the modified intent-to-treat analysis set.
    La proporzione di pazienti con guarigione clinica alla visita del trattamento di guarigione
    E.5.1.1Timepoint(s) of evaluation of this end point
    7-10 days after last infusion
    Da 7 a 10 giorni dopo l'ultima infusione
    E.5.2Secondary end point(s)
    1)The proportion of patients with clinical cure in the modified intent to treat analysis set.
    2)The proportion of patients with clinical cure in the extended microbiologically evaluable analysis set.
    3)The proportion of patients with clinical cure by pathogen (eg, E. coli, Klebsiella spp., Pseudomonas aeruginosa) in the modified intent to treat analysis set.
    4)The proportion of patients with clinical cure by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the modified intent to treat analysis set.
    5)The proportion of patients with clinical cure by entry diagnosis (complicated intra-abdominal infection/complicated urinary tract infection) in the modified intent to treat analysis set.
    6)The proportion of patients with clinical cure by pathogen (eg, E. coli, Klebsiella spp., Pseudomonas aeruginosa) in the extended microbiologically evaluable analysis set.
    7)The proportion of patients with clinical sure by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the extended microbiologically evaluable analysis set.
    8)The proportion of patients with clinical cure by entry diagnosis (complicated intra-abdominal infection/complicated urinary tract infection) in the extended microbiologically evaluable analysis set.
    9)The proportion of patients with clinical cure by previously failed treatment class (eg, quinolone, β lactam/β lactamase inhibitor, third- or fourth generation cephalosporin, carbapenem), in the modified intent to treat analysis set.
    10)The proportion of patients with clinical cure by previously failed treatment class (eg, quinolone, β lactam/β lactamase inhibitor, third- or fourth generation cephalosporin, carbapenem) in the extended microbiologically evaluable analysis set.
    11)The proportion of patients with favorable per-pathogen microbiological response in the modified intent to treat analysis set
    12)The proportion of patients with favorable per-pathogen microbiological response in the extended microbiologically evaluable analysis set.
    13)The proportion of patients with a favorable per-patient microbiological response in the modified intent to treat analysis set.
    14)The proportion of patients with a favorable per-patient microbiological response in the extended microbiologically evaluable analysis set.
    15)The proportion of patients with a favorable microbiological response by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the modified intent to treat analysis set.
    16)The proportion of patients with a favorable microbiological response by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the extended microbiologically evaluable analysis set.
    17)The proportion of favorable per-pathogen microbiologic response by minimum inhibitory concentration in the modified intent to treat analysis set.
    18)The proportion of favorable per-pathogen microbiologic response by minimum inhibitory concentration in the extended microbiologically evaluable analysis set.
    19)The reasons for treatment change and/or discontinuation in the modified intent to treat analysis set.
    20)The 28-day mortality rate in the microbiological modified intent to treat analysis set.
    21)The 28-day mortality rate in the extended microbiological evaluable analysis set.
    22)The safety and tolerability by incidence and severity of adverse events and serious adverse events, vital signs, clinical laboratory tests, ECGs and physical exams.
    23)Pharmacokinetics: maximum concentration (Cmax), minimum concentration, area under plasma concentration time curve at study state and terminal half-life.
    1) La proporzione di pazienti con guarigione clinica nel gruppo
    di analisi Intent-to-Treat modificato.
    2) La proporzione di pazienti con guarigione clinica nel
    gruppo esteso di analisi microbiologicamente valutabili .
    3) La proporzione di pazienti con guarigione clinica in base a patogeni (per es. E. Coli,
    Klebsiella spp., Pseudomonas aeruginosa) nel gruppo di analisi Intent-to-Treat
    modificato.
    4) la proporzione di pazienti con guarigione clinica in base a meccanismo di resistenza
    (ad es. produttori di Klebsiella pneumoniae carbapenemasi,
    produttori di β-lattamasi a spettro esteso) nel gruppo di analisi Intent-to-Treat
    modificato.
    5) La proporzione di pazienti con guarigione clinica in base alla diagnosi d'ingresso
    (infezione intra-addominale complicata/infezione del tratto urinario complicata)
    nel gruppo di analisi Intent-to-Treat modificato.
    6) La proporzione di pazienti con guarigione clinica in base a patogeni (ad es. E. Coli,
    Klebsiella spp., Pseudomonas aeruginosa) nel gruppo esteso di analisi
    microbiologicamente valutabili .
    7) La proporzione di pazienti con guarigione clinica in base a meccanismo di resistenza
    (ad es. produttori di Klebsiella pneumoniae carbapenemasi,
    produttori di β-lattamasi a spettro esteso) nel gruppo esteso di analisi microbiologicamente
    valutabili .
    8) La proporzione di pazienti con guarigione clinica in base alla diagnosi d'ingresso
    (infezione intra-addominale complicata/infezione del tratto urinario complicata)
    nel gruppo estesodi analisi microbiologicamente valutabili.
    9) La proporzione di pazienti con guarigione clinica in base a classe di trattamento precedentemente non riuscita
    (ad es. chinoloni, inibitori di β-lattame/β-lattamasi, cefalosporina di terza
    o quarta generazione, carbapenemi), nel gruppo
    di analisi Intent-to-Treat modificato.
    10) La proporzione di pazienti con guarigione clinica in base a classe di trattamento precedentemente non riuscita
    (ad es. chinoloni, inibitori di β-lattame/β-lattamasi, cefalosporina di terza o
    quarta generazione, carbapenemi) nel gruppo esteso di analisi
    microbiologicamente valutabili .
    11) La proporzione di pazienti con risposta microbiologica per agente patogeno favorevole
    nel gruppo di analisi Intent-to-Treat modificato.
    12) La proporzione di pazienti con risposta microbiologica per agente patogeno favorevole
    nel gruppo esteso di analisi microbiologicamente valutabili.
    13) La proporzione di pazienti con risposta microbiologica per agente patogeno favorevole
    nel gruppo di analisi Intent-to-Treat modificato.
    14) La proporzione di pazienti con risposta microbiologica per agente patogeno favorevole
    nel gruppo esteso di analisi microbiologicamente valutabili.
    15) La proporzione di pazienti con risposta microbiologica
    per meccanismo di resistenza favorevole (ad es. produttori di Klebsiella pneumoniae carbapenemasi, produttori di β-lattamasi a spettro esteso) nel gruppo di analisi
    Intent-to-Treat modificato.
    16) La proporzione di pazienti con risposta microbiologica
    per meccanismo di resistenza favorevole (ad es. produttori di Klebsiella pneumoniae carbapenemasi,
    produttori di β-lattamasi a spettro esteso) nel gruppo esteso di analisi
    microbiologicamente valutabili .
    17) La proporzione di risposta microbiologica per agente patogeno favorevole in base alla
    concentrazione minima di inibitore nel gruppo di analisi Intent-to-Treat
    modificato.
    18) La proporzione di risposta microbiologica per agente patogeno favorevole in base alla
    concentrazione minima di inibitore nel gruppo esteso di analisi microbiologicamente
    valutabili .
    19) Le ragioni per il cambio di trattamento e/o discontinuità nel
    gruppo di analisi Intent-to-Treat modificato.
    20) Il tasso di mortalità al giorno 28 nel gruppo di analisi Intent-to-Treat modificato.
    21) Il tasso di mortalità al giorno 28 nel gruppo di analisi esteso microbiologicamente valutabili.
    22) La sicurezza e tollerabilità in base all'incidenza e severità di eventi avversi
    e gravi eventi avversi, segni vitali, test clinici di laboratorio,
    ECG ed esami fisici.
    23) Farmacocinetica: concentrazione massima (Cmax), concentrazione minima, area sotto la curva di concentrazione plasmatica-tempo
    allo stato stazionario e all'emivita terminale.
    E.5.2.1Timepoint(s) of evaluation of this end point
    (1, 2, 10-14, 17, 18) Within 24 hours after last infusion of study therapy, 21-35 days after randomization and 28-32 days after randomization
    3-9, At 7-10,15,16 days after last infusion of study therapy
    (19) Study duration [Day 1 through last follow up visit (up to 35 days)]
    (20, 21) At 28 days after randomization
    (22)At study duration (from screening visit (Day-1) through last follow up visit (up to 35 days)]
    (23) At anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug
    (1, 2, 10-14, 17, 18) entro 24 ore dopo l'ultima infusione della terapia dello studio,
    da 21 a 35 giorni dopo la randomizzazione e da 28 a 32 giorni dopo la randomizzazione
    (3-9) da 7 a -10 giorni, 15, 16 giorni dopo l'ultima infusione della terapia dello studio
    (19) durata dello studio [dal giorno 1 fino all'ultima visita di follow-up (per un massimo di 35 giorni)]
    (20, 21) a 28 giorni dopo la randomizzazione
    (22) per la durata dello studio [(dalla visita di screening (giorno 1) fino all'ultima visita di
    follow-up (per un massimo di 35 giorni)]
    (23) in qualsiasi momento entro 15 minuti prima o dopo l'interruzione dell'assunzione del farmaco dello studio, in qualsiasi momento tra 30 e 90 minuti dopo l'interruzione dell'assunzione del farmaco ...., Vedere protocollo.
    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 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 concerned3
    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 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
    Australia
    Brazil
    Canada
    Chile
    China
    India
    Israel
    Japan
    Korea, Republic of
    Mexico
    Peru
    Philippines
    Russian Federation
    South Africa
    Taiwan
    Turkey
    Ukraine
    United States
    E.8.7Trial 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
    LVLS
    LVLS
    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 months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days5
    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: 256
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 144
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 230
    F.4.2.2In the whole clinical trial 400
    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)
    Standard of care
    Terapia standard
    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 Decision2013-03-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-24
    P. End of Trial
    P.End of Trial StatusCompleted
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