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    Summary
    EudraCT Number:2011-003895-35
    Sponsor's Protocol Code Number:D4280C00005
    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:2012-07-23
    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 number2011-003895-35
    A.3Full title of the trial
    A Phase III, Randomized, Multicenter, Double Blind, Double-Dummy Parallel-Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime Avibactam (CAZ104) Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra Abdominal Infections (cIAI) in Hospitalized Adults
    Studio Comparativo di Fase III, Randomizzato, Multicentrico, in Doppio Cieco, Doppio - Mascheramento, a Gruppi Paralleli per Determinare l'Efficacia, la Sicurezza e la Tollerabilita' di Ceftazidima Avibactam (CAZ104) Piu' Metronidazolo Rispetto a Meropenem nel Trattamento di Infezioni Intra-Addominali Complicate (cIAIs) in Adulti Ospedalizzati
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Compare Ceftazidime Avibactam + Metronidazole vs Meropenem for hospitalized adults with complicated Intra-Abdominal Infections
    Confrontare il trattamento con Ceftazidime Avibactam + Metronidazole vs Meropenem in pazienti adulti ospedalizzati con infezioni intra-addominali complicate.
    A.4.1Sponsor's protocol code numberD4280C00005
    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 Center
    B.5.3 Address:
    B.5.3.1Street AddressRollins 12th Floor, 1800 Concord Pike, PO Box 15437
    B.5.3.2Town/ cityWilmington
    B.5.3.3Post codeDE 19850-5437
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 800 236 9933
    B.5.5Fax number+1 302 885 3516
    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 CAZ104
    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 1192491-61-4
    D.3.9.2Current sponsor codeNXL104
    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 metronidazolo Baxter 500 mg/100 ml
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter Healthcare SA
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 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 INNmetronidazolo
    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 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.3.9.4EV 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.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
    D.8 Placebo: 2
    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
    Complicated Intra-Abdominal Infection (cIAI)
    Infezione addominale complicata
    E.1.1.1Medical condition in easily understood language
    Abdominal infection
    Infezione addominale
    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 10056570
    E.1.2Term Intra-abdominal infection
    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
    To assess the non inferiority of ceftazidime avibactam (CAZ104) plus metronidazole compared to meropenem alone with respect to clinical cure at the test-of-cure in patients who have at least 1 identified pathogen.
    Valutare la non-inferiorità di ceftazidima avibactam (CAZ104) più metronidazolo rispetto a meropenem in relazione alla guarigione clinica alla visita di valutazione della cura (Test-of-Cure, TOC) in pazienti che hanno almeno 1 patogeno identificato.
    E.2.2Secondary objectives of the trial
    To determine the efficacy of CAZ104 plus metronidazole compared to meropenem with respect to clinical cure at TOC in patients who are microbiologically evaluable (ME) • To determine the efficacy of CAZ104 plus metronidazole compared to meropenem with respect to clinical cure at End of Treatment (EOT) with intravenous (IV) therapy, and at Late Follow-up (LFU) both in patients who have at least 1 identified pathogen and in patients who are ME • To determine the efficacy of CAZ104 plus metronidazole compared to meropenem with respect to clinical cure at EOT, TOC, and LFU in patients who are clinically evaluable (CE) • To determine the per-patient and per-pathogen microbiologic response of CAZ104 plus metronidazole compared to meropenem at EOT, TOC, and LFU both in patients who have at least 1 identified pathogen and in patients who are ME • To evaluate the efficacy of CAZ104 ....
    •Determinare l'efficacia di CAZ104 più metronidazolo rispetto a meropenem in relazione alla guarigione clinica alla TOC in pazienti valutabili microbiologicamente (ME)•Determinare l'efficacia di CAZ104 più metronidazolo rispetto a meropenem in confronto alla guarigione clinica alla Fine del trattamento (EOT) con terapia endovenosa (IV),e al Follow-up a distanza di tempo (Late Follow-up,LFU) sia in pazienti che hanno almeno 1 patogeno identificato che in pazienti che sono microbiologicamente valutabili•Determinare l'efficacia di CAZ104 più metronidazolo confrontato con meropenem in relazione alla guarigione clinica in occasione di EOT,TOC e LFU in pazienti clinicamente valutabili (CE)•Determinare la risposta microbiologica per paziente e per patogeno di CAZ104 più metronidazolo rispetto a meropenem in occasione di EOT,TOC e LFU nei pazienti che hanno almeno 1 patogeno.....
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For inclusion in the study patients should fulfill the following criteria: 1. Patient must provide a signed written informed consent prior to any study-specific procedures. However, if a patient is unable, the patient’s legally acceptable representative may provide written consent, as approved by the institutional-specific guidelines. Those patients who are unconscious or considered by the investigator to be clinically unable to consent at Screening and who are entered into the study by the consent of a legally acceptable representative, should provide their own written informed consent for continuing to participate in the study as soon as possible on recovery, as applicable in accordance with local regulations. 2. Patient must be 18 to 90 years of age inclusive. 3. Women are authorized to participate if they meet the following criteria: (a) Surgical sterilization or (b) Completed menopause, as defined by criteria in footnote1 (If criteria not met, should be regarded as having childbearing potential) OR (c) Female patient capable of having children and agrees not to attempt pregnancy while receiving IV study therapy and for a period of 1 week after. Acceptable methods of contraception for this study are: • Prior to and during the study, use of an intrauterine device, regular depo-progesterone injections, or sexual intercourse with only vasectomized partners • Complete sexual abstinence for the recommended period. EITHER: Intra-operative/postoperative enrollment with visual confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection associated with peritonitis. Surgical intervention includes open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery. Specimens from the surgical intervention must be sent for culture. The patient must have one of the following diagnoses: (a) Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall (b) Diverticular disease with perforation or abscess (c) Appendiceal perforation or peri-appendiceal abscess (d) Acute gastric or duodenal perforations, only if operated on >24 hours after perforation occurs (e) Traumatic perforation of the intestines, only if operated on >12 hours after perforation occurs (f) Secondary peritonitis (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites) (g) Intra-abdominal abscess (including of liver or spleen provided that there is extension beyond the organ with evidence of intraperitoneal involvement) OR Preoperative enrollment where the following clinical criteria are met with confirmation of infection by surgical intervention within 24 hours of entry: (a) Requirement for surgical intervention, defined per protocol as open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery (b) Evidence of systemic inflammatory response, with at least one of the following: − Fever (defined as body temperature >38°C) or hypothermia with a core body temperature <35°C − Elevated white blood cells (>12000 cells/mm3) − Drop in blood pressure (BP) (however, systolic BP must be >90 mm Hg without pressor support) − Increased heart rate( >90 bpm) and respiratory rate (RR) (>20 breaths/min) − Hypoxia − Altered mental status. (c) Physical findings consistent with intra-abdominal infection, such as: − Abdominal pain and/or tenderness, with or without rebound − Localized or diffuse abdominal wall rigidity − Abdominal mass. (d) Supportive radiologic imaging findings of intra-abdominal infection such as perforated intraperitoneal abscess detected on computed tomography scan, magnetic resonance image, or ultrasound. (e) Specimens from the surgical intervention will be sent for culture. For inclusion in the genetic component of the study, patients must fulfill the following ....
    Per essere inclusi nello studio i pazienti devono soddisfare i seguenti criteri: 1. il paziente deve fornire un consenso informato scritto firmato prima di qualsiasi procedura specifica dello studio. Tuttavia, se un paziente non ne è in grado, il rappresentante legalmente riconosciuto del paziente può fornire consenso scritto, come viene approvato dalle specifiche linee guida istituzionali. I pazienti che non sono coscienti o che sono considerati dallo sperimentatore clinicamente non in grado di dare il consenso allo screening e che sono entrati nello studio con il consenso di un rappresentante legalmente riconosciuto, devono fornire il proprio consenso informato scritto per continuare a partecipare allo studio il più presto possibile al recupero dello stato di coscienza, come da normativa locale. 2. Il paziente deve essere di età compresa tra 18 e 90 anni inclusi. 3. Le donne sono autorizzate a partecipare se soddisfano i seguenti criteri: (a) Sterilizzazione chirurgica o (b) Menopausa completata, come viene definito dai criteri alla nota (Se i criteri non sono soddisfatti, si dovrebbe considerare come in età fertile) oppure (c) Paziente di sesso femminile in grado di procreare e che si impegna a non tentare di iniziare una gravidanza durante la terapia endovenosa dello studio e per un periodo successivo di 1 settimana. I metodi contraccettivi accettabili per questo studio sono i seguenti: • Prima e durante lo studio, l'uso di un dispositivo intrauterino, regolare iniezioni di depo progesterone, o rapporti sessuali solo con partner vasectomizzati • Completa astinenza sessuale per il periodo raccomandato. In alternativa: Arruolamento intra-operatorio/postoperatorio con conferma visiva (presenza di pus all'interno della cavità addominale) di un'infezione intra addominale associata a peritonite. L'intervento chirurgico comprende laparotomia aperta, drenaggio percutaneo di un ascesso, o chirurgia laparoscopica. I campioni provenienti dall'intervento chirurgico devono essere inviati per la coltura. Il paziente deve ricevere una delle seguenti diagnosi: (a) Colecistite gangrenosa con rottura o perforazione o progressione dell'infezione oltre la parete della colecisti (b) Malattia diverticolare con perforazione o ascesso (c) Perforazione appendicolare o ascesso peri appendicolare (d) Perforazioni gastriche o duodenali acute, solo se operato &gt;24 ore dopo il verificarsi della perforazione (e) Perforazione traumatica dell'intestino, solo se operato &gt;12 ore dopo il verificarsi della perforazione (f) Peritonite secondaria (ma non peritonite batterica spontanea associata a cirrosi e ascite cronica) (g) Ascesso intra addominale (compreso del fegato o della milza a condizione che vi sia l'estensione oltre l'organo con evidenza di coinvolgimento intraperitoneale) oppure Arruolamento preoperatorio qualora siano soddisfatti i seguenti criteri clinici con conferma di infezione mediante intervento chirurgico entro le 24 ore dall'ingresso: (a) Requisito per l'intervento chirurgico, definito dal protocollo come laparotomia aperta, drenaggio percutaneo di un ascesso, o chirurgia laparoscopica. (b) Evidenza di risposta infiammatoria sistemica, con almeno uno dei seguenti:  Febbre (definita come temperatura corporea &gt;38°C) o ipotermia, con una temperatura corporea &lt;35°C  Elevata conta di globuli bianchi (&gt; 12.000 cellule/mm3)  Calo della pressione arteriosa (PA) (comunque, la PA sistolica deve essere&gt; 90 mm Hg senza supporto pressorio)  Aumento della frequenza cardiaca (&gt; 90 bpm) e della frequenza respiratoria (RR) (&gt; 20 respiri/min)  Ipossia  Alterazione dello stato mentale. (c) Risultati dell'esame fisico coerenti con infezione intra-addominale, come ad esempio:  Dolore e/o indolenzimento addominale con o senza rimbalzo  Rigidità localizzata o diffusa della parete addominale  Massa addominale. (d) .....
    E.4Principal exclusion criteria
    Patients should not enter the study if any of the following exclusion criteria are fulfilled: 1. Patient is diagnosed with traumatic bowel perforation undergoing surgery within 12 hours; perforation of gastroduodenal ulcers undergoing surgery within 24 hours. Other intra-abdominal processes in which the primary etiology is not likely to be infectious. 2. Patient has abdominal wall abscess or bowel obstruction without perforation or ischemic bowel without perforation. 3. Patient has simple cholecystitis, or gangrenous cholecystitis without rupture, or simple appendicitis, or acute suppurative cholangitis; or infected necrotizing pancreatitis or pancreatic abscess. 4. Patient’s surgery will include staged abdominal repair, or “open abdomen” technique, or marsupialization. Patient is known at study entry to have a cIAI caused by pathogens resistant to the study antimicrobial agents. 6. Patient needs effective concomitant systemic antibacterials (oral, IV, or intramuscular) or antifungals in addition to those designated in the 2 study groups, except vancomycin, linezolid, or daptomycin if started for known or suspected methicillin-resistant Staphylococcus aureus (MRSA) or Enterococcus species as per protocol Section 5.6. 7. Patient has evidence of sepsis with shock not responding to IV fluid challenge or anticipated to require the administration of vasopressors for >12 hours. 8. Patient has perinephric infections. 9. Patient has indwelling peritoneal dialysis catheter. 10. Patient has suspected intra-abdominal infections due to fungus, parasites (eg, amebic liver abscess), virus, or tuberculosis. 11. Patient has a known history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to carbapenem or cephalosporin antibiotics or other β lactam antibiotics or metronidazole. 12. Patient has any of the following laboratory values as defined below: (a) Estimated creatinine clearance ≤30 mL/min calculated by Cockcroft-Gault method (Cockcroft and Gault 1976). Refer to Appendix E for calculation information. (b) Hematocrit <25% or hemoglobin <8 g/dL (c) Absolute neutrophil count <1000/mm3 (d) Platelet count <75000/mm3 (e) Bilirubin >3 × the upper limit of normal (ULN), unless isolated hyperbilirubinemia is directly related to the acute infection or known Gilbert’s disease (f) ALT or AST >3 × ULN values at Screening. Patients with elevations of AST and/or ALT up to 5 × ULN are eligible if these elevations are acute and directly related to the infectious process being treated. This must be documented. (g) Alkaline phosphatase >3 × ULN. Patients with values >3.0 × ULN and <5.0 × ULN are eligible if this value is acute and directly related to the infectious process being treated. This must be documented. 13. Patient has a body mass index >45 kg/m2. Patient has APACHE II score >30 (see Appendix F). 15. Patient is considered unlikely to survive the 6- to 8-week study period or has a rapidly progressive or terminal illness. 16. Patient is unlikely to respond to 5 to 14 days of treatment with antibiotics. 17. Patient has received systemic antibacterial agents within the 72-hour period prior to study entry, unless either of the following pertains: (a) Patient has a new infection (not considered a treatment failure) and both of the following are met: − Patient received no more than 24 hours of total prior antibiotic therapy − Patient received ≤1 dose of a treatment regimen postoperatively and antibiotics were not received more than 6 hours postprocedure (defined as 6 hours from the time of skin closure for surgical procedures) (b) Patient is considered to have failed the previous treatment regimen. In this case, preoperative treatment of any duration with nonstudy systemic antimicrobial therapy for peritonitis or abscess is permitted provided that all of the .....
    I pazienti non devono entrare nello studio se soddisfano uno dei seguenti criteri di esclusione: 1. Al paziente viene diagnosticata perforazione intestinale traumatica durante intervento chirurgico entro 12 ore; perforazione di ulcere gastroduodenali durante intervento chirurgico entro 24 ore. Altri processi intra addominali in cui l'eziologia primaria non rischia di essere infettiva. 2. Il paziente presenta ascesso alla parete addominale o ostruzione intestinale senza perforazione o ischemia intestinale senza perforazione. 3. Il paziente presenta colecistite semplice, o colecistite gangrenosa senza rottura, o semplice appendicite o colangite acuta suppurativa; o pancreatite necrotizzante infetta o ascesso pancreatico. 4. L'intervento chirurgico del paziente includerà riparazione addominale in più fasi, o tecnica ad ''addome aperto'', o marsupializzazione. 5. E’ noto dall'inizio dello studio che il paziente soffra di cIAI causata da patogeni resistenti agli agenti antimicrobici dello studio. 6. Il paziente ha bisogno di efficaci antibatterici concomitanti sistemici (orali, endovenosi, o intramuscolari) e antimicotici in aggiunta a quelli indicati nei 2 gruppi dello studio, ad eccezione di vancomicina, linezolid, o daptomicina se iniziati per noto o sospetto stafilococco aureo resistente alla meticillina (MRSA) o specie di enterococco come indicato nella Sezione 5.6 del protocollo . 7. Il paziente riporta evidenza di sepsi con shock che non risponde al test del fluido endovenoso o che si prevede richieda la somministrazione di vasopressori per &gt;12 ore. 8. Il paziente presenta infezioni perinefriche. 9. Il paziente ha un catetere per dialisi peritoneale. 10. Si sospetta che il paziente abbia infezioni intra-addominali dovute a micosi, parassiti (ad esempio, ascesso amebico al fegato), virus, o tubercolosi. 11. Il paziente ha un'anamnesi nota di allergia grave, ipersensibilità (ad esempio, anafilassi), o qualsiasi grave reazione agli antibiotici carbapenemici o cefalosporinici o altri antibiotici β-lattamici o al metronidazolo. 12. Il paziente presenta uno dei valori di laboratorio come definiti di seguito: (a) Clearance della creatinina calcolata ≤ 30 ml/min attraverso il metodo Cockcroft Gault (Cockcroft and Gault 1976)). Fare riferimento all'Appendice E per le informazioni sul calcolo. (b) Ematocrito &lt;25% o emoglobina &lt;8 g/dl (c) Conteggio assoluto dei neutrofili &lt;1000/mm3. (d) Conta piastrinica &lt;75000/mm3 (e) Bilirubina &gt; 3 × limite superiore della norma (ULN), a meno che l'iperbilirubinemia isolata non sia direttamente correlata all'infezione acuta o alla malattia nota di Gilbert (f) ALT o AST &gt; 3 × valori ULN allo screening. I pazienti con aumenti di AST e/o ALT fino a 5 x ULN sono ammessi soltanto se questi aumenti sono acuti e direttamente connessi con il processo infettivo che viene trattato. Questo deve essere documentato. (g) Fosfatasi alcalina &gt; 3 x ULN. I pazienti con valori &gt; 3,0 × ULN e &lt; 5,0×ULN sono ammessi soltanto se questo valore è acuto e direttamente connesso con il processo infettivo che viene trattato. Questo deve essere documentato. 13. Il paziente ha un indice di massa corporea &gt; 45 kg/m2. 14. Il paziente ha un punteggio APACHE II &gt;30 (ved. Appendice F). 15. Si considera improbabile che il paziente sopravviva al periodo dello studio da 6 a 8 settimane, o questo soffre di una malattia rapidamente progressiva o terminale. 16. È improbabile che il paziente risponda ad un periodo compreso tra 5 e 14 giorni di trattamento con gli antibiotici. 17. Il paziente ha ricevuto agenti antibatterici sistemici nel periodo di 72 ore prima di entrare nello studio, a meno che si applichi una delle seguenti opzioni: (a) Il paziente presenta una nuova infezione (non considerata un insuccesso del trattamento) e entrambe le seguenti condizioni vengono soddisfatte: .............
    E.5 End points
    E.5.1Primary end point(s)
    To assess the proportion of patients with clinical cure in the microbiological modified intent-to-treat analysis set.
    La percentuale di pazienti con normale pratica clinica alla visita TOC nel set di analisi intent to treat microbiologico modificato (mMITT).
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the test of cure visit.
    Alla visita di valutazione della cura (TOC).
    E.5.2Secondary end point(s)
    1. To assess the proportion of patients with clinical cure in the microbiologically evaluable analysis set. 2. To assess the proportion of patients with clinical cure in the microbiological modified intent-to-treat and microbiologically evaluable analysis sets. 3. To assess the proportion of patients with clinical cure in the clinically evaluable anlaysis set. 4. To assess the proportion of patients with a favorable per-patient microbiological response in the microbiological modified intent to treat and microbiologically evaluable analysis sets. 5. To assess the proportion of favorable per-pathogen microbiological response in the microbiological modified intent to treat and microbiologically evaluable anlaysis sets. 6. To assess the favorable per-pathogen microbiologic response by minimum inhibitory concentration (MIC) categories in the microbiological modified intent to treat and microbiologically evaluable analysis sets. 7. To assess the favorable per-patient clinical response and favorable per patient microbiological response for patients infected with ceftazidimeresistant pathogens in the microbiological modified intent to treat and microbiologically evaluable analysis sets. 8. To assess the proportion of patients with a favorable per pathogen microbiological response for patients infected with ceftazidime-resistant pathogens in the microbiological modified intent to treat and microbiologically evaluable anlaysis sets. 9. To assess the time to first defervescence in the clinically evaluable and microbiologically evaluable anlaysis sets for patients who have fever at study entry. 10. To assess the safety and tolerability by incidence and severity of adverse events and serious adverse events, vital signs, clinical laboratory tests, ECGs and physical exams.
    Le variabili secondarie di risultati di efficacia comprendono quanto segue: 1)Percentuale di pazienti con guarigione clinica alla visita TOC nel set di analisi valutabili microbiologicamente 2)Percentuale di pazienti con guarigione clinica alle visite EOT e LFU nei set di analisi mMITT e valutabili microbiologicamente 3)Percentuale di pazienti con guarigione clinica alle visite EOT, TOC e LFU nel set di analisi valutabili clinicamente 4)Percentuale di pazienti con risposta microbiologica favorevole per paziente alle visite EOT, TOC e LFU nei set di analisi mMITT e valutabili microbiologicamente 5)Percentuale di pazienti con risposta microbiologica favorevole per patogeno alle visite EOT, TOC e LFU nei set di analisi mMITT e valutabili microbiologicamente 6) Risposta microbiologica per patogeno favorevole alla EOT, TOC e LFU mediante categorie di concentrazione minima inibitoria (CMI) nei set di analisi mMITT e valutabili microbiologicamente 7)Risposta clinica favorevole per paziente e risposta microbiologica favorevole per paziente alla visita TOC per i pazienti infettati con patogeni resistenti a ceftazidima nei set di analisi mMITT e valutabili microbiologicamente 8)Percentuale di pazienti con risposta microbiologica favorevole per patogeno alla visita TOC per i pazienti infettati con patogeni resistenti a ceftazidima nei set di analisi mMITT e valutabili microbiologicamente 9)Intervallo di tempo fino alla prima defervescenza mentre in terapia endovenosa nei set di analisi valutabili microbiologicamente e valutabili clinicamente per pazienti che presentano febbre all'ingresso nello studio. 10 )Sicurezza e tollerabilità saranno valutate mediante l'incidenza e la gravità degli eventi avversi (AE) e degli eventi avversi gravi (SAE), dei segni vitali, risultati dell'esame fisico, parametri di ECG e dei valori di laboratorio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. at the test of cure visit 2. at the end of treatment and late follow-up visits 3. at the end of treatment, test of cure and late follow-up visits 4. at the end of treatment, test of cure and late follow-up visits 5. at the end of treatment, test of cure and late follow-up visits 6. at the end of treatment, test of cure and late follow-up visits 7. at the test of cure visit 8. at the test of cure visit 9. while on IV study therapy 10. study duration
    1) Alla visita di valutazione della cura 2) alla visita di fine trattamento e al follow-up a distanza di tempo 3) alla visita di fine trattamento, di valutazione della cura e al follow-up a distanza di tempo 4) alla visita di fine trattamento, di valutazione della cura e al follow-up a distanza di tempo 5) alla visita di fine trattamento, di valutazione della cura e al follow-up a distanza di tempo 6) alla visita di fine trattamento, di valutazione della cura e al follow-up a distanza di tempo 7) alla visita di fine trattamento 8) alla visita di valutazione della cura 9) durante la terapia endovenosa dello studio 10) per l'intera durata dello studio
    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 Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarkers and microbiology cultures
    Studio dei biomarkers e studio delle 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA55
    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
    Canada
    India
    Israel
    Mexico
    Peru
    Russian Federation
    South Africa
    Taiwan
    Thailand
    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 years0
    E.8.9.1In the Member State concerned months18
    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 months21
    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: 885
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 221
    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 potrebbero necessitare di intubazione e susseguente sedazione, e pertanto non 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 state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 273
    F.4.2.2In the whole clinical trial 1106
    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 Decision2012-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-04-17
    P. End of Trial
    P.End of Trial StatusOngoing
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