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    Summary
    EudraCT Number:2011-000484-28
    Sponsor's Protocol Code Number:LRS114688
    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:2011-12-20
    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 number2011-000484-28
    A.3Full title of the trial
    A randomised, double-blind, dose-finding, multicenter study of the safety, tolerability, and efficacy of GSK2251052 therapy compared to imipenem-cilastatin in the treatment of adult subjects with febrile complicated lower urinary tract infections and acute pyelonephritis
    Studio multicentrico, randomizzato, in doppio cieco, di definizione della dose, per valutare la sicurezza, la tollerabilita' e l'efficacia di GSK2251052 nel trattamento di soggetti adulti con infezioni febbrili complicate del tratto urinario inferiore e pielonefrite acuta.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    GSK2251052 therapy compared to imipenem-cilastatin in the treatment of adult subjects with febrile complicated lower urinary tract infections and acute pyelonephritis
    Studio su un nuovo farmaco, un antibiotico per somministrazione endovenosa (GSK2551052), in adulti con infezione complicata del tratto urinario o pielonefrite
    A.3.2Name or abbreviated title of the trial where available
    LRS114688
    LRS114688
    A.4.1Sponsor's protocol code numberLRS114688
    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 SponsorGLAXO SMITHKLINE
    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 supportGlaxo Smith Kline Research & Development Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Ltd
    B.5.2Functional name of contact pointClinical Trial Helpdesk
    B.5.3 Address:
    B.5.3.1Street Address1-3 Iron Bridge Road
    B.5.3.2Town/ cityStockley Park, Uxbridge
    B.5.3.3Post codeUB11 1BU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0044 20 8990 4466/800786766
    B.5.5Fax number0044 20 8990 1234
    B.5.6E-mailGSKClinicalSupportHD@gsk.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 nameGSK2251052
    D.3.2Product code GSK2251052
    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.3.9.1CAS number 1093643-37-8
    D.3.9.2Current sponsor codeGSK2251052
    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 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 nameGSK2251052
    D.3.2Product code GSK2251052
    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.3.9.1CAS number 1093643-37-8
    D.3.9.2Current sponsor codeGSK2251052
    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 TIENAM*INFUS 1FL 500MG+500MG
    D.2.1.1.2Name of the Marketing Authorisation holderMERCK SHARP & DOHME SpA
    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.3.4Pharmaceutical 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.3.10 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    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 Urinary tract infections (cUTI)
    Infezioni complicate del tratto urinario (cUTI)
    E.1.1.1Medical condition in easily understood language
    a urinary infection or kidney infection (also known as pyelonephritis)
    infezione alle vie urinarie o renali (conosciute anche come pielonefriti)
    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 PT
    E.1.2Classification code 10059517
    E.1.2Term Bacterial pyelonephritis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10054088
    E.1.2Term Urinary tract infection bacterial
    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 evaluate the safety and tolerability of GSK2251052 in the treatment of adult subjects with lower cUTI and pyelonephritis (complicated and uncomplicated). To evaluate the clinical and microbiological efficacy of GSK2251052 in microbiologically evaluable adult subjects with lower cUTI and pyelonephritis (complicated and uncomplicated).
    - Valutare la sicurezza e la tollerabilità di GSK2251052 nel trattamento di soggetti adulti con cUTI del tratto urinario inferiore e pielonefrite (complicata e non complicata). - Valutare l’efficacia clinica e microbiologica di GSK2251052 in soggetti adulti con cUTI del tratto urinario inferiore e pielonefrite (complicata e non complicata) valutabili da un punto di vista microbiologico.
    E.2.2Secondary objectives of the trial
    To compare the clinical and bacteriological efficacy of GSK2251052 to imipenemcilastatin in microbiologically evaluable adult subjects with lower cUTI and acute pyelonephritis (complicated and uncomplicated). To evaluate the pharmacokinetics of GSK2251052 and to characterise the pharmacokinetic/pharmacodynamic relationship in this study population.
    - Confrontare l’efficacia clinica e microbiologica di GSK2251052 rispetto a imipenem-cilastina in soggetti adulti con cUTI del tratto urinario inferiore e pielonefrite (complicata e non complicata) valutabili da un punto di vista microbiologico. - Valutare la farmacocinetica di GSK2251052 e caratterizzare la relazione farmacocinetica/farmacodinamica (PK/PD) in questa popolazione in studio.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Italian female subjects: In Italy, a female subject will be eligible for inclusion in this study only if they are off non-childbearing potential.1. Adult subjects aged at least 18 years. N.B. Females of non-childbearing or childbearing potential may be enrolled. It is not contraindicated to enrol females of childbearing potential, however, they must have a a negative pregnancy test at study entry and must have practiced adequate contraception for at least 30 days prior to study entry. (see protocol list) 2. Subject requires hospitalisation and has clinical signs and symptoms of lower cUTI or pyelonephritis (complicated or uncomplicated) as defined below, that requires parenteral treatment only with a treatment course of a minimum of 5 days and a maximum of 14 days: a. Lower cUTI – subjects must have documented fever defined as >38°C oral, >38.5°C tympanic or >39°C rectal, within the last 24 hours, exceptions would be; i. Afebrile subjects with lower cUTI who have a white blood cell count (WBC) ≥15,000 cells/mm3 ii. Afebrile subjects with a lower cUTI following requiring parenteral therapy due to a specific indication e.g. • Before and during an operative procedure, when oral antibiotics are not indicated • Or in cases where the cUTI is suspected to be due to a pathogen resistant to current oral antibiotics, and at least two of the following UTI symptoms including dysuria, frequency, urgency or suprapubic pain, with the presence of a complicating factor: iii. Male gender; iv. Current bladder instrumentation or indwelling urinary catheter that has to be removed two days before the end of IV study drug administration; v. Obstructive uropathy that is expected to be medically or surgically treated during the course of IV study drug administration;vi. Urogenital surgery within 7 days preceding administration of the first dose of study drug; vii. Functional or anatomical abnormality of the urogenital tract including anatomic malformations or neurogenic bladder (with voiding disturbance of at least 100 mL residual urine. b. Acute pyelonephritis (complicated or uncomplicated): subjects must have documented fever defined as >38°C oral, >38.5°C tympanic or >39°C rectal, within the last 24 hours and flank pain or costovertebral angle tenderness (CVA). Complicating factors for pyelonephritis are the same as for complicated UTI. 3. Subject has pyuria (white blood cell [WBC] count > 10/μL (or >5/high-power field [HPF] in a conventional urinalysis) in unspun clean-catch midstream urine (MSU) or catheter urine sample or ≥ 10 WBC/HPF in spun MSU or catheter urine). 4. Subject has Gram-negative organism(s) on direct examination of a Gram-stained specimen from unspun or spun MSU or catheter urine sample. 5. Subject has provided a pre-therapy urine specimen obtained within 48 hours prior to the start of therapy, which when cultured has grown at least one and not more than two Gram-negative uropathogens at ≥105 CFU/mL. a. A subject may be enrolled before the results of the pre-therapy urine culture is known, but the subject should be withdrawn from the study if the culture does not yield at least one but not more than two qualifying Gram-negative uropathogens at ≥105 CFU/mL or if the culture yields Gram-positive uropathogens. b. A subject with lower cUTI or pyelonephritis (complicated or uncomplicated) who has failed a previous antibacterial treatment regimen is eligible provided a urine specimen is positive for one and not more than two bacterial Gram-negative uropathogens at ≥105 CFU/mL. Subjects who are treatment failures due to imipenem-cilastatin should not be enrolled. 6. QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block
    Soggetti italiani di sesso femminile: In Italia un soggetto di sesso femminile potrà essere arruolato solo se non potenzialmente fertile.Potranno essere iclusi 1.Soggetti adulti di almeno 18 anni di età.N.B. Potranno essere arruolate donne potenzialmente o non potenzialmente fertili.Non è controindicato arruolare donne potenzialmente fertili, ma dovranno avere un test di gravidanza negativo al momento dell’ingresso in studio e aver praticato una contraccezione adeguata per almeno 30 giorni prima dell’ingresso in studio.Dovranno acconsentire ad utilizzare uno dei seguenti metodi contraccettivi per tutta la durata del periodo di trattamento:astinenza;contraccezione orale, sia con combinazione estrogeni/progesterone che con solo progesterone, INSIEME A un metodo aggiuntivo di barriera (preservativo, cappuccio occlusivo (diaframma o cappuccio cervicale) o agenti spermicidi vaginali (schiuma/gel/film/crema/candeletta)];progesterone iniettabile;impianti di levonorgestrel;anello vaginale con estrogeni;cerotti contraccettivi percutanei;dispositivo intrauterino o sistema intrauterino che mostri un tasso di fallimento inferiore all’1% nell’etichetta dello IUD o IUS;partner maschile sterilizzato (vasectomia con documentazione di azoospermia);metodo a doppia barriera:preservativo e cappuccio occlusivo associato ad un agente spermicida vaginale.Le donne sono considerate non potenzialmente fertili se sottoposte a legatura delle tube o isterectomia documentate;donne in post-menopausa, definita come 12 mesi di amenorrea spontanea [nei casi dubbi, si considererà confermatorio un campione di sangue con FSH&gt;40MlU/ml ed estradiolo&lt;40pg/ml (&lt;147pmol/L)].2.Soggetti che richiedono un ricovero ospedaliero e presentano segni e sintomi di cUTI del tratto urinario inferiore o pielonefrite(complicata e non), che richiedono trattamento parenterale solo se di durata minima di 5 giorni e massima di 14: a.cUTI del tratto urinario inferiore – presenza documentata di febbre nelle precedenti 24 ore, potranno essere un eccezione i soggetti con:i.assenza di febbre in cUTI del tratto urinario inferiore associata a conta leucocitaria alterata – WBC≥15.000 cellule/mm3 ii.assenza di febbre in cUTI del tratto urinario inferiore e necessità di una terapia per via parenterale per una specifica indicazione come ad esempio:prima e durante un intervento chirurgico, nel caso in cui gli antibiotici per via orale non sono indicati o nei casi in cui l’infezione cUTI si sospetta essere causata da un patogeno resistente agli attuali antibiotici orali e almeno due dei seguenti sintomi di UTI quali disuria, pollachiuria, urgenza di urinare o dolore sovrapubico, con la presenza di uno dei seguenti fattori complicanti:i.sesso maschile;ii.presenza di strumentazione vescicale o catetere urinario a permanenza che deve essere rimosso due giorni prima della fine della somministrazione per via endovenosa del farmaco in studio;iii.uropatia ostruttiva per la quale si attende un trattamento farmacologico o chirurgico nel corso della terapia per via endovenosa con il farmaco in studio;iv.chirurgia urogenitale nei 7 giorni precedenti la somministrazione della prima dose del farmaco in studio;v.anomalia funzionale o anatomica del tratto urogenitale, comprese malformazioni anatomiche o vescica neurogenica con disturbi di svuotamento di almeno100mL di urina residua.b.Pielonefrite acuta(complicata per cui un precedente regime di trattamento antibatterico è fallito è eleggibile a condizione che il campione di urine sia positivo per uno e non più di due uropatogeni batterici Gram-negativinella misura di CFU/mL 105. I soggetti che costituiscono un fallimento del trattamento a causa di imipenem-cilastatina non devono essere arruolati.6.QTcB o QTcF &lt; 450 msec; o intervallo QTc&lt;480msec in soggetti con Blocco di Branca
    E.4Principal exclusion criteria
    Concomitant infection requiring systemic antibacterial therapy other than study drugs at the time of randomisation. 2. Subject is known to have one or more of the following: a. A urinary catheter that is not being removed during the study b. Complete permanent obstruction of the urinary tract; c. A permanent indwelling catheter or comparable instrumentation including nephrostomy that will not be emoved during IV study drug administration; d. Suspected or confirmed prostatitis; e. Suspected or confirmed perinephric or intrarenal abscess; f. A UTI suspected or confirmed to be fungal in origin (with ≥ 103 fungal CFU/mL); g. A UTI suspected or confirmed to be due to a Gram-positive uropathogen(s), with ≥105 Gram-positive organism CFU/mL; h. A UTI known at study entry to be caused by a pathogen(s) resistant to the study antimicrobial agent; i. Known ileal loops or vesico-ureteral reflux ; j. Polycystic kidney disease. 3. Subject has an APACHE II score >20. 4. Subject has known severe impairment of renal function including: a calculated creatinine clearance (CrCl) of less equal than 51 mL/min; requirement for peritoneal dialysis, haemodialysis, or haemofiltration; oliguria (less than 20 mL urine output per hour over 24 hours); 5. Subject with an intractable lower cUTI requiring more than 14 Days IV treatment. 6. Subjects with asymptomatic lower cUTI, such as subjects with spinal cord injury with lower cUTI who are not able to perceive symptoms due to their injury. 7. Subject with lower cUTI or pyelonephritis (complicated and uncomplicated) who has received any amount of a potentially therapeutic antibiotic within the 96 h before providing the baseline urine culture specimen or prior to the start of the study. 8. Subject has Gram-positive organism(s) on direct examination of a Gramstained specimen of spun/unspun MSU or catheter urine. 9. Subject is considered unlikely to survive the 4-6 week study period or has any rapidly progressing disease or immediately life-threatening illness 29 10. Subject has evidence of known or pre-existing severe hepatic disease. 11. Subject has a known baseline haemoglobin less than 10 g/dL ,haematocrit less than 30% and/or a known reticulocyte count of >5% (i.e., reticulocytes >5% of total RBC mass) 12. Subject has known neutropenia or is anticipated to develop neutropenia during the course of the study (i.e., new chemotherapy subject), with absolute neutrophil count less than 1000 cells/mm3.13. Subject has a known platelet count less than 75,000 cells /mm3 (subjects with platelet counts as low as 50,000 cells /mm3 are eligible if the reduction is historically stable). 14. Subject has an immunocompromising illness; including known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), organ transplantation, hematological malignancy, and/or immunosuppressive therapy , including high-dose corticosteroids ( 15. Subject has participated in any investigational drug or device study within 30 days of study entry or within 5 half-lives, whichever is longer. 16. Subject has previously received treatment with GSK2251052. 17. Subject has a prior history of seizures or has a CNS abnormality predisposing them to seizures or has a lowered seizure threshold and/or is using concomitant medications with seizure potential. 18. Subject requires probenicid or valproic acid medications. 19. Subject with a history of moderate or severe hypersensitivity to β-lactam antibiotics. 20. Subject is pregnant or nursing.21. Subject, in the opinion of the investigator may be significantly compromised by a potential drop in haemoglobin> equal 2.5g/dl which is not related to the condition under study.
    1.Soggetti con infezione concomitante che richiede terapia antibatterica sistemica diversa dal trattamento in studio al momento della randomizzazione.2.Soggetti con anamnesi nota per:a.catetere urinario che non viene rimosso durante lo studio (o soggetti per cui ci si attende che venga inserito un catetere durante la terapia con il farmaco in studio e che non venga rimosso durante il periodo di studio- il cateterismo intermittente di breve durata è accettabile);b.ostruzione completa permanente del tratto urinario;c.catetere permanente o strumentazione simile compresa la nefrotomia che non sarà rimosso durante la somministrazione via IV del farmaco in studio;d.prostatite sospetta o confermata;e.ascesso perinefrico o intrarenale sospetto o confermato;f.UTI con sospetta o confermata origine micotica g.UTI sospetto o confermato da uropatogeno/i Gram-positivi, con presenza di organismi Gram-positivi≥105 CFU/mL;h.UTI nota all’inizio dello studio di essere causata da patogeno/patogeni resistenti all’agente antimicrobico in studioi.Presenza di anastomosi uretero-ileale o reflusso vescico-uretrale j.patologia renale policistica3.Soggetti con punteggio APACHE II&gt;30.4.Soggetti con noto deterioramento severo della funzione renale;necessità di dialisi peritoneale, emodialisi o emofiltrazione; oliguria 5.Soggetti con cUTI del tratto urinario inferiore non trattabile che necessitano di oltre 14 giorni di trattamento per via endovenosa.6.Soggetti con cUTI del tratto urinario inferiore asintomatica.7.Soggetti con cUTI del tratto urinario inferiore o pielonefrite(complicata e non) che hanno ricevuto un qualsiasi quantitativo di un antibiotico potenzialmente terapeutico nelle 96 ore prima di fornire il campione per l’urinocoltura basale o prima dell’inizio dello studio.8.Soggetti con evidenziata presenza di organismi Gram-positivi alla colorazione striscio di Gram in campione di urine da mitto intermedio centrifugato/non centrifugato o in campione di urine da catetere.9.Soggetti con un’aspettativa di vita inferiore alle 4-6 settimane del periodo di studio o con una patologia a rapida progressione o con malattia con immediato pericolo di vita 10.Soggetti con evidenza di patologia epatica grave nota o pregressa (punteggio Child-Pugh B o C).
    11.Soggetti con nota emoglobina basale inferiore a 10g/dL, ematocrito inferiore a 30% e/o conta reticolocitica&gt;5% 12.Soggetti con neutropenia nota o che si prevede che sviluppino neutropenia nel corso dello studio con conta assoluta dei neutrofili inferiore a 1.000cellule/mm3 13.Soggetti con conta piastrinica nota inferiore a 75.000 cellule/mm3 14. Soggetti con malattia immuno-compromettente, comprese HIV o AIDS, il trapianto d’organo (incluso il midollo osseo) la patologia onco-ematologica, e pazienti in terapia immunosoppressiva, compresi i corticosteroidi ad alto dosaggio 15.Soggetti che hanno partecipato a qualsiasi studio con un farmaco sperimentale o un dispositivo medico nei 30 giorni precedenti l’ingresso in studio o entro 5 emivite.16.Soggetti precedentemente sottoposti a trattamento con GSK2251052.17.Soggetti con anamnesi precedente di attacchi epilettici o con anomalie del sistema nervoso centrale che aumentino la predisposizione agli attacchi epilettici, o che presentano un abbassamento della soglia per gli attacchi epilettici e/o che stanno utilizzando farmaci concomitanti con potenziale per attacchi epilettici.18.Soggetti che necessitano di trattamento con probenicid o acido valproico.19.Soggetti con anamnesi di ipersensibilità moderata o severa agli antibiotici beta-lattamici.20.Donne in gravidanza o allattamento 21.Soggetti il cui stato di salute possa essere compromesso in maniera significativa in seguito ad una riduzione dell’emoglobina ≥ 2.5 g/dl non correlata alle condizioni per le quali è entrato nello studio
    E.5 End points
    E.5.1Primary end point(s)
    Safety evaluation of data from clinical laboratory tests, urinalysis, spontaneous/elicited adverse event reporting, ECGs and vital signs in all subjects who had at least one dose of study medication. Primary efficacy outcome measure is the therapeutic response (combined per-subject clinical and microbiological response) at the Test of Cure visit in subjects who have a qualifying Gram-negative uropathogen at Baseline and have had a minimum of 5 days of IV therapy.
    Valutazioni di sicurezza dei dati degli esami clinici di laboratorio, esami delle urine, reporting spontaneo/successivamente derivato degli eventi avversi, ECG e segni vitali per tutti i soggetti arruolati che hanno assunto almeno una dose di farmaco in studio. Per la misurazione dell’esito di efficacia si utilizzerà la risposta terapeutica (risposta clinica e microbiologica combinate per lo stesso soggetto) alla Visita Test of Cure nei soggetti per i quali è stato individuato un uropatogeno Gram-negativo qualificante alla visita basale e la cui terapia endovenosa abbia una durata di almeno 5 giorni.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint is to be evaluated at the test of cure visit (5 to 9 days post IV treatment)
    L'endpoint primario deve essere valutato alla visita del test of cure (da 5 a 9 giorni dopo il trattamento EV)
    E.5.2Secondary end point(s)
    Microbiological response at the End of IV Therapy Visit, Test of Cure Visit and Late Follow-Up Visit. • Clinical response at the End of IV Therapy Visit, Test of Cure Visit and Late Follow-Up Visit • Therapeutic response (combined clinical and microbiological response) at the End of IV Visit and Late Follow-Up Visit, • GSK2251052 pharmacokinetics and population PK/PD in the patient population•
    • Risposta microbiologica alla Visita di fine della terapia endovenosa, alla Visita Test of Cure e all’ultima visita di Follow-up • Risposta clinica alla Visita di fine della terapia endovenosa, alla Visita Test of Cure e all’ultima visita di Follow-up • Risposta terapeutica (risposta clinica e microbiologica combinate) alla Visita di fine della terapia endovenosa e all’ultima visita di Follow-up • Farmacocinetica di GSK2251052 e popolazione PK/PD nella popolazione di soggetti.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints are to be evaluated at the test of cure visit (5 to 9 days post IV treatment), end of IV therapy visit and late follow-up visit (21-28 days post IV treatment)
    Gli endpoint secondari devono essere valutati alla visita del test of cure (da 5 a 9 giorni dopo il trattamento EV), alla visita di fine della terapia EV e all'ultima visita di follow-up (21-28 giorni dopo il trattamento EV)
    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 No
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Imipinem-cilastatina - Stesso farmaco ad altro dosaggio
    Imipinem-cilastatina - same IMP used at different dosage
    E.8.2.4Number of treatment arms in the trial3
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA46
    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
    Russian Federation
    South Africa
    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 months12
    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 months12
    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: 105
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 105
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 168
    F.4.2.2In the whole clinical trial 210
    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)
    The investigator is responsible for ensuring that consideration has been given to the post-study care of the patient's medical condition whether or not GSK is providing specific post study treatment. No post-study medication is provided as part of this protocol.
    Lo sperimentatore ha la responsabilità di garanire ai soggetti la migliore assistenza dopo mlo studio sia cge GSK fornisca o meno una terapia post studio. Nessuna terapia post-studio è prevista da questo protocollo
    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 Decision2012-01-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-11-17
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2012-03-05
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