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    Summary
    EudraCT Number:2015-000066-62
    Sponsor's Protocol Code Number:7655A-013
    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:2018-02-28
    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 number2015-000066-62
    A.3Full title of the trial
    A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Estimate the Efficacy and Safety of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium + Imipenem/Cilastatin in Subjects with Imipenem-Resistant Bacterial Infection
    Studio di fase III, randomizzato, in doppio cieco, controllato con farmaco attivo di confronto per valutare l’efficacia e la sicurezza di Imipenem/Cilastatina/Relebactam (MK7655A) verso Colistimetato di Sodio + Imipenem/Cilastatina in pazienti affetti da infezioni batteriche resistenti a Imipenem
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    IMI/REL (MK7655-A) vs. CMS + IMI in Subjects with Imipenem-Resistant Bacterial Infection
    IMI/REL (MK-7655A) verso CMS + IMI in pazienti affetti da infezioni batteriche resistenti a Imipenem
    A.3.2Name or abbreviated title of the trial where available
    IMI/REL (MK7655-A) vs. CMS + IMI in Subjects with Imipenem-Resistant Bacterial Infection
    IMI/REL (MK-7655A) verso CMS + IMI in pazienti affetti da infezioni batteriche resistenti a Imipenen
    A.4.1Sponsor's protocol code number7655A-013
    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 SponsorMERCK SHARP & DOHME CORP. UNA SUSSIDIARIA DI MERCK & CO. INC.
    B.1.3.4CountryUnited States
    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 supportMerck Sharp&Dhome Corp sussidiaria di Merck&Co Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMSD Italia S.r.l.
    B.5.2Functional name of contact pointDivisione Ricerca Clinica
    B.5.3 Address:
    B.5.3.1Street AddressVia Fratelli Cervi, snc - Centro Direzionale Due - Palazzo Canova
    B.5.3.2Town/ citySegrate (MI)
    B.5.3.3Post code20090
    B.5.3.4CountryItaly
    B.5.4Telephone number+39 02 21018402
    B.5.5Fax number+39 02 21018629
    B.5.6E-mailgcto.italy@merck.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 nameImipenem/Cilastatin + MK-7655
    D.3.2Product code MK-7655A
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIMIPENEM
    D.3.9.1CAS number 64221-86-9
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive nameIMIPENEM
    D.3.9.4EV Substance CodeSUB08151MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCILASTATINA
    D.3.9.1CAS number 82009-34-5
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive nameCILASTATINA
    D.3.9.4EV Substance CodeSUB06264MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRELEBACTAM
    D.3.9.2Current sponsor codeMK-7655
    D.3.9.4EV Substance CodeSUB120519
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP 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 Primaxin
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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/Cilastatin
    D.3.2Product code MK-0787B
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIMIPENEM
    D.3.9.1CAS number 64221-86-9
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive nameIMIPENEM
    D.3.9.4EV Substance CodeSUB08151MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCILASTATINA
    D.3.9.1CAS number 82009-34-5
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive nameCILASTATINA
    D.3.9.4EV Substance CodeSUB06264MIG
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 Colistimethate for Injection, USP
    D.2.1.1.2Name of the Marketing Authorisation holderX-GEN Pharmaceuticals, Inc
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameColistimethate for Injection, USP
    D.3.2Product code .
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCOLISTIMETATO SODICO
    D.3.9.1CAS number 8068-28-8
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive nameNDC: 39822-0615-2
    D.3.9.4EV Substance CodeSUB06801MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Imipenem-resistant bacterial infections, including hospital-associated or venntilator acquired pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI) or complicated urinary tract infection (cUTI)
    Infezioni batteriche resisitenti a Imipenem, incluse la polmonite nosocomiale o da ventilazione meccanica (HABP / VABP), infezione intra-addominale complicata (cIAI) o infezione complicata del tratto urinario (cUTI)
    E.1.1.1Medical condition in easily understood language
    Antibiotic-resistant bacterial infections of the lungs, abdomen or urinary tract
    Infezioni batteriche antibiotico-resistenti dei polmoni, addome o tratto urinario
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10071097
    E.1.2Term Beta-lactam antibiotic resistance
    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
    (1) To estimate the proportion of subjects with favorable overall response to IMI/MK-7655 (Treatment Group 1 only) and to CMS + IMI (Treatment Group 2).
    The overall response will be estimated based on the following: (a) survival (based upon all-cause mortality) through Day 28 post-randomization in subjects with HABP/VABP, (b) clinical response at Day 28 post-randomization for subjects with cIAI and (c) the composite clinical and microbiological response at the early follow-up visit, EFU (Day 5 to 9 post-randomization) for subjects with cUTI.
    (2) To evaluate the safety and tolerability profile of IMI/MK-7655 (Treatment Group 1 only).
    (1) Obiettivo: Stimare la percentuale di soggetti con risposta complessiva favorevole a IMI/REL (solo Gruppo di trattamento 1) e a CMS+IMI (Gruppo di trattamento 2).
    La risposta complessiva sarà stimata sulla base di quanto segue: (a) sopravvivenza (in base alla mortalità da tutte le cause) fino al Giorno 28 post-randomizzazione nei soggetti con HABP/VABP, (b) risposta clinica al Giorno 28 post-randomizzazione per i soggetti con cIAI e (c) risposta composita clinica e microbiologica alla visita di follow-up precoce, EFU (da Giorno 5 a giorno 9 post-randomizzazione) per i soggetti con cUTI.
    (2) Obiettivo: Valutare il profilo di sicurezza e tollerabilità di IMI/REL (solo Gruppo di trattamento 1).
    E.2.2Secondary objectives of the trial
    (1) To estimate the proportion of subjects with a favorable clinical response to IMI/MK-7655 (Treatment Group 1 only) and CMS + IMI (Treatment Group 2) at Day 28 post-randomization; (2) To estimate the incidence of all-cause mortality through Day 28 post-randomization in Treatment Group 1 (IMI/MK-7655) and in Treatment Group 2 (CMS + IMI); (3) To estimate the proportion of subjects who experience treatment-emergent nephrotoxicity in Treatment Group 1 (IMI/MK-7655) and in Treatment Group 2 (CMS + IMI). Other secondary objective include evaluation of clinical response at various other timepoints during the trial, including on-therapy and post-therapy visits as well as evaluation of microbiological response in subjects with cUTI.
    (1) Obiettivo: Stimare la percentuale di soggetti con risposta clinica favorevole a IMI/REL (solo Gruppo di trattamento 1) e a CMS+IMI (Gruppo di trattamento 2) al Giorno 28 post-randomizzazione.
    (2) Obiettivo: Stimare l’incidenza della mortalità da tutte le cause fino al Giorno 28 post-randomizzazione nel Gruppo di trattamento 1 (IMI/REL) e nel Gruppo di trattamento 2 (CMS+IMI).
    (3) Obiettivo: Stimare la percentuale di soggetti che sviluppa una nefrotossicità successiva al trattamento nel Gruppo di trattamento 1 (IMI/REL) e nel Gruppo di trattamento 2 (CMS+IMI).
    Altri obiettivi secondari includono la valutazione della risposta clinica effettuata in vari altri timepoints durante lo studio, incluse le visite effettuate nel corso e dopo la fine del trattamento, come anche la valutazione della risposta microbiologica nei soggetti con cUTI.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described
    elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to
    ensure that subjects receive the correct dose of the correct drug at the correct time.
    Merck condurrà una Ricerca Biomedica Futura su campioni di DNA (estratti dal sangue) raccolti nel corso di questo studio clinico. Tale ricerca ha lo scopo di esaminare vari biomarcatori per rispondere a domande che stanno emergendo e che non sono descritte in altre parti del protocollo (nell’ambito dello studio principale), e verrà condotta solo su campioni di soggetti che abbiano rilasciato apposito consenso. L'obiettivo della raccolta dei campioni per la Ricerca Biomedica Futura è quello di esplorare e identificare biomarcatori che contribuiscano scientificamente alla comprensione delle malattie e/o della relative terapie. L'obiettivo ultimo è quello di utilizzare tali informazioni per sviluppare farmaci più sicuri e più efficaci, e/o per garantire che i soggetti ricevano la dose giusta del giusto farmaco al momento giusto.
    E.3Principal inclusion criteria
    Treatment Groups 1, 2 and 3 unless otherwise specified
    In order to be eligible for participation in this trial, the subject must:
    1. be ≥ 18 years of age on the day of signing informed consent at the randomization visit.
    2. require hospitalization and treatment with IV antibiotic therapy for a new, persistent (defined as inadequate response to current therapy or failure to improve as expected) or progressing (defined as clinically worsening despite treatment) bacterial infection with at least one of the following primary infection types:
    •Hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial
    pneumonia (VABP)
    •Complicated intra-abdominal infection (cIAI)
    •Complicated urinary tract infection (cUTI)
    3. has positive culture data obtained from the primary infection-site specimen collected within 1 week of study entry and at least one of the suspected causative pathogen(s) from that specimen meets all of the following criteria:
    a.has been identified as a Gram-negative bacterium, AND
    Treatment Groups 1, 2
    based on panels provided by the Sponsor:
    b. has culture-confirmed IMI resistance (MIC of isolate is above the IMIsusceptible breakpoint), AND
    c. has culture-confirmed susceptibility to colistin (MIC of isolate is at or below the colistin-susceptible breakpoint) and to IMI/REL (MIC of isolate is at or below the IMI-susceptible breakpoint).
    Treatment group 3
    based on panels provided by the Sponsor:
    b. has culture-confirmed IMI resistance (MIC of isolate is above the IMIsusceptible breakpoint) and colistin resistance (MIC of isolate is above the colistin-susceptible breakpoint),
    AND
    c. has culture-confirmed susceptibility to IMI/REL (MIC of isolate is at or below the IMI-susceptible breakpoint).
    4. agree to allow any bacterial isolates obtained from protocol-required specimens related to the current infection to be provided the Central Microbiology Reference Laboratory for study-related microbiological testing, long-term storage, and other future testing.
    5. understand (or have a legal representative that understands) the study procedures, alternative treatments available, and risks involved with the study, and voluntarily agree to participate by giving written informed consent for the trial. The subject or legally acceptable representative may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
    6. Meet one of the following categories:
    a) The subject is not of reproductive potential,
    b) The subject is is of reproductive potential and agrees to avoid becoming pregnant or impregnating a partner from the time of consent through completion of the study by complying with one of the following: (1) practice abstinence from heterosexual activity OR (2) use (or have their partner use) acceptable contraception during heterosexual activity.
    Gruppi di trattamento 1 , 2 e 3, se non diversamente specificato
    Per essere eleggibile alla partecipazione a questa sperimentazione, il soggetto deve:
    1. avere ≥18 anni d’età il giorno della firma del consenso informato in occasione della visita di randomizzazione.
    2. richiedere l’ospedalizzazione e un trattamento con terapia antibiotica per via EV per un’infezione batterica di nuova insorgenza, persistente (definita come risposta inadeguata alla terapia in corso o come mancato raggiungimento del miglioramento atteso) o in progressione (definita come peggioramento clinico nonostante il trattamento) con almeno uno dei seguenti tipi principali di infezione:
    • Polmonite batterica nosocomiale (HABP) o polmonite batterica da ventilazione meccanica (VABP)
    • Infezione intra-addominale complicata (cIAI)
    • Infezione complicata del tratto urinario (cUTI)
    3. presentare dati colturali positivi ottenuti dal campione raccolto a livello del sito primario di infezione entro 1 settimana dall’ingresso nello studio, con almeno uno dei patogeni causali sospetti isolati da quel campione che soddisfa tutti i seguenti criteri: a. è stato identificato come batterio Gram-negativo, E
    Gruppi di trattamento 1 , 2
    Sulla base dei pannelli forniti dallo sponsor:
    b. presenta una resistenza a IMI confermata all’esame colturale(la concentrazione minima inibente (minimum inhibitory concentration, MIC) dell’isolato è al di sopra del valore soglia di suscettibilità a IMI), E
    c. presenta una suscettibilità confermata all’esame colturale a colistina (la MIC dell’isolato è uguale o al di sotto del valore soglia di suscettibilità a colistina) e a IMI/REL (la MIC dell’isolato è uguale o al di sotto del valore soglia di suscettibilità a IMI)
    Gruppo di trattamento 3
    Sulla base dei pannelli forniti dallo sponsor:
    b. presenta una resistenza confermata all’esame colturale a IMI (la MIC dell’isolato è al di sopra del valore soglia di suscettibilità a IMI) e a colistina (la MIC dell’isolato è al di sopra del valore soglia di suscettibilità a colistina), E
    c. presenta una suscettibilità confermata all’esame colturale a IMI/REL (la MIC dell’isolato è uguale o al di sotto del valore soglia di suscettibilità a IMI),
    4. essere d’accordo a consentire che gli isolati batterici correlati all’infezione in corso ottenuti dai campioni richiesti dal protocollo siano forniti al Laboratorio microbiologico centrale di riferimento per le analisi microbiologiche relative allo studio, la conservazione a lungo termine e altre analisi future.
    5. comprendere (o avere un rappresentante legale che comprenda) le procedure dello studio, i trattamenti alternativi disponibili e i rischi correlati allo studio e acconsentire volontariamente a partecipare fornendo il consenso informato scritto alla sperimentazione. Il soggetto o un rappresentante legalmente accettabile può inoltre fornire il consenso per la Ricerca biomedica futura. Tuttavia, il soggetto può partecipare alla sperimentazione principale senza prendere parte alla Ricerca biomedica futura.
    6. rientrare in una delle seguenti categorie:
    a) Il soggetto non è potenzialmente fertile
    b) Il soggetto è potenzialmente fertile e accetta di evitare di restare incinta o di mettere incinta la partner dal momento del consenso fino al completamento dello studio, utolizzando metodi di contraccezione accettabili
    E.4Principal exclusion criteria
    Treatment Groups 1, 2 and 3 unless otherwise specified
    The subject must be excluded from participating in the trial if the subject:
    1. has an APACHE II score >30 at screening (Tr. groups 1 and 2 only)
    2. has an infection in which any of the causative pathogens are any of the following:
    •IMI-R Acinetobacter spp.
    •suspected Class B metallo-beta-lactamase-producing bacteria (including NDM-1,
    IMP or VIM-containing strains)
    3. has a concurrent infection that would interfere with evaluation of response to the study antibiotics (IMI/REL or CMS + IMI [for Tr. groups 1 and 2 only]), including any of the following:
    •endocarditis
    •osteomyelitis
    •meningitis
    •prosthetic joint infection
    •active pulmonary tuberculosis
    •a disseminated fungal infection
    4. Tr. groups 1 and 2 only: has received treatment with any form of systemic colistin for > 24 hours within the 72 hours immediately prior to initiation of study therapy.
    5. has HABP/VABP caused by an obstructive process, including lung cancer (or other malignancy metastatic to the lungs resulting in pulmonary obstruction) or other known obstruction.
    6. has cUTI which meets any of the following:
    •complete obstruction of any portion of the urinary tract (requiring a permanent indwelling urinary catheter or instrumentation)
    •known ileal loop
    •intractable vesico-uretral reflux
    •presence of indwelling urinary catheter which cannot be removed at study entry
    7. has a history of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to any of the following:
    •any carbapenem, cephalosporin, penicillin, or other β-lactam agent
    •colistimethate sodium (colistin) or to polymyxin B
    •other β-lactamase inhibitors (e.g., tazobactam, sulbactam, clavulanic acid, avibactam)
    8. is a female who is pregnant or is expecting to conceive (or is a male partner of a female who is expecting to conceive), is breastfeeding, or plans to breastfeed prior to completion of the study.
    9. has any of the following medical conditions at screening:
    •history of a seizure disorder (requiring ongoing treatment with anti-convulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years)
    Tr. groups 1 and 2 only
    •myasthenia gravis
    •porphyria
    •cystic fibrosis
    •granulomatous disease
    10. is anticipated to be treated with any of the following medications during the course of study therapy:
    •valproic acid or divalproex sodium (or has used valproic acid or divalproex sodium in the 2 weeks prior to screening)
    Tr. groups 1 and 2 only
    •concomitant systemic (IV or oral) antimicrobial agents with known Gramnegative bacterial coverage, in addition to those designated in the study treatment groups
    Tr. Group 3 only
    •concomitant systemic (IV or oral) antimicrobial agents in addition to those designated in the study treatment groups (prior use of antimicrobial agents is permitted).
    11. has an estimated or actual creatinine clearance of less than 15 mL/min at screening based on the findings of local laboratory values. Creatinine clearance in mL/min may be calculated from serum creatinine concentration by the Cockcroft-Gault (C-G) equation
    12. is currently undergoing hemodialysis.
    Gruppi di trattamento 1 , 2 e 3, se non diversamente specificato
    Il soggetto deve essere escluso dalla partecipazione alla sperimentazione nei seguenti casi:
    1. presenta un punteggio APACHE II >30 allo screening (solo Gruppi di trattamento 1 , 2)
    2. presenta un’infezione in cui il patogeno causale è uno qualsiasi dei seguenti:
    • Acinetobacter IMI-R spp.
    • sospetti batteri con produzione di metallo-beta-lattamasi di Classe B (inclusi ceppi contenenti NDM-1, IMP o VIM)
    3. ha un’infezione concomitante che interferirebbe con la valutazione della risposta agli antibiotici dello studio (IMI/REL o CMS+IMI), inclusa una qualsiasi delle seguenti:
    • endocardite
    • osteomielite
    • meningite
    • infezione di protesi articolare
    • infezione fungina disseminata
    4. Solo Gruppi di trattamento 1 , 2: ha ricevuto un trattamento con qualsiasi forma di colistina per via sistemica per >24 ore nelle 72 ore immediatamente precedenti l’avvio della terapia dello studio.
    5. presenta una HABP/VABP causata da un processo ostruttivo, tra cui tumore polmonare (o altra neoplasia maligna metastatica ai polmoni che causi ostruzione polmonare) o altra ostruzione nota.
    6. presenta una cUTI che soddisfa uno qualsiasi dei seguenti:
    • ostruzione completa di qualsiasi porzione del tratto urinario (con necessità di catetere urinario a permanenza o strumentazione)
    • ansa ileale nota
    • reflusso vescico-uretrale non suscettibile di trattamento
    • presenza di catetere urinario a permanenza non rimovibile all’ingresso nello studio
    7. ha un’anamnesi di allergia grave, ipersensibilità (per es., anafilassi) o reazione grave a qualsiasi dei seguenti:
    • qualunque carbapenemico, cefalosporina, penicillina o altro agente β-lattamico
    • colistimetato sodico (colistina) o polimixina B
    • altri inibitori delle β-lattamasi (per es., tazobactam, sulbactam, acido clavulanico, avibactam)
    8. è una donna in stato di gravidanza o che prevede di concepire (o è il partner maschile di una donna che prevede di concepire), che sta allattando o che prevede di allattare prima del completamento dello studio.
    . presenta una qualsiasi delle seguenti condizioni mediche allo screening:
    • anamnesi di disturbo convulsivo (che richieda un trattamento in corso con terapia anticonvulsivante o abbia richiesto un precedente trattamento con terapia anticonvulsivante negli ultimi 3 anni)
    Solo Gruppi di trattamento 1 , 2
    • miastenia gravis
    • porfiria
    • fibrosi cistica
    • malattia granulomatosa
    10. prevede di essere trattato con uno qualsiasi dei seguenti farmaci nel corso della terapia dello studio:
    • acido valproico o divalproex sodico (oppure ha utilizzato acido valproico o divalproex sodico nelle 2 settimane precedenti lo screening)
    Solo Gruppi di trattamento 1 , 2
    • agenti antimicrobici concomitanti per via sistemica (per via EV od orale) con copertura nota nei confronti di batteri Gram-negativi, in aggiunta a quelli assegnati nei gruppi di trattamento dello studio
    Solo Gruppo di trattamento 3
    • agenti antimicrobici concomitanti per via sistemica (per via EV od orale) in aggiunta a quelli assegnati nei gruppi di trattamento dello studio (l’impiego precedente di agenti antimicrobici è consentito).
    11. ha una clearance della creatinina stimata o reale inferiore a 15 ml/min allo screening in base ai risultati del laboratorio locale. La clearance della creatinina in ml/min può essere calcolata a partire dalla concentrazione sierica della creatinina mediante l’equazione di Cockcroft-Gault (C-G)
    12. si sta attualmente sottoponendo a emodialisi.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint of the study is overall response. As the efficacy in clinical studies is typically measured differently for different infection types, overall response will be estimated based on the following: (a) all-cause mortality trough Day 28 post-randomization in subjects with HABP/VABP, (b) clinical response at Day 28 post-randomization for subjects with cIAI e (c) the composite clinical and microbiological response at EFU (Day 5 to 9 post-randomization) for subjects with cUTI.
    L’endpoint primario di efficacia è la risposta complessiva favorevole. Poiché l’efficacia negli studi clinici è misurata in modo diverso a seconda del tipo di infezione, la risposta complessiva sarà stimata sulla base di quanto segue: (a) sopravvivenza (in base alla mortalità da tutte le cause) fino al Giorno 28 post-randomizzazione nei soggetti con HABP/VABP, (b) risposta clinica al Giorno 28 post-randomizzazione per i soggetti con cIAI e (c) risposta composita clinica e microbiologica alla visita di follow-up precoce, EFU (da Giorno 5 a giorno9 post-randomizzazione) per i soggetti con cUTI.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The timing is dependent on the subject's primary infection site. For HABP/VABP and cIAI, it is Day 28 post-randomization and for cUTI it is 5 to 9 days following completion of study therapy.
    La valutazione dipende dal sito primario d’infezione del soggetto. Per i soggetti con HABP/VABP e cIAI corrisponde al Giorno 28 post-randomizzazione, mentre per i soggetti con cUTI corrisponde ai giorni 5 e 9 successivi al completamento dello studio
    E.5.2Secondary end point(s)
    There are two key secondary measurements for efficacy in this study:
    • Clinical response at 28 days following initiation of IV study therapy (through Day 28 post-randomization)
    • All-cause mortality within 28 days after initiation of study therapy (through Day 28 post-randomization)
    Additional secondary endpoints include the following:
    • Clinical response at various other timepoints during the trial, including at Day 3 of study therapy (OTX), End of study therapy (EOT) and EFU.
    •Microbiological response in subjects with cUTI will be evaluated at OTX, EOT and at EFU.
    Lo studio possiede 2 endpoints secondari chiave d’efficacia:
    ● La risposta clinica favorevole dopo al giorno 28 dall’inizio della terapia in studio per via endovenosa (fino al Giorno 28 post-randomizzazione).
    ● La mortalità da tutte le cause fino al Giorno 28 dall’inizio della terapia in studio per via endovenosa (fino al Giorno 28 post-randomizzazione).
    Altri endpoints secondari includono:
    ● la risposta clinica favorevole ad altri punti temporali in corso di studio, fra cui il giorno 3 di terapia in studio (OTX), il termine della terapia in studio ( EOT) ed EFU
    ● la risposta microbiologica favorevole ai punti temporali OTX, EOT ed EFU nei soggetti con cUTI
    E.5.2.1Timepoint(s) of evaluation of this end point
    Both key secondary endpoints will be evaluated 28 days following randomization. Evaluation of other secondary endpoints is varied and included on Day 3 of study therapy, at the end of study therapy and 5 to 9 days following the end of study therapy.
    Entrambi gli endpoints secondari chiave saranno valutati 28 giorni dopo la randomizzazione. LA valutazione degli altri endpoints secondari è variabile ed include il giorno 3 di terapia in studio, la fine della terapia in studio e 5-9 giorni dopo il termine della terapia in 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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Lo studio comprende sia i gruppi di trattamento in doppio cieco che in aperto
    The trial includes both double-blind and open-label treatment groups.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Brazil
    Colombia
    Estonia
    Germany
    Italy
    Korea, Republic of
    Latvia
    Mexico
    Peru
    Portugal
    Romania
    South Africa
    Turkey
    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 months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    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: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 44
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Seriously ill and ventilated patients included in study; consent by legally acceptable representative is permitted.
    Pazienti gravemente malati e sottoposti a ventilazione meccanica vengono inclusi nello studio; previo consenso del rappresentante legale riconosciuto.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 33
    F.4.2.2In the whole clinical trial 54
    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
    Cura 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 Decision2015-07-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-09-18
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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