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    Summary
    EudraCT Number:2014-003242-28
    Sponsor's Protocol Code Number:D4280C00015
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-03-09
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2014-003242-28
    A.3Full title of the trial
    A single blind, randomised, multi-centre, active controlled, trial to evaluate safety, tolerability, pharmacokinetics and efficacy of ceftazidime and avibactam when given in combination with metronidazole, compared with meropenem, in children from 3 months to less than 18 years of age with complicated intra-abdominal infections (cIAIs)
    Estudio simple ciego, aleatorizado, multicéntrico, con control activo para evaluar la seguridad, tolerabilidad, farmacocinética y eficacia de ceftazidima y avibactam cuando se proporcionan con metronidazol en comparación con meropenem en niños de 3 meses a menos de 18 años de edad con infecciones intraabdominales complicadas (IIAcs)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This study will assess the safety, efficacy and pharmacokinetics of ceftazidime avibactam plus metronidazole vs meropenem in pediatric population with complicated Intra-abdominal infections
    Este estudio evaluará la seguridad, eficacia y farmacocinética de ceftazidima avibactam mas metronidazol versus meropenem en población pediátrica con infecciones intrabdominales complicadas.
    A.4.1Sponsor's protocol code numberD4280C00015
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/133/2014
    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 supportAstraZenecaAB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation Centre
    B.5.3 Address:
    B.5.3.1Street Address1800 Concord Pike
    B.5.3.2Town/ cityWilmington
    B.5.3.3Post codeDE 19850-5437
    B.5.3.4CountryUnited States
    B.5.6E-mailinformation.center@astrazeneca.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameceftazidime avibactam
    D.3.2Product code CAZ104
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Yes
    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.3.10 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 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.3.1Product namemeropenem
    D.3.4Pharmaceutical form Powder for solution for injection/infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntramuscular and intravenous use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmeropenem
    D.3.9.2Current sponsor code119478-56-7
    D.3.9.3Other descriptive nameMeropenem trihydrate
    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
    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)
    Infección Intrabdominal complicada (IIAc)
    E.1.1.1Medical condition in easily understood language
    Abdominal infection
    Infección abdominal
    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 17.1
    E.1.2Level LLT
    E.1.2Classification code 10056570
    E.1.2Term Intra-abdominal infection
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the safety and tolerability of CAZ AVI plus metronidazole given at the selected dose regimen versus meropenem in paediatric patients aged ?3 months to <18 years with cIAI
    Evaluar la seguridad y tolerabilidad del CAZ AVI más metronidazol en las pautas de dosis indicadas frente a meropenem en pacientes pediátricos, con edades comprendidas entre ? 3 meses y < 18 años de edad, con IIAc
    E.2.2Secondary objectives of the trial
    Evaluate the descriptive efficacy of CAZ AVI plus metronidazole versus meropenem in paediatric patients aged ?3 months to <18 years with cIAI

    Evaluate the PK of CAZ AVI in paediatric patients aged ?3 months to <18 years with cIAI
    Evaluar la eficacia descriptiva del CAZ AVI más metronidazol frente a meropenem en pacientes pediátricos, con edades comprendidas entre ? 3 meses y < 18 años de edad, con IIAc.

    Evaluar la FC del CAZ AVI en pacientes pediátricos, con edades comprendidas entre ? 3 meses y < 18 años de edad, con IIAc
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1Must be ?3 calendar months to <18 years of age.
    2Written informed consent from parent(s) or other legally acceptable representative(s), and informed assent from patient (if age appropriate according to local regulations)
    3If female and has reached menarche, or has reached Tanner stage 3 development (even if not having reached menarche) (refer to Appendix E for further details on Tanner staging), the patient is authorised to participate in this clinical study if the following criteria are met:
    At screening:
    (i)(a) Patient reports sexual abstinence for the prior 3 months or reports use of at least one of the acceptable methods of contraception, including an intrauterine device (with copper banded coil), levonorgestrel intrauterine system (eg, Mirena®), or regular medroxyprogesterone injections (Depo-Provera®); or (b) Patient agrees to initiate sexual abstinence from the time of screening until 7 days after end of treatment with study drug; and
    (ii)Patient is advised to avoid conception from the time of screening until 7 days after receipt of study drug and agrees not to attempt pregnancy from the time of screening until 7 days after end of treatment with study drug; and
    (iii)Patient is provided guidelines regarding continuation of abstinence, initiation of abstinence, or about allowed contraception; and
    (iv)Patient has a negative serum ß-human chorionic gonadotropin ( ß-hCG) test just prior to study entry. Since serum tests may miss an early pregnancy, relevant menstrual history and sexual history, including methods of contraception, should be considered. Note: if the result of the serum ß-hCG test cannot be obtained prior to dosing of investigational product, a patient may be enrolled on the basis of a negative urine pregnancy test, though a serum ß-hCG test result must still be obtained.
    4.Must, based on the judgment of the Investigator, require hospitalisation initially and antibacterial therapy for 7 to 15 days in addition to surgical intervention for the treatment of the current cIAI
    5.Require surgical intervention (eg, laparotomy, laparoscopic surgery or percutaneous drainage) to manage the cIAI
    6.Must have clinical evidence of cIAI as follows:
    (i)Pre-operative enrolment inclusion:
    (a)Requires surgical intervention that is expected to be completed within 24 hours of enrolment
    -Laparotomy, laparoscopy, or percutaneous drainage
    (b)Evidence of a systemic inflammatory response (at least one):
    -Fever (defined as oral temperature >38.5°C, or equivalent to method used) or hypothermia (with a core body or rectal temperature <35°C, or equivalent to method used)
    -Elevated white blood cells (WBC) (>15000 cells/mm3)
    -C-reactive protein (CRP) levels (>10 mg/L)
    (c)Physical Findings consistent with intra-abdominal infection, such as:
    -Abdominal pain and/or tenderness
    -Localised or diffuse abdominal wall rigidity
    -Abdominal mass
    (d)Intention to send specimens from the surgical intervention for culture
    (e)(Optional) Supportive radiologic findings of intra-abdominal infection, such as perforated intraperitoneal abscess detected on:
    -Computed tomography (CT) scan or
    -Magnetic resonance imaging (MRI) or
    -Ultrasound or
    (ii)Intra-operative/postoperative enrolment inclusion:
    Visual confirmation of intra-abdominal infection associated with peritonitis at laparotomy, laparoscopy or percutaneous drainage (to be confirmed pending feasibility); must have one of these diagnoses:
    (a)Appendiceal perforation or peri-appendiceal abscess
    (b)Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall
    (c)Acute gastric or duodenal perforations, only if operated on >24 hours after singular perforation occurs
    (d)Traumatic perforation of the intestines, only if operated on >12 hours after perforation occurs
    (e)Secondary peritonitis (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
    1Su edad debe ser ? 3 meses naturales hasta < 18 años.
    2Se debe disponer del consentimiento informado escrito del progenitor o progenitores, o tutor o tutores legales válidos, y asentimiento informado del paciente (cuando corresponda según la edad del paciente y conforme a la normativa local vigente).
    3Si la paciente es niña y ha pasado la menarquia, o ha llegado a la fase 3 de Tanner del desarrollo (incluso aún sin haber pasado la menarquia), se le podrá autorizar a participar en este estudio clínico siempre y cuando cumpla los siguientes criterios:
    en la selección:
    (i)(a)la paciente manifiesta abstinencia sexual durante los 3 meses anteriores o afirma haber utilizado por lo menos 1 de los métodos anticonceptivos considerados aceptables; o (b) la paciente acepta abstenerse de mantener relaciones sexuales desde la selección hasta 7 días después de terminar el tratamiento con el fármaco del estudio; y
    (ii)se informa a la paciente que no podrá quedarse embarazada desde el momento de la selección hasta 7 días después de haber recibido el tratamiento con el fármaco del estudio, y esta acepta no intentar quedarse embarazada desde el momento de la selección hasta 7 días después de terminar el tratamiento con el fármaco del estudio; y
    (iii)se le darán instrucciones a la paciente sobre cómo mantener la abstinencia, iniciar la abstinencia, o sobre los métodos anticonceptivos permitidos en el estudio; y
    (iv)la paciente ha obtenido un resultado negativo para la prueba de gonadotropina coriónica humana ß (GCh ß) en suero antes de entrar en el estudio. Como las pruebas en suero pueden no detectar un embarazo en sus primeras fases, se habrán de tener en cuenta el historial justo anterior de menstruaciones y encuentros sexuales, así como los métodos anticonceptivos utilizados. Nota: Si no se dispone del resultado de la prueba de GCh ß en suero antes de administrar la dosis del fármaco experimental, podrá inscribirse a la paciente si se le realiza una prueba de embarazo en orina y esta resulta negativa, aunque aún deberá obtenerse el resultado de la prueba de GCh ß en suero.
    Nota 1: Los anticonceptivos hormonales por vía oral, en parches, o los dispositivos por vía vaginal no deberán utilizarse como método de control de natalidad porque no se ha podido establecer aún el efecto del CAZ-AVI sobre la eficacia de estos tipos de anticonceptivos.
    Nota 2: Se pueden emplear métodos anticonceptivos de barrera (como el preservativo masculino) para prevenir enfermedades de transmisión sexual, pero no son admisibles como método anticonceptivo en este ensayo.
    4.Deben, según el criterio del investigador, precisar el ingreso hospitalario inicialmente, así como tratamiento antibacteriano durante 7 a 15 días además de necesitar ser intervenidos quirúrgicamente para tratar la IIAc que padecen.
    5.Necesitan ser operados (por ejemplo, laparotomía, cirugía laparoscópica o drenaje percutáneo) para poder tratar la IIAc.
    6.Deben mostrar confirmación clínica de IIAc según se indica a continuación:
    (i)Inclusión preoperatoria en el proceso de inscripción:
    (a)El paciente precisa una operación quirúrgica cuya realización esté prevista para las 24 horas siguientes a la inscripción
    -Laparotomía, laparoscopia o drenaje percutáneo
    (b)Pruebas de reacción inflamatoria sistémica (al menos una):
    -Fiebre (definida como temperatura, medida en la boca, > 38,5 °C, u obtenida mediante un método equivalente) o hipotermia (con temperatura interna corporal o temperatura rectal < 35 °C, o método equivalente para obtenerla)
    -Aumento del nivel de leucocitos (LC) (> 15.000 células/mm3)
    -Niveles de proteína C-reactiva (CRP) (> 10 mg/l)
    (c)Datos obtenidos en la exploración clínica que coinciden con una posible infección intraabdominal, como:
    Dolor abdominal y/o dolor a la palpación;Rigidez abdominal, delimitada o general; Masa abdominal
    (d)Intención de enviar muestras procedentes de la operación quirúrgica para su cultivo
    (e)(Opcional) Hallazgos radiológicos complementarios de infección intraabdominal, como absceso perforado intraperitoneal, detectado mediante:
    tomografía computerizada (CT) o resonancia magnética nuclear (RMN) o ecografía.
    (ii)Inclusión intraoperatoria/posoperatoria en el proceso de inscripción:
    Confirmación visual de la infección intraabdominal, asociada a peritonitis, durante la laparotomía, laparoscopia o drenaje percutáneo (a confirmar hasta saber la fiabilidad); debe tener uno de estos diagnósticos:
    (a)Perforación apendicular o absceso periapendicular
    (b)Colecistitis con desgarro o perforación de carácter gangrenoso, o expansión de la infección más allá de la vesícula biliar
    (c)Perforaciones gástricas o duodenales agudas, solamente si se operó > 24 horas después de que se diera la perforación en cuestión
    (d)Perforación traumática de los intestinos, solamente si se operó > 12 horas después de que se diera la perforación en cuestión
    (e)Peritonitis secundaria (pero no una peritonitis espontánea bacteriana asociada a cirrosis ni ascitis crónica)
    E.4Principal exclusion criteria
    1Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
    2Previous enrolment or randomisation in the present study
    3Participation in another clinical study with an investigational product (IP) during the last 30 days before the first dose of IV study drug or have previously participated in the current study or in another study of CAZ-AVI (in which an active agent was received)
    4History of hypersensitivity reactions to carbapenems, cephalosporins, penicillin, other ßlactam antibiotics or metronidazole
    5Concurrent infection, that may interfere with the evaluation of response to the study antibiotics at the time of randomisation
    6Patient needs effective concomitant systemic antibacterials (oral, IV, or intramuscular) in addition to those designated in the 2 study groups(CAZ-AVI plus metronidazole group or meropenem group) (see Section 7.8)
    7Receipt of non-study systemic antibiotic therapy for cIAI for more than 24 hours immediately preceding the start of the infusion of the first dose of IV study drug therapy, except in proven resistant organisms and or worsening of the clinical condition
    8Patient is considered unlikely to survive the 6 to 8 week study period
    9Patient is unlikely to respond to 7 to 15 days of treatment with antibiotics
    10Patient is receiving haemodialysis or peritoneal dialysis
    11Diagnosis of abdominal wall abscess confined to musculature of the abdominal wall or ischaemic bowel disease without perforation, traumatic bowel perforation requiring surgery within 12 hours of perforation, or perforation of gastroduodenal ulcers requiring surgery within 24 hours of perforation (these are considered situations of peritoneal soiling before the infection has become established)
    12Simple (uncomplicated), non-perforated appendicitis or gangrenous appendicitis without rupture into the peritoneal cavity identified during a surgical procedure OR presence of primary peritonitis (ie, spontaneous bacterial peritonitis) or peritonitis associated with cirrhosis or chronic ascites
    13At the time of randomisation, patient is known to have a cIAI caused by pathogens resistant to the study antimicrobials planned to be used in the study
    14Presence of any of the following clinically significant laboratory abnormalities:
    (a)Haematocrit <25% or haemoglobin <8 g/dL (<80g/L , <4.9mmol/L)
    (b)Absolute neutrophil count <500/mm3
    (c)Platelet count <50,000/mm3
    (d)Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×the age-specific upper limit of normal (ULN), or total bilirubin >2×ULN (except known Gilbert´s disease).
    15Creatinine clearance ?50 mL/min/1.73 m2 calculated using the child´s measured height (length) and serum creatinine within the updated "bedside" Schwartz formula (Schwartz et al, 2009): CrCl (mL/min/1.73m2)=0.413×height (length) (cm)/serum creatinine (mg/dL)
    16Patient has:
    (a)Evidence of immunocompromising condition
    (b)Concomitant medications that could interfere with the evaluation of antibacterial drug efficacy (e.g., immunosuppressant therapy)
    (c)Requirement for high-dose (eg, ?2 mg/kg/day or a maximum of 20 mg/day of prednisone or equivalent) or prolonged systemic corticosteroid therapy. (Short courses of corticosteroids, such as those for currently worsening asthma, are permitted.)
    17History of seizures, excluding well-documented febrile seizure of childhood
    18Any situation or condition (eg, cystic fibrosis, severe burns, malignancy, hepatitis B virus, hepatitis C virus, or human immunodeficiency virus) that would make the patient, in the opinion of the Investigator, unsuitable for the study (eg, would place a patient at risk or compromise the quality of the data) or may interfere with optimal participation in the study
    19If female, currently pregnant or breast feeding
    1Implicación en la planificación y/o realización del estudio (se aplica tanto al personal de AstraZeneca como al personal del centro)
    2Inscripción o aleatorización previas en el presente estudio
    3Participación en otro estudio clínico con un medicamento en investigación (MI) en los últimos 30 días antes de la primera dosis de fármaco en estudio IV, o haber participado con anterioridad en este mismo estudio o en otro estudio con CAZ-AVI (en el que se recibió un fármaco activo)
    4Antecedentes de reacciones de hipersensibilidad a los carbapenemos, cefalosporinas, penicilina, otros antibióticos ß lactámicos o metronidazol
    5Infección concurrente, que pudiera interferir en la evaluación de la respuesta a los antibióticos del estudio en el momento de la aleatorización
    6El paciente precisa un tratamiento concurrente eficaz con antibacterianos sistémicos (por vía oral, IV o intramuscular) además de los tratamientos indicados en los 2 grupos del estudio (grupo con CAZ-AVI más metronidazol o grupo con meropenem) (consulte la sección 7.8)
    7El paciente ha recibido un tratamiento antibiótico sistémico, distinto a los del estudio, para la IIAc, durante más de 24 horas justo inmediatamente antes de iniciarse la infusión intravenosa de la primera dosis IV del tratamiento con el fármaco del estudio, excepto en el caso de presencia confirmada de microorganismos resistentes y/o empeoramiento de la afección clínica
    8No es probable que la esperanza de vida del paciente llegue a las 6 a 8 semanas que dura el periodo de estudio
    9No es probable que el paciente responda al tratamiento con antibióticos de entre 7 y 15 días de duración
    10El paciente está bajo tratamiento con hemodiálisis o diálisis peritoneal
    11Diagnóstico de absceso perforado intraperitoneal delimitado a la musculatura abdominal o enteropatía isquémica sin perforación, perforación traumática del intestino que precise cirugía en las 12 horas siguientes a la perforación, o perforación de úlceras gastroduodenales que requiera cirugía en las 24 horas siguientes a la perforación (estas se consideran situaciones de encopresis antes de que haya arraigado la infección)
    12Apendicitis simple (no complicada), sin perforación o apendicitis gangrenosa sin desgarro hacia la cavidad peritoneal, detectada durante una intervención quirúrgica O BIEN presencia de peritonitis primaria (peritonitis bacteriana espontánea) o peritonitis asociada a cirrosis o ascitis crónica
    13En el momento de la aleatorización, se confirma que el paciente padece una IIAc provocada por patógenos resistentes a los fármacos antimicrobianos que se prevé utilizar en el estudio
    14Presencia de cualquiera de las anomalías clínicamente significativas siguientes:
    (a)Hematocrito < 25% o hemoglobina < 8 g/dl (< 80 g/l, < 4,9 mmol/l)
    (b)Recuento absoluto de neutrófilos < 500/mm3
    (c)Recuento plaquetario < 50.000/mm3
    (d) Alanina aminotransferasa (ALT) o aspartato aminotransferasa (AST) séricas > 3 × el límite superior de la normalidad (LSN) específico para cada edad o bilirrubina total > 2 × LSN (a no ser que haya un diagnóstico confirmado de enfermedad de Gilbert)
    Para los supuestos a) a d): a menos que estos valores se presenten de manera aguda y estén directamente relacionados con el proceso infeccioso en tratamiento.
    15Aclaramiento de creatinina ? 50 ml/min./1,73 m2 calculado midiendo la estatura del paciente y la creatinina sérica empleando la fórmula de Schwartz adaptada al análisis diagnóstico inmediato o "a pie de cama" (Schwartz et al, 2009):
    ACr (ml/min./1,73 m2)=0,413×estatura (cm)/creatinina sérica (mg/dl)
    16El paciente presenta:
    (a)Indicios de enfermedad inmunodepresora
    (b)Medicaciones concurrentes que podrían interferir con la evaluación de la eficacia del fármaco antibacteriano (por ejemplo, tratamiento inmunodepresor)
    (c)Necesidad de una dosis elevada (por ejemplo, ? 2 mg/kg/día o un máximo de 20 mg/día de prednisona o tratamiento equivalente) o un tratamiento sistémico con corticosteroides de manera prolongada (sí se permiten tratamientos cortos con corticosteroides, como los aplicados por un episodio de empeoramiento pasajero de una enfermedad asmática)
    17Antecedentes de convulsiones, excepto las convulsiones febriles infantiles confirmadas
    18Cualquier situación o afección (por ejemplo, fibrosis quística, quemaduras graves, neoplasia, virus de la hepatitis B, virus de la hepatitis C o virus de la inmunodeficiencia humana) que suponga que el paciente sea, en opinión del investigador, no apto para el estudio (por ejemplo, si ello pusiera al paciente en riesgo o alterase la calidad de los datos) o que pueda interferir con su óptima participación en el mismo
    19Si la paciente es mujer que está actualmente embarazada o si está amamantando
    E.5 End points
    E.5.1Primary end point(s)
    To assess the safety and tolerability by :
    a) adverse events (AEs) and serious adverse events(SAEs)
    b) vital signs (pulse , blood pressure , respiratory rate, temperature)
    c) ECG (electrocardiogram)
    d) laboratory tests(complete blood count with differential and comprehensive metabolic panel )
    e) creatinine clearance (CrCl)
    Evaluar la seguridad y tolerabilidad por:
    a)Acontecimientos Adversos (AA) y acontecimientos adversos graves(AAG)
    b)Signos vitales (pulso, presión sanguínea, frecuencia respiratoria, temperaturea.
    c)ECG (electrocardiograma)
    d)Analisis de laboratorio:hemograma completo, con perfil metabólico completo y diferencial
    e)Aclaramiento de creatinina (ACr)
    E.5.1.1Timepoint(s) of evaluation of this end point
    a) from ICF to LFU visit (27 to 50 days after start of study treatment)
    b)from ICF to LFU visit (27 to 50 days after start of study treatment)
    c) baseline, Day 1, TOC
    d)baseline , Days 4 to 15, EoIV (end of intravenous treatment) and TOC (test of cure)
    e)baseline
    a)Desde el CI hasta la ESLP (27 a 50 días después del inicio del tratamiento del estudio)
    b)from ICF to LFU visit (27 to 50 days after start of study treatment)
    c)Basal, Día 1, CDC
    d)Basal, Días 4 a 15, FDTIV(fin del tratamiento intravenoso) y CDC(confirmación de curación)
    E.5.2Secondary end point(s)
    1To assess the efficacy by:
    a)clinical outcomes
    b)microbiological response
    c)clinical relapse
    d) emergent infections

    2To evaluate the PK of CAZ-AVI in pediatric patients aged aged >3 months to <18 years with cIAI
    1Evaluar la eficacia con:
    a) Respuesta clínica
    b)Respuesta microbiologica
    c) Recidiva clínica
    d)Infecciones emergentes.

    2Evaluar la FC de CAZ-AVI en pacientes pediátricos de edad >3 meses hasta <18 años con IIAc
    E.5.2.1Timepoint(s) of evaluation of this end point
    1
    a)end of 72 hours' treatment, end of intravenous treatment (EOIV), end of treatment (EOT) and test of cure (TOC)
    b) EOIV, EOT, TOC and LFU
    c)LFU
    d)study duration

    2Days 2 and 3
    1
    a)Fin de las 72 horas de tratamiento, fin del tratamiento intravenoso (FDTIV), fin de tratamiento(FDT) y Confirmación de curación (CDC).
    b)FDTIV,FDT, CDC and ESLP
    c)ESLP
    D)Duracion del estudio

    2Dias 2 y 3
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    Tolerabilidad
    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 Yes
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Meropenem
    meropenem
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA41
    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
    Chile
    Czech Republic
    Greece
    Hungary
    Poland
    Romania
    Russian Federation
    Spain
    Taiwan
    Turkey
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    last patient last visit
    Ultima visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    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 Yes
    F.1.1Number of subjects for this age range: 102
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 14
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 54
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 34
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    subjects below the age of consent
    Pacientes por debajo de la edad de consentimiento
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    children from 3 months to 18 years old
    Niños desde 3 meses a 18 años
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 102
    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
    Practica clínica habitual
    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 Decision2015-05-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-06-01
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