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    Summary
    EudraCT Number:2015-002726-39
    Sponsor's Protocol Code Number:D4910C00009
    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:2016-02-03
    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 number2015-002726-39
    A.3Full title of the trial
    A Phase IIa prospective, open-label, multicenter study to determine the pharmacokinetics (PK) and safety and tolerability of aztreonam-avibactam (ATM-AVI) for the treatment of complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults
    Estudio prospectivo Fase IIa, abierto y multicéntrico para determinar la farmacocinética (PK), seguridad y tolerabilidad de aztreonam-avibactam (ATM-AVI) para el tratamiento de infecciones intra-abdominales complicadas (cIAIs) en adultos hospitalizados
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to determine how the drug(ATM-AVI) is moved in your body and whether the drug is safe and tolerable for the treatment of complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults
    Estudio para determinar cómo se mueve la droga (ATM-AVI) en su cuerpo y si el medicamento es seguro y tolerable para el tratamiento de infecciones intra-abdominales complicadas (cIAIs) en adultos hospitalizados
    A.3.2Name or abbreviated title of the trial where available
    REJUVENATE
    REJUVENATE
    A.4.1Sponsor's protocol code numberD4910C00009
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca Farmacéutica Spain, S.A.
    B.5.2Functional name of contact pointUnidad de Investigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressC/ Serrano Galvache, 56; Parque Norte, Edificio Álamo
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28033
    B.5.3.4CountrySpain
    B.5.4Telephone number900200444
    B.5.6E-mailinformacionEECC-Spain@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 nameAVIBACTAM
    D.3.2Product code AVI
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNavibactam sodium
    D.3.9.1CAS number 1192491-61-4
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number600
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name AZACTAM 1 g vial
    D.2.1.1.2Name of the Marketing Authorisation holderE.R. Squibb & Sons Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code J01DF01
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNaztreonam
    D.3.9.1CAS number 827611-49-4
    D.3.9.3Other descriptive nameAZTREONAM LYSINE
    D.3.9.4EV Substance CodeSUB30777
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Metronidazole 500 mg/ 100 ml intravenous infusion
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter Healthcare Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMetronidazole 500 mg/100 ml Intravenous
    D.3.2Product code SUB08922MIG
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMetronidazole
    D.3.9.1CAS number 442-48-1
    D.3.9.2Current sponsor codeMetronidazole
    D.3.9.3Other descriptive nameMetronidazole
    D.3.9.4EV Substance CodeSUB08922MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name AZACTAM 2 g
    D.2.1.1.2Name of the Marketing Authorisation holderE.R. Squibb & Sons Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNaztreonam
    D.3.9.1CAS number 827611-49-4
    D.3.9.3Other descriptive nameAZTREONAM LYSINE
    D.3.9.4EV Substance CodeSUB30777
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name AZACTAM 2 g
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Company
    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.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNaztreonam
    D.3.9.1CAS number 827611-49-4
    D.3.9.3Other descriptive nameAZTREONAM LYSINE
    D.3.9.4EV Substance CodeSUB30777
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name AZACTAM 1 g
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Company
    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.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNaztreonam
    D.3.9.1CAS number 827611-49-4
    D.3.9.3Other descriptive nameAZTREONAM LYSINE
    D.3.9.4EV Substance CodeSUB30777
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 7
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Aztreonam
    D.2.1.1.2Name of the Marketing Authorisation holderAPP Pharmaceuticals LLC
    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.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNaztreonam
    D.3.9.1CAS number 827611-49-4
    D.3.9.3Other descriptive nameAZTREONAM LYSINE
    D.3.9.4EV Substance CodeSUB30777
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 8
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name AZACTAM 2 g
    D.2.1.1.2Name of the Marketing Authorisation holderAPP Pharmaceuticals LLC
    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.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAztreonam
    D.3.9.1CAS number 78110-38-0
    D.3.9.2Current sponsor codeAztreonam
    D.3.9.3Other descriptive nameAztreonam
    D.3.9.4EV Substance CodeSUB30777
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 Infections (cIAIs) in hospitalized adults
    Infecciones intra-abdominales complicadas (cIAIs) en adultos hospitalizados
    E.1.1.1Medical condition in easily understood language
    Adult patients with infections in the abdomen that requires surgical intervention and treatment with antibiotics.
    Pacientes adultos hospitalizados con infecciones en el abdomen que requieren intervención quirúrgica y tratamiento con antibióticos.
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the PK of ATM-AVI and to assess the safety of ATM-AVI in the patient population
    Determinar la farmacocinética (PK) de ATM-AVI en la población de estudio.
    Evaluar la seguridad de ATM-AVI en la población de estudio.
    E.2.2Secondary objectives of the trial
    To assess the treatment outcome per patient at the test of cure (TOC) visit;
    To assess the relationship between exposure and clinical cure for ATM-AVI
    Evaluar la variable resultado tratamiento por paciente en la visita ?test de cura? (TOC);
    Evaluar la relación entre la exposición y la cura clínica para ATM-AVI
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of informed consent prior to any study-specific procedures.
    2. Male or female from 18 to 90 years of age inclusive.
    3. Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met
    4. Diagnosis of cIAI
    EITHER:
    Intra-operative/postoperative enrolment with visual confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection associated with peritonitis. Surgical intervention includes open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery. Specimens from the surgical intervention must be sent for culture. Patients who undergo a surgical procedure with complete fascial closure are appropriate for the trial. The skin incision may be left open for purposes of wound management as long as complete fascial closure is accomplished. The patient has at least 1 of the following diagnosed during the surgical intervention:
    (a) Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall
    (b) Diverticular disease with perforation or abscess
    (c) Appendiceal perforation or peri-appendiceal abscess
    (d) Acute gastric or duodenal perforations, only if operated on >24 hours after perforation occurs
    (e) Traumatic perforation of the intestines, only if operated on >12 hours after perforation occurs
    (f) Secondary peritonitis (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
    (g) Intra abdominal abscess (including of liver or spleen provided that there is extension beyond the organ with evidence of intraperitoneal involvement)
    OR
    Preoperative enrollment where the following clinical criteria are met with confirmation of infection by surgical intervention within 24 hours of entry:
    (a) Requirement for surgical intervention, defined per protocol as open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery
    (b) Evidence of systemic inflammatory response, with at least one of the following:
    ? Fever (defined as body temperature >38°C) or hypothermia with a core body temperature <35°C
    ? Elevated white blood cells (>12000 cells/µL)
    ? Systolic blood pressure <90 mmHg or mean arterial pressure <70 mmHg, or a systolic blood pressure decrease of >40 mmHg?
    Increased heart rate ( >90 bpm) and respiratory rate (>20 breaths/min)
    ? Hypoxemia (defined as oxygen saturation < 95% by pulse oximetry)
    ? Altered mental status.
    (c) Physical findings consistent with intra-abdominal infection, such as:
    ? Abdominal pain and/or tenderness, with or without rebound
    ? Localized or diffuse abdominal wall rigidity
    ? Abdominal mass.
    (d) Supportive radiologic imaging findings of intra-abdominal infection such as perforated intraperitoneal abscess detected on computed tomography scan, magnetic resonance image, or ultrasound.
    (e) Specimens from the surgical intervention will be sent for culture for isolation of both aerobic and anaerobic bacteria.

    5. Patients who failed prior antibacterial treatment for their current cIAI can be enrolled but must:
    ? Have a documented pathogen causing cIAI that is resistant to the prior therapy while assuming the organism is known to be sensitive to ATM-AVI.
    ? Require surgical intervention.
    6. Patient must have or will have a surgical intervention within 24 hours (before or after) the administration of the first dose of study drug
    1.Prestación del consentimiento informado antes de iniciar ningún procedimiento específico del ensayo. Si un paciente no puede prestar su conocimiento informado en el momento de la consulta de Cribado, podrá ser incluido en el ensayo por su tutor o representante legal cuando lo permita la normativa nacional y local y de acuerdo con las directrices específicas de la institución. Aquellos pacientes que se incluyan mediante el consentimiento de un representante legalmente aceptado deberán prestar su propio consentimiento informado para continuar participando en el ensayo tan pronto como sea posible tras su recuperación en la forma que proceda de acuerdo con la normativa nacional y local.
    2.Varones o mujeres de 18 a 90 años ambos inclusive.
    3.Se autoriza a las pacientes mujeres a participar en este estudio si cumplen al menos uno de los criterios siguientes: a)Esterilización quirúrgica, incluyendo histerectomía y/o ooforectomía bilateral y/o salpingectomía bilateral, pero excluyendo la oclusión tubárica bilateral;
    b)Edad ?50 y postmenopáusica, definida por amenorrea durante 12 meses o más tras la interrupción de todos los tratamientos hormonales exógenos;
    c)Edad <50 y postmenopáusica, definida por niveles de hormona luteinizante (LH) y hormona folículo estimulante (FSH) en el rango postmenopáusico MÁS amenorrea durante 12 meses o más tras la interrupción de todos los tratamientos hormonales exógenos. (Nota: si se desea se puede comprobar la LH y la FSH a la entrada en el ensayo para determinar si mujeres <50 y amenorreicas durante 12 meses son postmenopáusicas, pero la paciente deberá cumplir el criterio ?d? hasta confirmar el estado postmenopáusico mediante LH y FSH);
    d)Se cumplen las dos condiciones siguientes:
    ?La paciente tiene una prueba de embarazo en suero negativa (Beta-gonadotropina coriónica humana [?-GCH]) en las 24 horas anteriores a su inclusión (si los resultados de la ?-GCH en suero no se pueden obtener antes de la dosificación del producto en fase de investigación clínica [PEI], una paciente podrá ser incluida basándose en una prueba de embarazo en orina negativa, pero será necesario obtener la ?-GCH en suero tras su inclusión). Si cualquiera de las dos pruebas es positiva la paciente deberá ser excluida. Dado que tanto la prueba de orina como la de suero pueden dar falsos negativos en los primeros días tras la concepción, se debería tener en cuenta la historia menstrual y sexual relevante, incluyendo métodos anticonceptivos.
    ?La paciente acepta no intentar quedarse embarazada mientras se le administran los fármacos del ensayo y durante los 7 días siguientes a la última dosis de la terapia IV del ensayo y acepta emplear los siguientes métodos anticonceptivos aceptables: antes de y durante el ensayo (incluyendo los 7 días siguientes a la última dosis de la terapia IV del ensayo) uso de un dispositivo intrauterino (con espiral de bandas de cobre), sistema intrauterino de levonorgestrel (por ej. Mirena®), inyecciones regulares de medroxiprogesterona (por ej. Depo-Provera®), o relaciones sexuales únicamente con parejas vasectomizadas (y confirmación verbal de azoospermia), o abstinencia sexual completa durante el período recomendado. La mujer debería llevar utilizando el método contraceptivo de su elección durante un mínimo de 3 meses en el momento de la firma del consentimiento informado previo al inicio de la terapia con PEI. Ver restricciones adicionales en la sección 3.8.
    4.Diagnóstico de Infección Intraabdominal compleja definida en la sección 3:
    O BIEN: Inclusión intraoperatoria/postoperatoria con confirmación visual (presencia de pus en la cavidad abdominal) de infección intraabdominal asociada a peritonitis. La intervención quirúrgica incluye laparotomía abierta, drenaje percutáneo de un absceso o cirugía laparoscópica. Hay que enviar muestras obtenidas en la intervención quirúrgica para su cultivo. Los pacientes sometidos a un procedimiento quirúrgico con cierre de la fascia son apropiados para el ensayo. La incisión cutánea podrá dejarse abierta con el fin de tratar la herida siempre y cuando se consiga el cierre fascial completo. Al paciente se le deberá haber diagnosticado durante la cirugía al menos uno de los siguientes trastornos: (a)Colecistitis con rotura gangrenosa o perforación o progresión de la infección más allá de la pared vesicular. (b)Enfermedad diverticular con perforación o absceso. (c)Perforación del apéndice o absceso periapendicular
    (d)Perforaciones gástricas o duodenales agudas, sólo si operadas >24 horas después del diagnóstico. (e)Perforación traumática de los intestinos, sólo si operada >12 horas después del diagnóstico. (f)Peritonitis secundaria (pero no peritonitis bacteriana espontánea asociada a cirrosis y ascitis crónica)
    (g)Absceso intraabdominal (incluyendo hepático o esplénico siempre que haya extensión más allá del órgano con evidencia de afección intraperitoneal)
    Por limitación a 5000 caracteres no se pueden incluir más criterios de inclusión.
    E.4Principal exclusion criteria
    1. Involvement in the planning and/or conduct of the study
    2. Patient has been previously enrolled in this study, previously treated with ATM-AVI or previously participated in an investigation study containing AVI
    3. Patient has participated or intends to participate in any other clinical study that involves the administration of an investigational medication at the time of presentation, during the course of the study, or during the 30 days prior to study start.
    4. Patient has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to aztreonam, carbapenem, monobactam or other ?-lactam antibiotics, avibactam, nitroimidazoles or metronidazole, or any of the excipients of the respective (investigational) medicinal products to be administered during the study
    5. Patient has a diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; traumatic bowel perforation with surgery within 12 hours; perforation of gastroduodenal ulcer with surgery within 24 hours (these are considered situations of peritoneal soiling before infection has become established); another intra-abdominal process in which the primary etiology is not likely to be infectious
    6. Patient has a simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess or ischaemic/necrotic intestine without perforation
    7. Patient has a cIAI managed by staged abdominal repair (STAR), open abdomen technique or any situation where infection source control is not likely to be achieved or in whom the abdomen is left open, particularly those for whom re-operation is planned, or those unlikely to solely respond to antimicrobial therapy
    8. At screening, if it is known the patient has an infection due to a pathogen that is unlikely to respond to ATM-AVI plus metronidazole treatment
    9. Patient has a rapidly progressive (expected to die in <30 days) or terminal illness, including acute hepatic failure, respiratory failure or septic shock with a high risk of mortality due to other causes than cIAI
    10. Patient has received systemic antibacterial agents within the 48-hour period prior to study entry, unless either of the following pertains:
    (a) Patient has a new infection (not considered a treatment failure) and the following is met:
    ? Patient received no more than 24 hours within the 48 hour period of total prior antibiotic therapy
    (b) Patient is considered to have failed the previous treatment regimen
    11. Patient has a concurrent infection that may interfere with the evaluation of clinical cure for the study therapy
    12. Patient needs effective concomitant systemic antibacterials (oral, IV, or intramuscular) or antifungals in addition to the investigational product and metronidazole
    13. Patient has creatinine clearance ?50 ml/min. Note: following review of PK and safety data from the first 10 enrolled patients, and the confirmation of a provisional dose schedule, patients with a creatinine clearance of 31 ? 50 mL/min may be included.
    14. Patient has had acute hepatitis in the prior 6 months, chronic hepatitis, cirrhosis (any Child-Pugh class), acute hepatic failure, or acute decompensation of chronic hepatic failure
    15. Presence of hepatic disease as indicated by aspartate aminotransferase (AST) or alanine transaminase (ALT) >3 × upper limit of normal (ULN) at Screening. Patients with AST and/or ALT >3 × ULN and < 5 × ULN are eligible if these elevations are acute, not accompanied by a total bilirubin ? 2xULN and documented by the investigator as being directly related to the infectious process being treated
    16. Patient has a total bilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly related to the acute infection or due to known Gilbert?s disease
    17. Alkaline phosphatase (ALP) >3 × ULN. Patients with values >3 × ULN and <5 x ULN are eligible if this value is acute and directly related to the infectious process being treated.
    18. Patients with an immunocompromising illness
    19. Known active Clostridium difficile associated diarrhoea
    20. Any other condition that, in the opinion of the investigator, may confound the results of the study or pose additional risks
    21. Patient with a do not resuscitate order
    22. Patient has an absolute neutrophil count <1000/µL
    23. Patient has a hematocrit <25% or hemoglobin <8 gm/dL.
    24. Patient has a platelet count <75,000/µL. Patients with a platelet as low as 50,000 /µL are permitted if the reduction is historically stable
    25. Patient is currently receiving treatment with probenecid or furosemide.
    26. Patient is pregnant or breastfeeding or if of child bearing potential,
    27. Patient is unlikely to comply with protocol,
    28. Patient is currently receiving anti-convulsant therapy to prevent recurrence of a past history of seizures.
    29. Patient has a prior liver, pancreas or small-bowel transplant.
    Los pacientes no deberían ser incluidos en el ensayo si cumplen alguno de los siguientes criterios de exclusión, que serán evaluados por un investigador en el centro:
    1. Implicación en la planificación y/o realización del ensayo (se aplica tanto a personal de AstraZeneca como a personal del centro donde se desarrolla el ensayo).
    2. El paciente ha estado incluido anteriormente en el ensayo, ha sido tratado anteriormente con ATM-AVI o ha participado anteriormente en un estudio de investigación que incluía AVI
    3. El paciente ha participado o va a participar en otro ensayo clínico que conlleva la administración de un producto en fase de investigación en el momento de la presentación, durante el ensayo o durante los 30 días anteriores al inicio del ensayo.
    4. El paciente tiene un historial de alergia grave, hipersensibilidad (por ej. anafilaxis) o cualquier reacción severa ante aztreonam, carbapenem, monobactam u otros antibióticos betalactámicos, avibactam, nitroimidazoles o metronidazol, o cualquiera de los excipientes de los respectivos productos (en fase de investigación) que serán administrados durante el ensayo.
    5. El paciente ha sido diagnosticado de absceso de la pared abdominal; obstrucción del intestino delgado o enfermedad isquémica del intestino delgado sin perforación; perforación traumática del intestino con cirugía dentro de las 12 horas siguientes al diagnóstico; perforación de úlcera gastroduodenal con cirugía dentro de las 24 horas siguientes al diagnóstico (se considera que estas son situaciones de contaminación peritoneal antes de que se haya instalado la infección); otros procesos intraabdominales en los que es probable que la etiología primaria no sea infecciosa.
    6. El paciente sufre colecistitis simple, colecistitis gangrenosa sin rotura, apendicitis simple, colangitis supurativa aguda, pancreatitis necrotizante infectada, absceso pancreático o intestino isquémico/necrótico sin perforación.
    7. El paciente sufre infección intraabdominal compleja tratada mediante reparación abdominal por etapas (STAR), técnica de abdomen abierto o cualquier situación en la que resulte improbable controlar el origen de la infección o en la que se deje abierto el abdomen, especialmente aquellos en los que está previsto nueva cirugía, o aquellos que es improbable que respondan a terapia antimicrobiana sola.
    8. En el Cribado, si se conoce que el paciente padece una infección causada por un patógeno que es improbable que responda al tratamiento ATM-AVI más metronidazol.
    9. El paciente padece de enfermedad en rápida progresión (esperanza de vida <30 días) o terminal, incluyendo fallo hepático agudo, fallo respiratorio o shock séptico con alto riesgo de mortalidad debido a causas distintas de la infección intraabdominal compleja.
    10. Al paciente se le han administrado agentes antibacterianos sistémicos en el plazo de 72 horas previo a la entrada en el ensayo, a menos que se aplique alguna de las condiciones siguientes:
    (a) El paciente sufre una infección nueva (no considerada fallo de tratamiento) y se cumple lo siguiente:
    ? El paciente ha recibido en total menos de 24 horas de terapia con antibióticos dentro de las 72 horas siguientes a su entrada en el ensayo
    (b) Se considera que el paciente ha fallado el régimen de tratamiento anterior (ver Criterio de inclusión nº 5)
    En este caso se permite el tratamiento preoperatorio de la peritonitis o el absceso con terapia antimicrobiana distinta a la del ensayo, siempre y cuando se cumplan todas las condiciones siguientes:
    ? El régimen de tratamiento ha sido administrado durante al menos 72 horas y se considera que ha sido inadecuado.
    ? El paciente ha sido intervenido dentro de las 24 horas anteriores a la entrada en el ensayo o está prevista una intervención quirúrgica dentro de las 24 horas siguientes a su entrada en el ensayo.
    ? Se han documentado manifestaciones de infección en la cirugía.
    ? En la intervención quirúrgica se han tomado muestras para cultivos bacterianos y pruebas de susceptibilidad que confirman la resistencia a la terapia anterior.
    ? No se siguen administrando otros antibacterianos distintos a los del ensayo tras la inclusión.
    11. El paciente presenta una infección concomitante que puede interferir con la evaluación de la curación clínica para la terapia del ensayo.
    12. El paciente necesita antibacterianos sistémicos concomitantes eficaces (orales, IV o intramusculares) o antifúngicos además de ATM-AVI y metronidazol, excepto vancomicina, linezolid, o daptomicina si se ha iniciado el tratamiento por sospecha o confirmación de Staphylococcus aureus resistente a meticilina (SARM) o Enterococcus spp. (ver sección 7.7).
    Por limitación de espacio a 5000 caracteres no se han incluido todos los criterios de exclusión del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    1.Concentrations of ATM and AVI in plasma; concentration-time profile of ATM and AVI
    The derived PK parameters Cmax, tmax, AUC(0-6), AUC(0-last), tlast, t1/2, Vss, Vz and CL for the patients undergoing intensive sampling on day 4;
    2. Safety and tolerability as assessed by adverse events, physical examination, vital signs, ECGs, and laboratory assessments
    1. Concentraciones de ATM y AVI en plasma
    Parámetros derivados PK: Cmax, tmax, AUC(0-6), AUC(0-last), tlast, t1/2, Vss, Vz y CL para los pacientes sometidos a muestreo intensivo en el Día 4.
    2. Seguridad y tolerabilidad según la evaluación de los eventos adversos, examen físico, signos vitales, ECGs y evaluaciones de laboratorio.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Sampling take Trough (within 10 min prior to IV infusion start), 0.5h 1, 2, 3 (within 15 minutes before IV infusion stop), 3.25, 3.5. 3.75, 4, 5, and 6 h after start of IV infusion on Day 4

    2. AE, Physical exam, vital sign, ECG and laboratory assessments conducted from screening to last visit
    1. concentraciones de ATM y AVI en plasma (muestras que se recogieron durante 6 horas tras el inicio de las 3 horas de infusión de ATM-AVI). Se analizarán en el conjunto de análisis PK.

    2. Seguridad y tolerabilidad según la evaluación de: eventos adversos, exámen físico, signos vitales, electrocardiogramas y evaluaciones de laboratorio
    E.5.2Secondary end point(s)
    Proportion of patients with clinical cure at the TOC visit;
    Correlation of derived PK parameters for ATM-AVI and clinical cure at TOC
    Proporción de pacientes con cura clínica en la visita TOC .
    Correlación de los parámetros derivados de la PK para ATM-AVI y cura clínica en la visita TOC
    E.5.2.1Timepoint(s) of evaluation of this end point
    at test of cure visit (Day 25 ± 3)
    En la prueba de la visita cura (Día 25 ± 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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    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 No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    Last visit of last subject
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months12
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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
    if a patient is unable, the patient?s legally acceptable representative may provide written consent, as approved by the institutional specific guidelines.
    Si un paciente no puede, el representante legal del paciente puede proporcionar consentimiento por escrito, según lo aprobado por las directrices específicas institucionales.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 40
    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)
    None.
    Ninguno.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-04-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-10-26
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