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    Summary
    EudraCT Number:2015-002726-39
    Sponsor's Protocol Code Number:D4910C00009/C3601001
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-12-09
    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 ConcernedGermany - BfArM
    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
    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
    A.3.2Name or abbreviated title of the trial where available
    REJUVENATE
    A.4.1Sponsor's protocol code numberD4910C00009/C3601001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02655419
    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 SponsorPfizer 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 supportPfizer Inc.
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportIMI Combacte-Care consortium
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18007181021
    B.5.5Fax number+13037391119
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.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 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 INN Metronidazole
    D.3.9.1CAS number 442-48-1
    D.3.9.2Current sponsor code Metronidazole
    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 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 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 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 1 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 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 Aztreonam 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 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
    E.1.1.1Medical condition in easily understood language
    Adult patients with infections in the abdomen that requires surgical intervention and treatment with antibiotics.
    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
    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
    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 diagnosis
    (e) Traumatic perforation of the intestines, only if operated on >12 hours after diagnosis
    (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 known or suspected pathogen causing cIAI resistant to the prior therapy while assuming the organism is sensitive to ATM-AVI.
    • Require surgical intervention.
    Such patients can be enrolled before the results of the culture are known (see also exclusion criterion 10).
    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

    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 β-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 of diagnosis; perforation of gastroduodenal ulcer with surgery within 24 hours of diagnosis (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, 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 72-hour period prior to study entry, unless either of the following pertains:
    (a) Patient has a new infection (not considered a treatment failure) and the following is met:
    • Patient received no more than 24 hours of total prior antibiotic therapy within the 72 hour period prior to study entry
    (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.
    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.
    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
    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


    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
    E.5.2.1Timepoint(s) of evaluation of this end point
    at test of cure visit (Day 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 Yes
    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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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
    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.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    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)
    Following discontinuation from study treatment for any reason, patients may receive any subsequent therapy for their disease at the discretion of the investigator.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation COMBACTE-CARE
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-02-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-10-26
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