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    Clinical Trial Results:
    A Phase I Study to Assess the Pharmacokinetics, Safety and Tolerability of a Single Dose of Ceftazidime Avibactam (CAZ AVI) in Children From 3 Months of Age to <18 Years Who Are Receiving Systemic Antibiotic Therapy for Suspected or Confirmed Infection

    Summary
    EudraCT number
    		 2013-001900-13
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    09 Oct 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2017
    First version publication date
    08 May 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4280C00014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01893346
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca Pharmaceuticals
    Sponsor organisation address
    Alderley Park, Macclesfield, United Kingdom, SK10 4TG
    Public contact
    Paul Newell, MBBS MRCP MFPM, AstraZeneca, paul.newell@astrazeneca.com
    Scientific contact
    Paul Newell, MBBS MRCP MFPM, AstraZeneca, paul.newell@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001313-PIP01-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to characterize the pharmacokinetics of single dose CAZ AVI in a pediatric population. Key PK parameters are shown for cohorts 1 and 2. For cohorts 3 and 4 (where children were <6 years of age), sparse sampling scheme was used for PK samples to limit the volume of blood required. PK parameters cannot be derived from these sparse PK samples without population PK analysis. Thus the PK is not described here, but will be reported in a separate population PK report.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonisation/Good Clinical Practice (GCP) and applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples. The investigator at each center ensured that the patient, parent, guardian, or legal representative (as appropriate) was given full and adequate oral and written information about the nature, purpose, possible risk, and benefit of the study. The patient, parent, guardian, or legal representative (as appropriate) were notified that they were free to discontinue from the study at any time and were given the opportunity to ask questions and allowed time to consider the information provided.
    Background therapy
    		 Patients in the study were hospitalized pediatric patients receiving systemic antibiotic therapy for suspected or confirmed infection.
    Evidence for comparator
    		 No comparator group
    Actual start date of recruitment
    26 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    8
    Children (2-11 years)
    16
    Adolescents (12-17 years)
    8
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient enrolled: 26 July 2013 Last patient last visit: 09 October 2014

    Pre-assignment
    Screening details
    		 Eligibility was determined by investigator, prior to enrollment. Patients were selected on the basis of the age requirements for the appropriate cohort and after obtaining written informed consent from the parent or legal guardian and assent from patients (as appropriate). Screening assessments were completed prior to study drug administration.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 aged ≥12 to <18 years
    Arm description
    		 aged ≥12 to <18 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftazidime
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg ceftazidime administered as a combined infusion with avibactam over a 2 hour period. for patients with moderate renal insufficiency the dose for both ceftazidime and avibactam was halved.

    Investigational medicinal product name
    Avibactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg avibactam administered as a combined infusion with ceftazidime over a 2 hour period. for patients with moderate renal insufficiency the dose for both ceftazidime and avibactam was halved.

    Arm title
    		 Cohort 2 aged ≥6 to <12 years
    Arm description
    		 aged ≥6 to <12 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avibactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg (patients >=40kg) or 12.5 mg/kg (patients <40kg) avibactam administered as a combined infusion with ceftazidime over a 2 hour period. for patients with moderate renal insufficiency the dose for both ceftazidime and avibactam was halved.

    Investigational medicinal product name
    Ceftazidime
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2000 mg (patients >=40kg) or 50 mg/kg (patients <40kg) ceftazidime administered as a combined infusion with avibactam over a 2 hour period. for patients with moderate renal insufficiency the dose for both ceftazidime and avibactam was halved

    Arm title
    		 Cohort 3 aged ≥2 to <6 years
    Arm description
    		 aged ≥2 to <6 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avibactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    12.5 mg/kg avibactam administered as a combined infusion with ceftazidime over a 2 hour period. for patients with moderate renal insufficiency the dose for both ceftazidime and avibactam was halved.

    Investigational medicinal product name
    Ceftazidime
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/kg ceftazidime administered as a combined infusion with avibactam over a 2 hour period. for patients with moderate renal insufficiency the dose for both ceftazidime and avibactam was halved

    Arm title
    		 Cohort 4 aged ≥3 months to <2 years
    Arm description
    		 aged ≥3 months to <2 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avibactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    12.5 mg/kg avibactam administered as a combined infusion with ceftazidime over a 2 hour period. for patients with moderate renal insufficiency the dose for both ceftazidime and avibactam was halved.

    Investigational medicinal product name
    Ceftazidime
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/kg ceftazidime administered as a combined infusion with avibactam over a 2 hour period. for patients with moderate renal insufficiency the dose for both ceftazidime and avibactam was halved

    Number of subjects in period 1
    		Cohort 1 aged ≥12 to <18 years Cohort 2 aged ≥6 to <12 years Cohort 3 aged ≥2 to <6 years Cohort 4 aged ≥3 months to <2 years
    Started
    8
    8
    8
    8
    Patients who received full infusion
    8
    8
    8
    8
    Completed
    8
    7
    8
    8
    Not completed
    0
    1
    0
    0
         Lost to follow-up
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 aged ≥12 to <18 years
    Reporting group description
    		 aged ≥12 to <18 years

    Reporting group title
    Cohort 2 aged ≥6 to <12 years
    Reporting group description
    		 aged ≥6 to <12 years

    Reporting group title
    Cohort 3 aged ≥2 to <6 years
    Reporting group description
    		 aged ≥2 to <6 years

    Reporting group title
    Cohort 4 aged ≥3 months to <2 years
    Reporting group description
    		 aged ≥3 months to <2 years

    Reporting group values
    		 Cohort 1 aged ≥12 to <18 years Cohort 2 aged ≥6 to <12 years Cohort 3 aged ≥2 to <6 years Cohort 4 aged ≥3 months to <2 years Total
    Number of subjects
    		 8 8 8 8 32
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 8 8
        Children (2-11 years)
    		 0 8 8 0 16
        Adolescents (12-17 years)
    		 8 0 0 0 8
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 14.945 ± 1.5599 8.02 ± 1.4036 3.519 ± 1.0044 0.924 ± 0.5007 -
    Gender, Male/Female
    Units: participants
        Female
    		 5 3 6 3 17
        Male
    		 3 5 2 5 15
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 0 0 1
        Asian
    		 0 0 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 1 2 0 3 6
        White
    		 6 6 7 5 24
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 1 3 1 5
        Not Hispanic or Latino
    		 8 7 5 7 27
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 aged ≥12 to <18 years
    Reporting group description
    		 aged ≥12 to <18 years

    Reporting group title
    Cohort 2 aged ≥6 to <12 years
    Reporting group description
    		 aged ≥6 to <12 years

    Reporting group title
    Cohort 3 aged ≥2 to <6 years
    Reporting group description
    		 aged ≥2 to <6 years

    Reporting group title
    Cohort 4 aged ≥3 months to <2 years
    Reporting group description
    		 aged ≥3 months to <2 years

    Primary: Pharmacokinetic parameters of avibactam and ceftazidime for cohort 1 and 2: AUC

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    End point title
    		 Pharmacokinetic parameters of avibactam and ceftazidime for cohort 1 and 2: AUC [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The data was only summarised for cohort 1 and cohort 2.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data was only summarised for cohort 1 and cohort 2.
    End point values
    		 Cohort 1 aged ≥12 to <18 years Cohort 2 aged ≥6 to <12 years
    Number of subjects analysed
    8 [3]
    8 [4]
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        AUC(0-8): Avibactam
    35140 ± 33.11
    33590 ± 22.15
        AUC(0-8): Ceftazidime
    219100 ± 29.69
    212400 ± 16.28
        AUC(0-t): Avibactam
    36250 ± 33.7
    34380 ± 23.37
        AUC(0-t): Ceftazidime
    229200 ± 30.86
    217800 ± 18.36
        AUC(0-inf): Avibactam
    36430 ± 33.61
    34820 ± 22.62
        AUC(0-inf): Ceftazidime
    230600 ± 30.7
    221200 ± 17.38
    Notes
    [3] - Pharmacokinetic analysis set. Cohorts 3 and 4 PK parameters not derived due to sparse sampling.
    [4] - Pharmacokinetic analysis set. Cohorts 3 and 4 PK parameters not derived due to sparse sampling.
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameters of avibactam and ceftazidime for cohort 1 and 2: Cmax

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    End point title
    		 Pharmacokinetic parameters of avibactam and ceftazidime for cohort 1 and 2: Cmax [5] [6]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The data was only summarised for cohort 1 and cohort 2.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data was only summarised for cohort 1 and cohort 2.
    End point values
    		 Cohort 1 aged ≥12 to <18 years Cohort 2 aged ≥6 to <12 years
    Number of subjects analysed
    8 [7]
    8 [8]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cmax: Avibactam
    15090 ± 52.42
    14140 ± 22.96
        Cmax: Ceftazidime
    79750 ± 41.81
    81270 ± 17.81
    Notes
    [7] - Pharmacokinetic analysis set
    [8] - Pharmacokinetic analysis set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 aged ≥12 to <18 years

    Reporting group title
    Cohort 2
    Reporting group description
    		 aged ≥6 to <12 years

    Reporting group title
    Cohort 3
    Reporting group description
    		 aged ≥2 to <6 years

    Reporting group title
    Cohort 4
    Reporting group description
    		 aged ≥3 months to <2 years

    Serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    4 / 8 (50.00%)
    2 / 8 (25.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Procedural site reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2013
    Amended to clarify the timing of protocol assessments (to provide clarification on the timing of protocol assessments and the allowable window of time around vital sign measurements). Amended inclusion criterion #3 with respect to early hospital discharge (to address realistic timelines for patient discharge and clarify that hospitalization was only mandatory for the first 24 hours after infusion. An early discharge was possible if the patient was able to return to the hospital or clinic for assessments on Day 3). Amended exclusion criterion #10 with respect to the upper limit BMI. Amended accountability language (Section 5.7.1 of the CSP).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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