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    Clinical Trial Results:
    Safety, Tolerability and Pharmacokinetics of Single Dose Intravenous Moxifloxacin in Pediatric Patients

    Summary
    EudraCT number
    		 2012-000737-40
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    12 Aug 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Sep 2016
    First version publication date
    26 Jun 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Bayer sponsor contact information to be updated

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY12-8039/11826
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01049022
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Project ID: 1962
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, D-51368, Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000288-PIP01-08
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to describe the pharmacokinetics (PK) of moxifloxacin in children of different ages, in order to determine a dose which will provide a similar exposure as seen in adults treated with the approved therapeutic dose of 400 milligram (mg).
    Protection of trial subjects
    All clinical work conducted in this study was subjected to the rules of Good Clinical Practice and under the guidelines of Declaration of Helsinki. Participating subjects or their legally authorized representative signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Since the study was conducted in children, both parents or legal guardian may have provided informed consent, in addition to the child assenting to participation in the study, when possible. Only children requiring antibiotic therapy were included in the study, as Moxifloxacin may provide some clinical benefit for these subjects, in addition to that of their prescribed medication. The study was following a stepwise staggered enrollment concept to allow for dose adjustment if deemed necessary due to safety reasons with dose not exceeding 10 milligram per kilogram (mg/kg) or 400 mg. Dosage predictions were based on a stepwise evaluation of the clinical PK information and safety results from group to group as well as from older to younger children.
    Background therapy
    		 All subjects received antibiotic (Non-quinolone) therapy for a suspected or proven infection at the time of study treatment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 May 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    31
    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)
    7
    Children (2-11 years)
    22
    Adolescents (12-17 years)
    2
    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
    		 The study was conducted at 6 study centers in the United States of America (USA) with first patient first visit (FPFV) on 24 May 2010 and last patient last visit (LPLV) as 12 August 2013.

    Pre-assignment
    Screening details
    		 A total of 44 subjects were screened, out of which 13 subjects had screening failure. Six subjects withdrew consent, 6 subjects were in violation of the protocol and 1 subject qualified for study entry but was not needed. Therefore, 31 subjects were assigned to treatment and received a dose of Moxifloxacin according to their assigned dose level.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 1
    Arm description
    		 Single intravenous (IV) infusion of moxifloxacin administered over 60 minutes, at an initial dosage of 5 milligram per kilogram per body weight (mg/kg/BW) with dose escalation to 6 mg/kg in subjects of age 6 years (yrs) to less than or equal to (<=) 14 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moxifloxacin
    Investigational medicinal product code
    BAY12-8039
    Other name
    Avelox
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of moxifloxacin administered over 60 minutes, at an initial dosage of 5 mg/kg/BW with dose escalation to 6 mg/kg in subjects.

    Arm title
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 2
    Arm description
    		 Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 7 mg/kg/BW with dose escalation to 8 mg/kg in subjects of age 2 years to less than (<) 6 years; dose escalation was based on evaluations of the PK and safety data from the subjects in a preceding cohort.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moxifloxacin
    Investigational medicinal product code
    BAY12-8039
    Other name
    Avelox
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of moxifloxacin administered over 60 minutes, at an initial dosage of 7 - 8 mg/kg/BW in subjects.

    Arm title
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 3
    Arm description
    		 Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 9 mg/kg/BW with dose escalation to 10 mg/kg in subjects of age 3 months to <2 years; dose escalation was based on evaluations of the PK and safety data from the subjects in a preceding cohort.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moxifloxacin
    Investigational medicinal product code
    BAY12-8039
    Other name
    Avelox
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 9 - 10 mg/kg/BW in subjects.

    Number of subjects in period 1
    		Moxifloxacin (Avelox, BAY12-8039), Cohort 1 Moxifloxacin (Avelox, BAY12-8039), Cohort 2 Moxifloxacin (Avelox, BAY12-8039), Cohort 3
    Started
    12
    12
    7
    Completed
    8
    11
    6
    Not completed
    4
    1
    1
         Lost to follow-up
    4
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 1
    Reporting group description
    		 Single intravenous (IV) infusion of moxifloxacin administered over 60 minutes, at an initial dosage of 5 milligram per kilogram per body weight (mg/kg/BW) with dose escalation to 6 mg/kg in subjects of age 6 years (yrs) to less than or equal to (<=) 14 years.

    Reporting group title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 2
    Reporting group description
    		 Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 7 mg/kg/BW with dose escalation to 8 mg/kg in subjects of age 2 years to less than (<) 6 years; dose escalation was based on evaluations of the PK and safety data from the subjects in a preceding cohort.

    Reporting group title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 3
    Reporting group description
    		 Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 9 mg/kg/BW with dose escalation to 10 mg/kg in subjects of age 3 months to <2 years; dose escalation was based on evaluations of the PK and safety data from the subjects in a preceding cohort.

    Reporting group values
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 1 Moxifloxacin (Avelox, BAY12-8039), Cohort 2 Moxifloxacin (Avelox, BAY12-8039), Cohort 3 Total
    Number of subjects
    		 12 12 7 31
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 7 7
        Children (2-11 years)
    		 10 12 0 22
        Adolescents (12-17 years)
    		 2 0 0 2
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.2 ± 2.4 3.9 ± 1.1 1.1 ± 0.6 -
    Gender categorical
    Units: Subjects
        Female
    		 3 3 1 7
        Male
    		 9 9 6 24
    Findings on Medical History
    All subjects who were enrolled and treated in the study had a pre-existing condition for which they were already receiving antibiotics for suspected or proven infection and for which treatment with a fluoroquinolone antibiotic infusion (such as moxifloxacin) was indicated. The variety of pre-existing medical conditions within the subject population confounds and limits the value in interpretation of the medical history across cohorts and in the overall subject population.
    Units: Subjects
        Any findings
    		 12 12 7 31
    Prior Medication
    Subjects received prior medications due to the enrollment requirement for a pre-existing condition and the inclusion criteria, which required all subjects to receive antibiotics for a suspected or proven infection at the time of study treatment. Prior medications that were used to treat pre-existing or treatment-emergent adverse events (TEAEs) were summarized by Anatomical Therapeutic Chemical code (ATC) generic name.
    Units: Subjects
        Any finding
    		 12 12 7 31

    End points

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    End points reporting groups
    Reporting group title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 1
    Reporting group description
    		 Single intravenous (IV) infusion of moxifloxacin administered over 60 minutes, at an initial dosage of 5 milligram per kilogram per body weight (mg/kg/BW) with dose escalation to 6 mg/kg in subjects of age 6 years (yrs) to less than or equal to (<=) 14 years.

    Reporting group title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 2
    Reporting group description
    		 Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 7 mg/kg/BW with dose escalation to 8 mg/kg in subjects of age 2 years to less than (<) 6 years; dose escalation was based on evaluations of the PK and safety data from the subjects in a preceding cohort.

    Reporting group title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 3
    Reporting group description
    		 Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 9 mg/kg/BW with dose escalation to 10 mg/kg in subjects of age 3 months to <2 years; dose escalation was based on evaluations of the PK and safety data from the subjects in a preceding cohort.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), 5.0 mg/kg, 6 to <=14 yrs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of Moxifloxacin administered over 60 minutes, at a dosage of 5.0 mg/kg per body weight in subjects of age 6 years to <=14 years.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), 6.0 mg/kg, 6 to <=14 yrs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of Moxifloxacin administered over 60 minutes, at a dosage of 6.0 mg/kg per body weight in subjects of age 6 years to <=14 years.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), 7.0 mg/kg, 2 to <6 yrs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of Moxifloxacin administered over 60 minutes, at a dosage of 7.0 mg/kg per body weight in subjects of age 2 years to <6 years.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), 8.0 mg/kg, 2 to <6 yrs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of Moxifloxacin administered over 60 minutes, at a dosage of 8.0 mg/kg per body weight in subjects of age 2 years to <6 years.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), 9.0 mg/kg, 3months to <2yrs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of Moxifloxacin administered over 60 minutes, at a dosage of 9.0 mg/kg per body weight in subjects of age 3 months to <2 years.

    Subject analysis set title
    Moxifloxacin(Avelox, BAY12-8039), 10.0 mg/kg, 3months to <2yrs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of Moxifloxacin administered over 60 minutes, at a dosage of 10.0 mg/kg per body weight in subjects of age 3 months to <2 years.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 1, Male
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of moxifloxacin administered over 60 minutes, at an initial dosage of 5 mg/kg/BW with dose escalation to 6 mg/kg in male subjects of age 6 years to <=14 years.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 1, Female
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of moxifloxacin administered over 60 minutes, at an initial dosage of 5 mg/kg/BW with dose escalation to 6 mg/kg in female subjects of age 6 years to <=14 years.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 2, Male
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 7 mg/kg/BW with dose escalation to 8 mg/kg in male subjects of age 2 years to <6 years; dose escalation was based on evaluations of the PK data from the subjects in a preceding cohort.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 2, Female
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 7 mg/kg/BW with dose escalation to 8 mg/kg in female subjects of age 2 years to <6 years; dose escalation was based on evaluations of the PK data from the subjects in a preceding cohort.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 3, Male
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 9 mg/kg/BW with dose escalation to 10 mg/kg in male subjects of age 3 months to <2 years; dose escalation was based on evaluations of the PK data from the subjects in a preceding cohort.

    Subject analysis set title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 3, Female
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 9 mg/kg/BW with dose escalation to 10 mg/kg in female subjects of age 3 months to <2 years; dose escalation was based on evaluations of the PK data from the subjects in a preceding cohort.

    Subject analysis set title
    Pharmacokinetic Analysis Set (PKS) population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PKS population included any subject who received moxifloxacin (BAY12-8039) and had an adequate number of PK samples collected.

    Subject analysis set title
    Safety Analysis Set (SAF) population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF population included all subjects who was assigned to treatment received at least 1 dose of study drug and had post-treatment safety data.

    Primary: Area under the Concentration-Time Curve (AUC) of Moxifloxacin and its Metabolites

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    End point title
    		 Area under the Concentration-Time Curve (AUC) of Moxifloxacin and its Metabolites [1]
    End point description
    The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. ‘99999’ in the reported data indicates that geometric coefficient of variation was not calculated as only 1 subject was evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose, 1 hour (end of infusion), 1.5, 4, 8, 12 and 24 hours (Day 2) after start of infusion (samples at 36 h and 48 h were optional)
    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: No inferential statistics done. Descriptive statistics evaluation of the parameters was performed in order to select the dose in children.
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), 5.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 6.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 7.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 8.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 9.0 mg/kg, 3months to <2yrs Moxifloxacin(Avelox, BAY12-8039), 10.0 mg/kg, 3months to <2yrs
    Number of subjects analysed
    7 [2]
    5 [3]
    7 [4]
    5 [5]
    6 [6]
    1 [7]
    Units: milligram*hour per liter
    geometric mean (geometric coefficient of variation)
        Moxifloxacin (BAY12-8039) (N=7, 5, 7, 5, 6, 1)
    19.73 ± 30.53
    24.04 ± 24.11
    28.21 ± 42.75
    27.18 ± 19.29
    25.52 ± 17.26
    40.51 ± 99999
        Metabolite M-1 (BAY31-8061) (N=6, 4, 7, 5, 6, 1)
    0.5648 ± 67.66
    0.9838 ± 47.59
    1.4482 ± 35.37
    1.1104 ± 54.27
    2.0205 ± 56.78
    3.6234 ± 99999
        Metabolite M-2 (BAY58-8178) (N=7, 5, 7, 5, 6, 1)
    7.602 ± 43.51
    6.995 ± 88.27
    15.05 ± 41.66
    10.517 ± 47.2
    17.593 ± 47.61
    20.515 ± 99999
    Notes
    [2] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [3] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [4] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [5] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [6] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [7] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    No statistical analyses for this end point

    Primary: Maximum Observed Drug Concentration in Plasma (Cmax) of Moxifloxacin and its Metabolites

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    End point title
    		 Maximum Observed Drug Concentration in Plasma (Cmax) of Moxifloxacin and its Metabolites [8]
    End point description
    Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. ‘99999’ in the reported data indicates that geometric coefficient of variation was not calculated as only 1 subject was evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose, 1 hour (end of infusion), 1.5, 4, 8, 12 and 24 hours (Day 2) after start of infusion (samples at 36 h and 48 h were optional)
    Notes
    [8] - 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: No inferential statistics done. Descriptive statistics evaluation of the parameters was performed in order to select the dose in children.
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), 5.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 6.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 7.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 8.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 9.0 mg/kg, 3months to <2yrs Moxifloxacin(Avelox, BAY12-8039), 10.0 mg/kg, 3months to <2yrs
    Number of subjects analysed
    7 [9]
    5 [10]
    7 [11]
    5 [12]
    6 [13]
    1 [14]
    Units: milligram per liter
    geometric mean (geometric coefficient of variation)
        Moxifloxacin (BAY12-8039)
    3.159 ± 33.33
    4.607 ± 17.1
    6.514 ± 43.54
    5.644 ± 10.71
    5.308 ± 14.67
    5.964 ± 99999
        Metabolite M-1 (BAY31-8061)
    0.0761 ± 43.52
    0.1158 ± 115.01
    0.2573 ± 44.12
    0.2142 ± 90.21
    0.3236 ± 40.05
    0.5005 ± 99999
        Metabolite M-2 (BAY58-8178)
    0.6661 ± 41.21
    0.8072 ± 98.07
    1.5942 ± 53.26
    1.3184 ± 74.63
    2.0927 ± 48.26
    1.9228 ± 99999
    Notes
    [9] - PKS
    [10] - PKS
    [11] - PKS
    [12] - PKS
    [13] - PKS
    [14] - PKS
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment Emergent Findings on Joint Assessment: Baseline

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    End point title
    		 Number of Subjects With Treatment Emergent Findings on Joint Assessment: Baseline [15]
    End point description
    Joint assessment included formal physical examination of all joints with special care and attention to the weight-bearing joints (such as, knees, hips, and ankles) and to the shoulder girdle. All joints were examined for pain/tenderness, evidence of inflammation (i.e., redness, warmth, deformity, swelling or ballotable fluid), loss of function (to the extent this could be assessed in younger children and infants), and any restrictions to expected active/passive range of motion. Both active and passive range of motion were assessed. An incidence count was reported as the number of subjects with at least one finding at baseline, regardless of side.
    End point type
    Primary
    End point timeframe
    Baseline
    Notes
    [15] - 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: No inferential statistics done. Descriptive statistics evaluation of the parameters was performed in order to select the dose in children.
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 1 Moxifloxacin (Avelox, BAY12-8039), Cohort 2 Moxifloxacin (Avelox, BAY12-8039), Cohort 3
    Number of subjects analysed
    12 [16]
    12 [17]
    7 [18]
    Units: subjects
        Achilles tendon: Any findings
    0
    0
    1
        Elbow: Any findings
    1
    2
    0
        Wrist: Any findings
    0
    1
    1
    Notes
    [16] - SAF
    [17] - SAF
    [18] - SAF
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment Emergent Findings on Joint Assessment : At any Time During Treatment

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    End point title
    		 Number of Subjects With Treatment Emergent Findings on Joint Assessment : At any Time During Treatment [19]
    End point description
    Joint assessment included formal physical examination of all joints with special care and attention to the weight-bearing joints (such as, knees, hips, and ankles) and to the shoulder girdle. All joints were examined for pain/tenderness, evidence of inflammation (i.e., redness, warmth, deformity, swelling or ballotable fluid), loss of function (to the extent this could be assessed in younger children and infants), and any restrictions to expected active/passive range of motion. Both active and passive range of motion were assessed. An incidence count was reported as the number of subjects with at least one finding at any time during treatment, regardless of side.
    End point type
    Primary
    End point timeframe
    Day 1 up to Year 5 (follow-up)
    Notes
    [19] - 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: No inferential statistics done. Descriptive statistics evaluation of the parameters was performed in order to select the dose in children.
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 1 Moxifloxacin (Avelox, BAY12-8039), Cohort 2 Moxifloxacin (Avelox, BAY12-8039), Cohort 3
    Number of subjects analysed
    12 [20]
    12 [21]
    7 [22]
    Units: subjects
        Elbow: Any findings
    1
    2
    0
        Wrist: Any findings
    0
    3
    1
    Notes
    [20] - SAF
    [21] - SAF
    [22] - SAF
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Drug Concentration in Plasma (tmax) of Moxifloxacin and its Metabolites

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    End point title
    		 Time to Reach Maximum Drug Concentration in Plasma (tmax) of Moxifloxacin and its Metabolites
    End point description
    tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour (end of infusion), 1.5, 4, 8, 12 and 24 hours (Day 2) after start of infusion (samples at 36 h and 48 h were optional)
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 1, Male Moxifloxacin (Avelox, BAY12-8039), Cohort 1, Female Moxifloxacin (Avelox, BAY12-8039), Cohort 2, Male Moxifloxacin (Avelox, BAY12-8039), Cohort 2, Female Moxifloxacin (Avelox, BAY12-8039), Cohort 3, Male Moxifloxacin (Avelox, BAY12-8039), Cohort 3, Female
    Number of subjects analysed
    9 [23]
    3 [24]
    9 [25]
    3 [26]
    6 [27]
    1 [28]
    Units: hour
    median (full range (min-max))
        Moxifloxacin (BAY12-8039)
    1.0333 (1 to 1.5)
    1.0333 (1.017 to 1.283)
    1.0333 (1.017 to 1.217)
    1.1667 (1 to 1.2)
    1.0917 (1 to 1.567)
    1.0667 (1.0667 to 1.0667)
        Metabolite M-1 (BAY31-8061)
    1.0333 (1 to 1.5)
    1.0333 (1.017 to 1.283)
    1.0333 (1.017 to 1.217)
    1.1667 (1 to 1.2)
    1.0917 (1 to 1.567)
    1.0667 (1.0667 to 1.0667)
        Metabolite M-2 (BAY58-8178)
    1.5167 (1.1 to 3.5)
    3.8667 (1.283 to 4)
    1.5667 (1.217 to 4.033)
    1.2 (1.167 to 1.5)
    1.525 (1.5 to 4)
    1.4833 (1.4833 to 1.4833)
    Notes
    [23] - PKS
    [24] - PKS
    [25] - PKS
    [26] - PKS
    [27] - PKS
    [28] - PKS
    No statistical analyses for this end point

    Secondary: Half Life Associated With Terminal Slope (t1/2) of Moxifloxacin and its Metabolites

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    End point title
    		 Half Life Associated With Terminal Slope (t1/2) of Moxifloxacin and its Metabolites
    End point description
    Half life associated with terminal slope refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in hours (h) and derived from the terminal slope of the concentration versus time curve. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. ‘99999’ in the reported data indicates that geometric coefficient of variation was not calculated as only 1 subject was evaluable.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour (end of infusion), 1.5, 4, 8, 12 and 24 hours (Day 2) after start of infusion (samples at 36 h and 48 h were optional)
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), 5.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 6.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 7.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 8.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 9.0 mg/kg, 3months to <2yrs Moxifloxacin(Avelox, BAY12-8039), 10.0 mg/kg, 3months to <2yrs
    Number of subjects analysed
    7 [29]
    5 [30]
    7 [31]
    5 [32]
    6 [33]
    1 [34]
    Units: hour
    geometric mean (geometric coefficient of variation)
        Moxifloxacin (BAY12-8039) (N=7, 5, 7, 5, 6, 1)
    7.887 ± 34.32
    6.164 ± 23.99
    5.66 ± 18.79
    6.031 ± 24.78
    6.817 ± 35.1
    5.938 ± 99999
        Metabolite M-1 (BAY31-8061) (N=6, 4, 7, 5, 6, 1)
    6.181 ± 80.62
    6.724 ± 43.26
    4.714 ± 47.04
    4.741 ± 41.41
    7.043 ± 106.68
    6.546 ± 99999
        Metabolite M-2 (BAY58-8178) (N=7, 5, 7, 5, 6, 1)
    7.015 ± 22.14
    5.79 ± 25.16
    5.26 ± 21.61
    5.171 ± 22.22
    5.928 ± 32.83
    5.704 ± 99999
    Notes
    [29] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [30] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [31] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [32] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [33] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [34] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    No statistical analyses for this end point

    Secondary: Total Amount Excreted in the Urine (Aeur) of Moxifloxacin and its Metabolites

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    End point title
    		 Total Amount Excreted in the Urine (Aeur) of Moxifloxacin and its Metabolites
    End point description
    Aeur refers to the total amount of moxifloxacin excreted in urine. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    Baseline up to 36 hour post-infusion
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), 5.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 6.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 7.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 8.0 mg/kg, 2 to <6 yrs
    Number of subjects analysed
    7 [35]
    5 [36]
    7 [37]
    5 [38]
    Units: milligram
    geometric mean (geometric coefficient of variation)
        Moxifloxacin (BAY12-8039) (N=6, 5, 3, 3)
    22.9 ± 33.23
    25.4 ± 27.5
    31.3 ± 32.38
    24.7 ± 54.41
        Metabolite M-1 (BAY31-8061) (N=6, 5, 3, 3)
    3.692 ± 79.22
    3.257 ± 126.05
    6.41 ± 90
    7.998 ± 26.85
        Metabolite M-2 (BAY58-8178) (N=6, 5, 3, 3)
    28.65 ± 57.74
    19.85 ± 100.61
    32.03 ± 25.89
    28.5 ± 35.69
    Notes
    [35] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [36] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [37] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [38] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State (Vss) of Moxifloxacin and its Metabolites

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    End point title
    		 Volume of Distribution at Steady State (Vss) of Moxifloxacin and its Metabolites
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. ‘99999’ in the reported data indicates that geometric coefficient of variation was not calculated as only 1 subject was evaluable.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour (end of infusion), 1.5, 4, 8, 12 and 24 hours (Day 2) after start of infusion (samples at 36 h and 48 h were optional)
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), 5.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 6.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 7.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 8.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 9.0 mg/kg, 3months to <2yrs Moxifloxacin(Avelox, BAY12-8039), 10.0 mg/kg, 3months to <2yrs
    Number of subjects analysed
    7 [39]
    5 [40]
    7 [41]
    5 [42]
    6 [43]
    1 [44]
    Units: liter
    geometric mean (geometric coefficient of variation)
        Moxifloxacin (BAY12-8039) (N=7, 5, 7, 5, 6, 1)
    73.8 ± 49.67
    45 ± 10.55
    26.8 ± 20.3
    28.46 ± 26.61
    23.45 ± 31.35
    16.74 ± 99999
        Metabolite M-1 (BAY31-8061) (N=6, 4, 7, 5, 6, 1)
    2805.3 ± 54.15
    1513.3 ± 65.08
    639 ± 54.86
    803.3 ± 90.5
    461.7 ± 55.73
    244.1 ± 99999
        Metabolite M-2 (BAY58-8178) (N=7, 5, 7, 5, 6, 1)
    302.47 ± 61.45
    249.51 ± 95.67
    90.03 ± 61.44
    117.84 ± 90.15
    55.46 ± 59.89
    53.36 ± 99999
    Notes
    [39] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [40] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [41] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [42] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [43] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [44] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    No statistical analyses for this end point

    Secondary: Plasma Clearance (CL) of Moxifloxacin and its Metabolites

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    End point title
    		 Plasma Clearance (CL) of Moxifloxacin and its Metabolites
    End point description
    Total body clearance of drug in plasma is expressed in litres per hour. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. ‘99999’ in the reported data indicates that geometric coefficient of variation was not calculated as only 1 subject was evaluable.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour (end of infusion), 1.5, 4, 8, 12 and 24 hours (Day 2) after start of infusion (samples at 36 h and 48 h were optional)
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), 5.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 6.0 mg/kg, 6 to <=14 yrs Moxifloxacin (Avelox, BAY12-8039), 7.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 8.0 mg/kg, 2 to <6 yrs Moxifloxacin (Avelox, BAY12-8039), 9.0 mg/kg, 3months to <2yrs Moxifloxacin(Avelox, BAY12-8039), 10.0 mg/kg, 3months to <2yrs
    Number of subjects analysed
    7 [45]
    5 [46]
    7 [47]
    5 [48]
    6 [49]
    1 [50]
    Units: liters per hour
    geometric mean (geometric coefficient of variation)
        Moxifloxacin (BAY12-8039) (N=7, 5, 7, 5, 6, 1)
    8.111 ± 40.08
    6.238 ± 32.37
    4.361 ± 26.19
    4.505 ± 21.75
    3.675 ± 27.1
    2.197 ± 99999
        Metabolite M-1 (BAY31-8061) (N=6, 4, 7, 5, 6, 1)
    330.82 ± 76.81
    177.25 ± 58.86
    101.92 ± 16.64
    132.31 ± 65.25
    55.7 ± 59.98
    29.46 ± 99999
        Metabolite M-2 (BAY58-8178) (N=7, 5, 7, 5, 6, 1)
    30.295 ± 52.2
    30.85 ± 81.39
    11.764 ± 36.83
    16.757 ± 56.87
    7.673 ± 56.9
    6.241 ± 99999
    Notes
    [45] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [46] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [47] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [48] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [49] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [50] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity Divided by Dose Per kilogram Body Weight (AUCnorm) of Moxifloxacin and its Metabolites

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    End point title
    		 Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity Divided by Dose Per kilogram Body Weight (AUCnorm) of Moxifloxacin and its Metabolites
    End point description
    AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUCnorm is defined as AUC divided by dose per kg body weight. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. ‘99999’ in the reported data indicates that geometric coefficient of variation was not calculated as only 1 subject was evaluable.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour (end of infusion), 1.5, 4, 8, 12 and 24 hours (Day 2) after start of infusion (samples at 36 h and 48 h were optional)
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 1, Male Moxifloxacin (Avelox, BAY12-8039), Cohort 1, Female Moxifloxacin (Avelox, BAY12-8039), Cohort 2, Male Moxifloxacin (Avelox, BAY12-8039), Cohort 2, Female Moxifloxacin (Avelox, BAY12-8039), Cohort 3, Male Moxifloxacin (Avelox, BAY12-8039), Cohort 3, Female
    Number of subjects analysed
    9 [51]
    3 [52]
    9 [53]
    3 [54]
    6 [55]
    1 [56]
    Units: kilogram*hour per liters
    geometric mean (geometric coefficient of variation)
        Moxifloxacin (BAY12-8039) (N=9, 3, 9, 3, 6, 1)
    3.7 ± 25.52
    4.911 ± 19.86
    3.871 ± 37.6
    3.409 ± 28.25
    3.035 ± 22.4
    2.721 ± 99999
        Metabolite M-1 (BAY31-8061) (N=7, 3, 9, 3, 6, 1)
    0.1311 ± 42.42
    0.07153 ± 83.93
    0.14791 ± 54.14
    0.13998 ± 27.13
    0.20152 ± 61.28
    0.19579 ± 99999
        Metabolite M-2 (BAY58-8178) (N=9, 3, 9, 3, 6, 1)
    0.9596 ± 62.79
    0.9065 ± 74.62
    1.1536 ± 55.86
    1.4244 ± 31.76
    1.4073 ± 46.74
    1.1655 ± 99999
    Notes
    [51] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [52] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [53] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [54] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [55] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    [56] - PKS. Here "N" signifies subjects who were evaluable for the specified category.
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration Divided by Dose Per kilogram Body Weight (Cmax,Norm) of Moxifloxacin and its Metabolites

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    End point title
    		 Maximum Observed Plasma Concentration Divided by Dose Per kilogram Body Weight (Cmax,Norm) of Moxifloxacin and its Metabolites
    End point description
    Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Cmax,norm is defined as Cmax divided by dose (mg) per kg body weight. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. ‘99999’ in the reported data indicates that geometric coefficient of variation was not calculated as only 1 subject was evaluable.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour (end of infusion), 1.5, 4, 8, 12 and 24 hours (Day 2) after start of infusion (samples at 36 h and 48 h were optional)
    End point values
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 1, Male Moxifloxacin (Avelox, BAY12-8039), Cohort 1, Female Moxifloxacin (Avelox, BAY12-8039), Cohort 2, Male Moxifloxacin (Avelox, BAY12-8039), Cohort 2, Female Moxifloxacin (Avelox, BAY12-8039), Cohort 3, Male Moxifloxacin (Avelox, BAY12-8039), Cohort 3, Female
    Number of subjects analysed
    9 [57]
    3 [58]
    9 [59]
    3 [60]
    6 [61]
    1 [62]
    Units: kilogram(s)/liter
    geometric mean (geometric coefficient of variation)
        Moxifloxacin (BAY12-8039)
    0.6679 ± 32.32
    0.7397 ± 14.21
    0.8671 ± 40.7
    0.7219 ± 7.49
    0.5953 ± 14.6
    0.5693 ± 99999
        Metabolite M-1 (BAY31-8061)
    0.015601 ± 78.9
    0.01017 ± 39.81
    0.025204 ± 69.35
    0.032342 ± 50.02
    0.03079 ± 42.26
    0.035878 ± 99999
        Metabolite M-2 (BAY58-8178)
    0.09804 ± 66.31
    0.07926 ± 60.23
    0.12784 ± 59.33
    0.17447 ± 76.73
    0.16201 ± 48.07
    0.13292 ± 99999
    Notes
    [57] - PKS
    [58] - PKS
    [59] - PKS
    [60] - PKS
    [61] - PKS
    [62] - PKS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 1 year (follow up) (Joint abnormalities followed until resolution, up to 5 years)
    Adverse event reporting additional description
    Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the study drug treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 1
    Reporting group description
    		 Single IV infusion of moxifloxacin administered over 60 minutes, at an initial dosage of 5 mg/kg/BW with dose escalation to 6 mg/kg in subjects of age 6 years to <= 14 years.

    Reporting group title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 3
    Reporting group description
    		 Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 9 mg/kg/BW with dose escalation to 10 mg/kg in subjects of age 3 months to < 2 years; dose escalation was based on evaluations of the PK data from the subjects in a preceding cohort.

    Reporting group title
    Moxifloxacin (Avelox, BAY12-8039), Cohort 2
    Reporting group description
    		 Single IV infusion of moxifloxacin administered over 60 minutes, at a dosage of 7 mg/kg/BW with dose escalation to 8 mg/kg in subjects of age 2 years to < 6 years; dose escalation was based on evaluations of the PK data from the subjects in a preceding cohort.

    Serious adverse events
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 1 Moxifloxacin (Avelox, BAY12-8039), Cohort 3 Moxifloxacin (Avelox, BAY12-8039), Cohort 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Biopsy bone
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Histiocytosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Moxifloxacin (Avelox, BAY12-8039), Cohort 1 Moxifloxacin (Avelox, BAY12-8039), Cohort 3 Moxifloxacin (Avelox, BAY12-8039), Cohort 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 12 (50.00%)
    5 / 7 (71.43%)
    6 / 12 (50.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Surgical and medical procedures
    Abscess drainage
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Application site urticaria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Chest discomfort
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Device occlusion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Infusion site erythema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Vessel puncture site pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Vessel puncture site pruritus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    Pneumothorax
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood cholesterol increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood urea decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Left atrial dilatation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Defect conduction intraventricular
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Right ventricular hypertrophy
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 7 (28.57%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Leukocytosis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Thrombocytosis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal sounds abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    3
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Erythema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Rash papular
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Renal and urinary disorders
    Pyuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Fluid overload
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoproteinaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2010
    The amendment reflected changes to the timing of the follow-up joint assessments. The original protocol included a 30 day follow-up. However, the Written Request Letter from the Food and Drug Administration (FDA) stipulated that additional assessments were to be made at 3 months, and 1 year after dosing. If any subjects have a musculoskeletal abnormality, they were to be followed at yearly intervals for 5 years or until resolution of the event.
    23 Mar 2010
    The amendment was specified the following modifications: - Defined the primary completion date as 3-month follow-up - Clarified exclusion criteria for renal and hepatic disease and musculoskeletal abnormalities - Removed the requirement for weighing dose administration materials - Clarified that use of concomitant medications up to Day 10 of the study were to be documented on the CRF - Added the exclusion criteria that subjects could not have participated in another clinical trial within 30 days (changed from 3 months) - Changed the documentation period of previous medication history to 4 weeks prior to dosing (changed from rather than 10 weeks) - Restricted the requirement for PK urine collection to subjects who were toilet trained or catheterized - Added vital signs and ECG at all PK sample time points up to 24 hours - Added PK parameters AUCnorm and Cmax, norm - Clarified the of systems covered by the complete physical exam - Revised the timeframe for following AEs - Gamma glutamyl transferase (GGT) was added to the clinical lab tests (blood chemistry) - Revised the Study Flow Chart to clarify PK sampling on Days 1 – 3 and to add vital signs and ECG evaluations
    14 Jun 2011
    Amendment 3 addressed issues of particular concern to Cohort 3 (ages 3 months to < 2 years) regarding breastfeeding, i.e., medications that the mother may have been taking, and the enrollment of premature infants. The amendment specified the following modifications: - ALT up to 3X ULN was allowed if not considered related to hepatic disease (i.e., elevation may be secondary to infection). This change was suggested by investigators, who felt subjects were being unnecessarily excluded, since elevated ALT could have been be related to the infection, rather than hepatic disease. - Added exclusion of subjects with a history of myasthenia gravis (to reflect the updated labeling of quinolones) - Incorporated items addressed in Administrative letter 2 and removed the coordinating investigator (thought not to be needed because the study was conducted only in the USA). This measure was not enacted. - Deleted procedures that were either not relevant to the protocol (e.g., body mass index [BMI]), or inconsistent with the actual study conduct (e.g., temperature not being measured), and clarified inconsistencies (e.g., discrepancies in urine PK volume between the PK manual and the protocol)

    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.
    Occurrence of "±” in relation with geometric CV is auto-generated and cannot be deleted. '99999' in the posting indicates data were not calculated. Decimal places were automatically truncated if last decimal equals zero.
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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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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