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    Clinical Trial Results:
    An open label, intravenous to oral switch, multiple dose study to evaluate the pharmacokinetics, safety and tolerability of voriconazole in immunocompromised adolescents aged 12 to less than (<) 17 years who were at high risk for systemic fungal infection

    Summary
    EudraCT number
    		 2012-001151-39
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    02 Dec 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Apr 2016
    First version publication date
    29 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A1501081
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00556998
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer Clinical Trials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.govCallCenter@pfizer.com
    Scientific contact
    Pfizer Clinical Trials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.govCallCenter@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000191-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 May 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the pharmacokinetics of voriconazole following an intravenous (IV) to oral switch regimen in immunocompromised adolescent subjects aged 12 to <17 years who were at high risk for systemic fungal infection.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jun 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    26
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    26
    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
    		 -

    Pre-assignment
    Screening details
    		 Total 26 subjects were recruited from 10 sites in United States. Study started on 10 June 2008 and completed on 02 December 2009.

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All Subjects
    Arm description
    		 Voriconazole intravenous (IV) loading doses every 12 hours on Day 1 and maintenance IV doses every 12 hours on Days 2 to 7 (up to Day 20 if clinically indicated). The oral maintenance dosing regimen was administered following voriconazole IV and lasted 6.5 days (up to Day 30 if clinically indicated).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Voriconazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Oral suspension
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Voriconazole IV loading dose of 6 milligram per kilogram (mg/kg) in the morning and evening on Day 1 and multiple IV doses of 4 mg/kg in the morning and evening on Days 2 to 7, up to Day 20 if clinically indicated. Oral maintenance dosing regimen of 300 mg every 12 hours or 150 mg every 12 hours if subject weighed less than 40 kg was administered following voriconazole IV and lasted 6.5 days, up to Day 30 if clinically indicated. One subject received 2 days of oral regimen then received IV again before discontinuing from study.

    Number of subjects in period 1
    		All Subjects
    Started
    26
    Completed
    26
    Period 2
    Period 2 title
    Voriconazole IV
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Voriconazole IV
    Arm description
    		 Voriconazole IV loading doses every 12 hours on Day 1 and maintenance IV doses every 12 hours on Days 2 to 7 (up to Day 20 if clinically indicated).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Voriconazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Voriconazole IV loading dose (6 mg/kg every 12 hours) in the morning and evening on Day 1 and multiple IV doses (4 mg/kg every 12 hours)  in the morning and evening on Days 2 to 7, up to Day 20 if clinically indicated. One subject received 2 days of oral regimen then received IV again before discontinuing from

    Number of subjects in period 2
    		Voriconazole IV
    Started
    26
    Completed
    21
    Not completed
    5
         Adverse event
    1
         Unspecified
    4
    Period 3
    Period 3 title
    Voriconazole Oral
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Voriconazole Oral
    Arm description
    		 Voriconazole oral doses were administered following voriconazole IV and lasted 6.5 days (up to Day 30 if clinically indicated).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Voriconazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The oral maintenance dosing regimen of 300 mg every 12 hours or 150 mg every 12 hours if subject weighed less than 40 kg was administered following voriconazole IV and lasted 6.5 days, up to Day 30 if clinically indicated. One subject received voriconazole 150 mg every 12 hours during oral phase.

    Number of subjects in period 3
    		Voriconazole Oral
    Started
    21
    Completed
    20
    Not completed
    1
         Adverse event
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All Subjects
    Reporting group description
    		 Voriconazole intravenous (IV) loading doses every 12 hours on Day 1 and maintenance IV doses every 12 hours on Days 2 to 7 (up to Day 20 if clinically indicated). The oral maintenance dosing regimen was administered following voriconazole IV and lasted 6.5 days (up to Day 30 if clinically indicated).

    Reporting group values
    		 All Subjects Total
    Number of subjects
    		 26 26
    Age categorical
    Units: Subjects
        12 years
    		 4 4
        13 years
    		 10 10
        Greater than (>) 13 to >17 years
    		 12 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.7 ( 1.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 17 17

    End points

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    End points reporting groups
    Reporting group title
    All Subjects
    Reporting group description
    		 Voriconazole intravenous (IV) loading doses every 12 hours on Day 1 and maintenance IV doses every 12 hours on Days 2 to 7 (up to Day 20 if clinically indicated). The oral maintenance dosing regimen was administered following voriconazole IV and lasted 6.5 days (up to Day 30 if clinically indicated).
    Reporting group title
    Voriconazole IV
    Reporting group description
    		 Voriconazole IV loading doses every 12 hours on Day 1 and maintenance IV doses every 12 hours on Days 2 to 7 (up to Day 20 if clinically indicated).
    Reporting group title
    Voriconazole Oral
    Reporting group description
    		 Voriconazole oral doses were administered following voriconazole IV and lasted 6.5 days (up to Day 30 if clinically indicated).

    Primary: Area Under the Curve Over Dosing Interval at Steady State (AUC12,ss) Following IV Administration

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    End point title
    		 Area Under the Curve Over Dosing Interval at Steady State (AUC12,ss) Following IV Administration [1]
    End point description
    AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method. Intent to treat (ITT) population of subjects who had completed pharmacokinetic (PK) blood sampling for at least one day.
    End point type
    Primary
    End point timeframe
    Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6, 8 and 12 hours after start of infusion
    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: Only descriptive data was planned to be reported.
    End point values
    		 Voriconazole IV
    Number of subjects analysed
    23 [2]
    Units: microgram (mcg)*hour (h)/milliliter (mL)
        geometric mean (standard deviation)
    22.39 ( 21.47 )
    Notes
    [2] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Primary: Peak Plasma Concentration at Steady State (Cmax,ss) Following IV Administration

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    End point title
    		 Peak Plasma Concentration at Steady State (Cmax,ss) Following IV Administration [3]
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Primary
    End point timeframe
    Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6, 8 and 12 hours after start of infusion
    Notes
    [3] - 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: Only descriptive data was planned to be reported.
    End point values
    		 Voriconazole IV
    Number of subjects analysed
    23 [4]
    Units: mcg/mL
        geometric mean (standard deviation)
    3.89 ( 2.59 )
    Notes
    [4] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Primary: Time to Reach Cmax (Tmax) Following IV Administration

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    End point title
    		 Time to Reach Cmax (Tmax) Following IV Administration [5]
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Primary
    End point timeframe
    Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6, 8 and 12 hours after start of infusion
    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: Only descriptive data was planned to be reported.
    End point values
    		 Voriconazole IV
    Number of subjects analysed
    23 [6]
    Units: hours
        median (full range (min-max))
    1.3 (1.17 to 3.95)
    Notes
    [6] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Primary: AUC12,ss Following Oral Administration

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    End point title
    		 AUC12,ss Following Oral Administration [7]
    End point description
    AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method. ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Primary
    End point timeframe
    Day 7 (up to Day 30) at predose, 1, 2, 4, 6, 8, and 12 hours postdose
    Notes
    [7] - 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: Only descriptive data was planned to be reported.
    End point values
    		 Voriconazole Oral
    Number of subjects analysed
    19 [8]
    Units: mcg*h/mL
        geometric mean (standard deviation)
    16.74 ( 13.5 )
    Notes
    [8] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Primary: Cmax,ss Following Oral Administration

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    End point title
    		 Cmax,ss Following Oral Administration [9]
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Primary
    End point timeframe
    Day 7 (up to Day 30) at predose, 1, 2, 4, 6, 8, and 12 hours postdose
    Notes
    [9] - 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: Only descriptive data was planned to be reported.
    End point values
    		 Voriconazole Oral
    Number of subjects analysed
    19 [10]
    Units: mcg/mL
        geometric mean (standard deviation)
    2.35 ( 1.41 )
    Notes
    [10] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Primary: Tmax Following Oral Administration

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    End point title
    		 Tmax Following Oral Administration [11]
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Primary
    End point timeframe
    Day 7 (up to Day 30) Predose, 1, 2, 4, 6, 8, and 12 hours postdose
    Notes
    [11] - 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: Only descriptive data was planned to be reported.
    End point values
    		 Voriconazole Oral
    Number of subjects analysed
    19 [12]
    Units: hours
        median (full range (min-max))
    2 (0.67 to 8.1)
    Notes
    [12] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Secondary: AUC12 Following IV Loading Dose

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    End point title
    		 AUC12 Following IV Loading Dose
    End point description
    AUC12 = Area under the plasma concentration-time profile from time zero (predose) to twelve hours. AUC12 was obtained by the Linear/Log trapezoidal method. ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Secondary
    End point timeframe
    Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion
    End point values
    		 Voriconazole IV
    Number of subjects analysed
    22 [13]
    Units: mcg*h/mL
        geometric mean (standard deviation)
    9.14 ( 4.9 )
    Notes
    [13] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Secondary: Tmax Following an IV Loading Dose

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    End point title
    		 Tmax Following an IV Loading Dose
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Secondary
    End point timeframe
    Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion
    End point values
    		 All Subjects
    Number of subjects analysed
    22 [14]
    Units: hours
        median (full range (min-max))
    1.97 (1.9 to 2.08)
    Notes
    [14] - N signifies number of subjects with analyzable data.
    No statistical analyses for this end point

    Secondary: Cmax Following an IV Loading Dose

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    End point title
    		 Cmax Following an IV Loading Dose
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Secondary
    End point timeframe
    Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion
    End point values
    		 Voriconazole IV
    Number of subjects analysed
    22 [15]
    Units: mcg/mL
        geometric mean (standard deviation)
    2.25 ( 0.86 )
    Notes
    [15] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Trough Concentration (Cmin)

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    End point title
    		 Minimum Observed Plasma Trough Concentration (Cmin)
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day. Here 'n', signifies the number of subjects who contributed to the data.
    End point type
    Secondary
    End point timeframe
    Day 7 (up to Day 20) for IV; Day 7 (up to Day 30) for oral at predose
    End point values
    		 All Subjects
    Number of subjects analysed
    21 [16]
    Units: mcg/mL
    geometric mean (standard deviation)
        IV Day 7 (up to Day 20) (n=21)
    1.05 ( 1.85 )
        Oral Day 7 (up to Day 30) (n=19)
    0.72 ( 0.81 )
    Notes
    [16] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Secondary: AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration

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    End point title
    		 AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration
    End point description
    AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method. ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Secondary
    End point timeframe
    Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion, Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6 8 and 12 hours after start of infusion
    End point values
    		 Voriconazole IV
    Number of subjects analysed
    25 [17]
    Units: mcg*h/mL
    geometric mean (standard deviation)
        Day 1
    21.18 ( 6.8 )
        Day 7 (up to Day 20)
    36.21 ( 9.2 )
    Notes
    [17] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Secondary: Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration

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    End point title
    		 Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Secondary
    End point timeframe
    Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion and on Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6 8 and 12 hours after start of infusion
    End point values
    		 Voriconazole IV
    Number of subjects analysed
    25 [18]
    Units: mcg/mL
    geometric mean (standard deviation)
        Day 1
    2.5 ( 0.84 )
        Day 7 (up to Day 20)
    3.48 ( 0.73 )
    Notes
    [18] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Secondary: Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration

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    End point title
    		 Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following IV Administration
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Secondary
    End point timeframe
    Day 1 at predose, 60, 118 minutes, 4, 6, 8 and 12 hours after start of infusion and on Day 7 (up to Day 20) at predose, 40, 78 minutes, 4, 6 8 and 12 hours after start of infusion
    End point values
    		 Voriconazole IV
    Number of subjects analysed
    25 [19]
    Units: mcg*h/mL
    median (full range (min-max))
        Day 1
    4 (1.97 to 8.03)
        Day 7 (up to Day 20)
    4.03 (0 to 12.1)
    Notes
    [19] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Secondary: AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration

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    End point title
    		 AUC12,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration
    End point description
    AUC12,ss = Area under the plasma concentration-time profile from time zero (predose) to twelve hours at steady-state. AUC12,ss was obtained by the Linear/Log trapezoidal method. ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Secondary
    End point timeframe
    On Day 7 (up to Day 30) at predose, 1, 2, 4, 6, 8, and 12 hours postdose
    End point values
    		 Voriconazole Oral
    Number of subjects analysed
    19 [20]
    Units: mcg*h/mL
        geometric mean (standard deviation)
    44.07 ( 13.86 )
    Notes
    [20] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Secondary: Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration

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    End point title
    		 Cmax,ss of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Secondary
    End point timeframe
    Day 7 (up to Day 30) at predose, 1, 2, 4, 6, 8, and 12 hours postdose
    End point values
    		 Voriconazole Oral
    Number of subjects analysed
    19 [21]
    Units: μg/mL
        geometric mean (standard deviation)
    4.44 ( 1.43 )
    Notes
    [21] - Number of subjects with analyzable data.
    No statistical analyses for this end point

    Secondary: Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration

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    End point title
    		 Tmax of N-oxide Voriconazole Metabolite (UK-121, 265) Following Oral Administration
    End point description
    ITT population of subjects who had completed PK blood sampling for at least one day.
    End point type
    Secondary
    End point timeframe
    Day 7 (up to Day 30) at predose, 1, 2, 4, 6, 8, and 12 hours postdose
    End point values
    		 Voriconazole Oral
    Number of subjects analysed
    19
    Units: hours
        median (full range (min-max))
    5.97 (1 to 8.1)
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic Parameters of Voriconazole in Adolescents Compared to Historical Adult Data - AUC12 IV Loading Dose

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    End point title
    		 Pharmacokinetic Parameters of Voriconazole in Adolescents Compared to Historical Adult Data - AUC12 IV Loading Dose
    End point description
    Data for this Outcome Measure was not reported here because the analysis population included subjects who were not enrolled in this study.
    End point type
    Other pre-specified
    End point timeframe
    Day 1
    End point values
    		 All Subjects
    Number of subjects analysed
    0 [22]
    Units: mcg*h/mL
        geometric mean (standard deviation)
    ( )
    Notes
    [22] - Data was not reported because the analysis included subjects who were not enrolled in this study.
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - AUC12 IV steady state

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    End point title
    		 Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - AUC12 IV steady state
    End point description
    Data for this Outcome Measure was not reported here because the analysis population includes subjects who were not enrolled in this study.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 of IV dosing
    End point values
    		 All Subjects
    Number of subjects analysed
    0 [23]
    Units: mcg*h/mL
        geometric mean (standard deviation)
    ( )
    Notes
    [23] - Data was not reported because the analysis included subjects who were not enrolled in this study.
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - AUC12 oral dose all subjects

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    End point title
    		 Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - AUC12 oral dose all subjects
    End point description
    Data for this Outcome Measure was not reported here because the analysis population includes subjects who were not enrolled in this study.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 Oral dosing
    End point values
    		 All Subjects
    Number of subjects analysed
    0 [24]
    Units: mcg*h/mL
        geometric mean (standard deviation)
    ( )
    Notes
    [24] - Data was not reported because the analysis included subjects who were not enrolled in this study.
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - AUC12 Oral 300mg

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    End point title
    		 Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - AUC12 Oral 300mg
    End point description
    Data for this Outcome Measure was not reported here because the analysis population includes subjects who were not enrolled in this study.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 oral dosing
    End point values
    		 All Subjects
    Number of subjects analysed
    0 [25]
    Units: mcg*h/mL
        geometric mean (standard deviation)
    ( )
    Notes
    [25] - Data was not reported because the analysis included subjects who were not enrolled in this study.
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - Cmax IV Loading dose

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    End point title
    		 Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - Cmax IV Loading dose
    End point description
    Data for this Outcome Measure was not reported here because the analysis population includes subjects who were not enrolled in this study.
    End point type
    Other pre-specified
    End point timeframe
    Day 1
    End point values
    		 All Subjects
    Number of subjects analysed
    0 [26]
    Units: mcg/mL
        geometric mean (standard deviation)
    ( )
    Notes
    [26] - Data was not reported because the analysis included subjects who were not enrolled in this study.
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - Cmax IV steady state

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    End point title
    		 Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - Cmax IV steady state
    End point description
    Data for this Outcome Measure was not reported here because the analysis population includes subjects who were not enrolled in this study.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 of Intravenous dosing
    End point values
    		 All Subjects
    Number of subjects analysed
    0 [27]
    Units: mcg*h/mL
        geometric mean (standard deviation)
    ( )
    Notes
    [27] - Data was not reported because the analysis included subjects who were not enrolled in this study.
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - Cmax Day 7 oral all subjects

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    End point title
    		 Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - Cmax Day 7 oral all subjects
    End point description
    Data for this Outcome Measure was not reported here because the analysis population includes subjects who were not enrolled in this study.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 of oral dosing
    End point values
    		 All Subjects
    Number of subjects analysed
    0 [28]
    Units: mcg/mL
        geometric mean (standard deviation)
    ( )
    Notes
    [28] - Data was not reported because the analysis included subjects who were not enrolled in this study.
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - Cmax 300 mg oral dose

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    End point title
    		 Pharmacokinetic parameters of voriconazole in adolescents compared to historical adult data - Cmax 300 mg oral dose
    End point description
    Data for this Outcome Measure was not reported here because the analysis population includes subjects who were not enrolled in this study.
    End point type
    Other pre-specified
    End point timeframe
    Day 7 of oral dosing
    End point values
    		 All Subjects
    Number of subjects analysed
    0 [29]
    Units: mcg/mL
        geometric mean (standard deviation)
    ( )
    Notes
    [29] - Data was not reported because the analysis included subjects who were not enrolled in this study.
    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 month after last dose of investigational product
    Adverse event reporting additional description
    The same event may appear as both an adverse event (AE) and a serious AE (SAE). An event may be categorized as serious in one subject and as nonserious in an  other subject. EU BR specific AE tables were generated separately as per EU format using latest coding.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Voriconazole Oral
    Reporting group description
    		 Voriconazole oral maintenance dosing regimen (300 mg every 12 hours or 150 mg every 12 hours if subject weighed less than 40 kg) was administered following voriconazole IV and lasted 6.5 days (up to Day 30 if clinically indicated).

    Reporting group title
    Voriconazole IV
    Reporting group description
    		 Voriconazole IV loading doses (6 mg/kg every 12 hours) hours on Day 1 and maintenance IV doses (4 mg/kg every 12 hours) on Days 2 to 7 (up to Day 20 if clinically indicated).

    Serious adverse events
    		 Voriconazole Oral Voriconazole IV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 22 (18.18%)
    4 / 26 (15.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease in liver
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Alpha haemolytic streptococcal infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Voriconazole Oral Voriconazole IV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 22 (100.00%)
    26 / 26 (100.00%)
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Flushing
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Hypotension
         subjects affected / exposed
    5 / 22 (22.73%)
    2 / 26 (7.69%)
         occurrences all number
    5
    3
    Hypertension
         subjects affected / exposed
    6 / 22 (27.27%)
    4 / 26 (15.38%)
         occurrences all number
    6
    4
    Vena cava thrombosis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Oxygen supplementation
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Chills
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Device occlusion
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Face oedema
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Gait disturbance
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Generalised oedema
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    9 / 22 (40.91%)
    11 / 26 (42.31%)
         occurrences all number
    13
    13
    Oedema
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 22 (18.18%)
    1 / 26 (3.85%)
         occurrences all number
    4
    1
    Pain
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Pyrexia
         subjects affected / exposed
    5 / 22 (22.73%)
    13 / 26 (50.00%)
         occurrences all number
    11
    17
    Suprapubic pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Engraftment syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    Graft versus host disease
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Graft versus host disease in skin
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Social circumstances
    Refusal of treatment by patient
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Perineal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pruritus genital
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Scrotal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Vulvovaginal discomfort
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    4 / 22 (18.18%)
    1 / 26 (3.85%)
         occurrences all number
    4
    1
    Epistaxis
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 26 (7.69%)
         occurrences all number
    3
    3
    Hypoxia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    Pulmonary oedema
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Rales
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Respiratory depression
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Respiratory distress
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Sneezing
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Tachypnoea
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Confusional state
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Drug dependence
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Flat affect
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Mental status changes
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    Nightmare
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Restlessness
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Blood cortisol decreased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Blood pressure systolic increased
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Blood triglycerides increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 26 (7.69%)
         occurrences all number
    1
    4
    Breath sounds abnormal
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    CSF protein increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Cardiac function test abnormal
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Hepatic enzyme increased
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 26 (11.54%)
         occurrences all number
    3
    4
    Immunosuppressant drug level increased
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Oxygen saturation decreased
         subjects affected / exposed
    5 / 22 (22.73%)
    1 / 26 (3.85%)
         occurrences all number
    6
    1
    Transaminases increased
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Viral test positive
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Weight decreased
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Ear abrasion
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Radiation pneumonitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Refractoriness to platelet transfusion
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Colour blindness
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Dizziness
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Drooling
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Dystonia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Encephalopathy
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    3 / 22 (13.64%)
    4 / 26 (15.38%)
         occurrences all number
    3
    4
    Mental impairment
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Myoclonus
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Neuralgia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Nystagmus
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    Sedation
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Tremor
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Anaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Leukopenia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Febrile neutropenia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 26 (11.54%)
         occurrences all number
    2
    3
    Pancytopenia
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Thrombocytopenia
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 26 (11.54%)
         occurrences all number
    3
    3
    Ear and labyrinth disorders
    Ear canal erythema
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Conjunctival irritation
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Dry eye
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Hypermetropia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Photophobia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Strabismus
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Visual impairment
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    Anorectal disorder
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Ascites
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Breath odour
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Chapped lips
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    5 / 22 (22.73%)
    5 / 26 (19.23%)
         occurrences all number
    6
    5
    Constipation
         subjects affected / exposed
    4 / 22 (18.18%)
    2 / 26 (7.69%)
         occurrences all number
    4
    2
    Dyspepsia
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Dysphagia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Faecal volume increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Frequent bowel movements
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Haematemesis
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    Haematochezia
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    Haemorrhoids
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Lip dry
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Lip haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Localised intraabdominal fluid collection
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    6 / 22 (27.27%)
    6 / 26 (23.08%)
         occurrences all number
    6
    6
    Mouth haemorrhage
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Oral pain
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    Pancreatitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Rectal fissure
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Toothache
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    5 / 22 (22.73%)
    5 / 26 (19.23%)
         occurrences all number
    5
    6
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Hepatomegaly
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 22 (13.64%)
    4 / 26 (15.38%)
         occurrences all number
    3
    4
    Jaundice
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    Dry skin
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Erythema
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Petechiae
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Ingrowing nail
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Purpura
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Rash
         subjects affected / exposed
    5 / 22 (22.73%)
    4 / 26 (15.38%)
         occurrences all number
    5
    4
    Rash macular
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Rash maculo-papular
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 26 (11.54%)
         occurrences all number
    3
    3
    Rash morbilliform
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Skin disorder
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Skin lesion
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Skin mass
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Dysuria
         subjects affected / exposed
    6 / 22 (27.27%)
    1 / 26 (3.85%)
         occurrences all number
    6
    1
    Haematuria
         subjects affected / exposed
    5 / 22 (22.73%)
    3 / 26 (11.54%)
         occurrences all number
    5
    3
    Glycosuria
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Ketonuria
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Micturition disorder
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Oliguria
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Proteinuria
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 26 (7.69%)
         occurrences all number
    3
    3
    Renal impairment
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    Urinary retention
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Back pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Bone pain
         subjects affected / exposed
    5 / 22 (22.73%)
    2 / 26 (7.69%)
         occurrences all number
    5
    2
    Limb discomfort
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Osteopenia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    5 / 22 (22.73%)
    3 / 26 (11.54%)
         occurrences all number
    5
    3
    Pain in jaw
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    BK virus infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Bacteraemia
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Bacterial infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Cellulitis orbital
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Cytomegalovirus viraemia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Device related infection
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Herpes simplex
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Human polyomavirus infection
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Oral herpes
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pneumonia fungal
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Sinusitis
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Staphylococcal bacteraemia
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Staphylococcal infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    Streptococcal sepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Urethritis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Varicella
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 26 (11.54%)
         occurrences all number
    4
    4
    Fluid overload
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Electrolyte imbalance
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    2
    2
    Fluid retention
         subjects affected / exposed
    5 / 22 (22.73%)
    4 / 26 (15.38%)
         occurrences all number
    5
    4
    Hyperglycaemia
         subjects affected / exposed
    4 / 22 (18.18%)
    3 / 26 (11.54%)
         occurrences all number
    5
    3
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Hypomagnesaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Malnutrition
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Aug 2008
    Addition of safety assessments to be performed every 5-7 days during the extended IV or oral treatment period and on the last day of voriconazole dosing and flexibility in urine pregnancy test (the serum pregnancy test can be used instead).

    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
    For support, Contact us.
    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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