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    Clinical Trial Results:
    A Phase 2, Open-Label, Non-Comparative Clinical Trial to Study the Safety and Efficacy of Posaconazole (POS, MK-5592) in Pediatric Participants Aged 2 to Less Than 18 Years With Invasive Aspergillosis

    Summary
    EudraCT number
    		 2019-002267-10
    Trial protocol
    		 HU   Outside EU/EEA   GR   BE   IT  
    Global end of trial date
    18 Dec 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 Mar 2025
    First version publication date
    15 Jun 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    5592-104
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04218851
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, Rahway, NJ, United States, P.O. Box 2000
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@msd.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@msd.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000468-PIP01-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Dec 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Dec 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will evaluate the safety, efficacy, and pharmacokinetics of posaconazole (POS) intravenous (IV) and oral formulations in pediatric participants 2 to <18 years of age with invasive aspergillosis (IA).
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jul 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Belgium: 6
    Worldwide total number of subjects
    31
    EEA total number of subjects
    9
    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)
    14
    Adolescents (12-17 years)
    17
    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
    		 Male or female participants with a diagnosis of possible, probable, or proven invasive aspergillosis (IA) aged 2 to <18 years were enrolled in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Age Cohort 1 (2 -< 12 years old)
    Arm description
    		 On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Posaconazole intravenous (IV)
    Investigational medicinal product code
    Other name
    MK-5592 SCH 056592 Noxafil®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Posaconazole (POS) 6 mg/kg body weight by IV infusion.

    Investigational medicinal product name
    Posaconazole tablet
    Investigational medicinal product code
    Other name
    MK-5592 SCH 056592 Noxafil®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    POS tablet 300 mg taken orally. Administered to participants >40 kg.

    Investigational medicinal product name
    Posaconazole gastro-resistant powder and solvent for oral suspension formulation (PFS)
    Investigational medicinal product code
    Other name
    MK-5592 SCH 056592 Noxafil®
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing based on weight-band. Administered to participants ≤40 kg.

    Arm title
    		 Age Cohort 2 (12 -< 18 years old)
    Arm description
    		 On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Posaconazole IV
    Investigational medicinal product code
    Other name
    MK-5592 SCH 056592 Noxafil®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    POS 6 mg/kg body weight by IV infusion.

    Investigational medicinal product name
    Posaconazole PFS
    Investigational medicinal product code
    Other name
    MK-5592 SCH 056592 Noxafil®
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing based on weight-band. Administered to participants ≤40 kg.

    Investigational medicinal product name
    Posaconazole tablet
    Investigational medicinal product code
    Other name
    MK-5592 SCH 056592 Noxafil®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    POS tablet 300 mg taken orally. Administered to participants >40 kg

    Number of subjects in period 1
    		Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old)
    Started
    14
    17
    Completed
    13
    14
    Not completed
    1
    3
         Adverse event, serious fatal
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Age Cohort 1 (2 -< 12 years old)
    Reporting group description
    		 On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation.

    Reporting group title
    Age Cohort 2 (12 -< 18 years old)
    Reporting group description
    		 On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation.

    Reporting group values
    		 Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old) Total
    Number of subjects
    		 14 17 31
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 14 0 14
        Adolescents (12-17 years)
    		 0 17 17
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.9 ( 2.7 ) 14.5 ( 1.7 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 7 1 8
        Male
    		 7 16 23
    Race
    Units: Subjects
        Asian
    		 3 5 8
        Multiple
    		 2 4 6
        White
    		 9 8 17
    Ethnicity
    Units: Subjects
        Hispanic Or Latino
    		 2 5 7
        Not Hispanic Or Latino
    		 12 12 24

    End points

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    End points reporting groups
    Reporting group title
    Age Cohort 1 (2 -< 12 years old)
    Reporting group description
    		 On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation.

    Reporting group title
    Age Cohort 2 (12 -< 18 years old)
    Reporting group description
    		 On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation.

    Subject analysis set title
    All participants (Ages 2 - < 18 years old)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    ‌On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation.

    Subject analysis set title
    Age Cohort 1 (2 -< 12 years old)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation

    Subject analysis set title
    Age Cohort 2 (12 -< 18 years old
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation.

    Subject analysis set title
    Age Cohorts 1 and 2 (2 -< 18 years old)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral (PFS or tablet) formulation, or they may remain on the IV formulation.

    Subject analysis set title
    Age Cohort 1 (2 -< 12 years old): IV formulation
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral (PFS or tablet) formulation, or they may remain on the IV formulation.

    Subject analysis set title
    Age Cohort 1 (2 -< 12 years old): PFS formulation
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral (PFS or tablet) formulation, or they may remain on the IV formulation.

    Subject analysis set title
    Age Cohort 1 (2 -< 12 years old): Tablet formulation
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral (PFS or tablet) formulation, or they may remain on the IV formulation.

    Subject analysis set title
    Age Cohort 2 (12 -< 18 years old): IV formulation
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral (PFS or tablet) formulation, or they may remain on the IV formulation.

    Subject analysis set title
    Age Cohort 2 (12 -< 18 years old): PFS formulation
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral (PFS or tablet) formulation, or they may remain on the IV formulation.

    Subject analysis set title
    Age Cohort 2 (12 -< 18 years old): Tablet formulation
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral (PFS or tablet) formulation, or they may remain on the IV formulation.

    Primary: Percentage of participants who experience one or more treatment-related adverse events (AEs)

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    End point title
    		 Percentage of participants who experience one or more treatment-related adverse events (AEs) [1]
    End point description
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. Treatment-related AEs were determined by the investigator to be related to the drug. The 95% confidence interval (CI) was based on the exact binomial method by Clopper- Pearson. The population analyzed consisted of all enrolled participants who received at least 1 dose of study treatment, regardless of their IA classification.
    End point type
    Primary
    End point timeframe
    Up to 14 days after treatment (up to Day 102)
    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: Statistical comparisons between treatment groups were neither planned nor performed for this primary endpoint.
    End point values
    		 Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old)
    Number of subjects analysed
    14
    17
    Units: Percentage of participants
        number (confidence interval 95%)
    14.3 (1.8 to 42.8)
    29.4 (10.3 to 56.0)
    No statistical analyses for this end point

    Secondary: Percentage of participants who have a favorable global clinical response through week 6

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    End point title
    		 Percentage of participants who have a favorable global clinical response through week 6
    End point description
    A global clinical response is assessed by the investigator as favorable if the participant is alive and has a complete response (CR) or partial response (PR). CR is defined as survival within the prespecified period of observation, resolution of all attributable symptoms and signs of disease, resolution of radiological lesion(s), and documented clearance of infected sites that are accessible to repeated sampling. PR is defined as survival within the prespecified period of observation, improvement in attributable symptoms and signs of disease, improvement of radiological lesion(s), and evidence of clearance of infected sites that are accessible to repeated sampling. The population analyzed was participants who have possible, probable, or proven IA; receive at least 1 dose of study treatment; have at least 1 post-allocation observation subsequent to at least 1 dose of study treatment; and have baseline data for those analyses that require baseline data.
    End point type
    Secondary
    End point timeframe
    Up to week 6
    End point values
    		 Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old)
    Number of subjects analysed
    14
    17
    Units: Percentage of participants
    number (not applicable)
        Success, Complete Response
    42.9
    17.6
        Success, Partial Response
    21.4
    52.9
    No statistical analyses for this end point

    Secondary: Percentage of participants who have a favorable global clinical response through week 12

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    End point title
    		 Percentage of participants who have a favorable global clinical response through week 12
    End point description
    A global clinical response is assessed by the investigator as favorable if the participant is alive and has a complete response (CR) or partial response (PR). CR is defined as survival within the prespecified period of observation, resolution of all attributable symptoms and signs of disease, resolution of radiological lesion(s), and documented clearance of infected sites that are accessible to repeated sampling. PR is defined as survival within the prespecified period of observation, improvement in attributable symptoms and signs of disease, improvement of radiological lesion(s), and evidence of clearance of infected sites that are accessible to repeated sampling. The population analyzed was participants who have possible, probable, or proven IA; receive at least 1 dose of study treatment; have at least 1 post-allocation observation subsequent to at least 1 dose of study treatment; and have baseline data for those analyses that require baseline data.
    End point type
    Secondary
    End point timeframe
    Up to week 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old)
    Number of subjects analysed
    14
    17
    Units: Percentage of participants
    number (not applicable)
        Success, Complete Response
    57.1
    41.2
        Success, Partial Response
    21.4
    35.3
    No statistical analyses for this end point

    Secondary: Percentage of participants who have a relapse of invasive aspergillosis (IA) at any point after achieving favorable global clinical response

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    End point title
    		 Percentage of participants who have a relapse of invasive aspergillosis (IA) at any point after achieving favorable global clinical response
    End point description
    In participants who achieved favorable global clinical response relapse of IA is defined as the re-emergence of clinical, radiographic, or other relevant abnormalities indicating IA. The population analyzed was participants who have possible, probable, or proven IA; receive at least 1 dose of study treatment; have at least 1 post-allocation observation subsequent to at least 1 dose of study treatment; have baseline data for those analyses that require baseline data; and who have achieved a favorable global clinical response at the end of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 28 days post-treatment (up to Day 116)
    End point values
    		 Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old)
    Number of subjects analysed
    12
    13
    Units: Percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Average plasma concentration (Cavg) of POS by age cohorts

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    End point title
    		 Average plasma concentration (Cavg) of POS by age cohorts
    End point description
    Steady state Cavg was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Cavg parameter values (1 for IV dosing, 1 for oral dosing). The population analyzed was all treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each age cohort, as well as the pooled age cohorts.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old Age Cohorts 1 and 2 (2 -< 18 years old)
    Number of subjects analysed
    13
    15
    28
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    2590 ( 50.8 )
    2770 ( 55.4 )
    2700 ( 53.0 )
    No statistical analyses for this end point

    Secondary: Minimum plasma concentration (Cmin) of POS by age cohorts

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    End point title
    		 Minimum plasma concentration (Cmin) of POS by age cohorts
    End point description
    Steady state Cmin was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Cmin parameter values (1 for IV dosing, 1 for oral dosing). The population analyzed was all treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each age cohort, as well as the pooled age cohorts.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old Age Cohorts 1 and 2 (2 -< 18 years old)
    Number of subjects analysed
    13
    15
    28
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    1610 ( 66.3 )
    1920 ( 63.9 )
    1790 ( 64.7 )
    No statistical analyses for this end point

    Secondary: Time to reach Cmax (Tmax) of POS by age cohorts

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    End point title
    		 Time to reach Cmax (Tmax) of POS by age cohorts
    End point description
    Steady state Tmax was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Tmax parameter values (1 for IV dosing, 1 for oral dosing). The population analyzed was all treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each age cohort, as well as the pooled age cohorts.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old Age Cohorts 1 and 2 (2 -< 18 years old)
    Number of subjects analysed
    13
    15
    28
    Units: hr
        median (full range (min-max))
    1.68 (1.25 to 7.10)
    1.63 (1.30 to 7.40)
    1.63 (1.25 to 7.40)
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve over the dosing interval (AUCtau) of POS by age cohorts

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    End point title
    		 Area under the concentration-time curve over the dosing interval (AUCtau) of POS by age cohorts
    End point description
    Steady state AUCtau was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 AUCtau parameter values (1 for IV dosing, 1 for oral dosing). The population analyzed was all treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each age cohort, as well as the pooled age cohorts.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old Age Cohorts 1 and 2 (2 -< 18 years old)
    Number of subjects analysed
    13
    15
    28
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    62200 ( 50.8 )
    66400 ( 55.4 )
    64700 ( 53.0 )
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (Cmax) of POS by age cohorts

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    End point title
    		 Maximum plasma concentration (Cmax) of POS by age cohorts
    End point description
    Steady state Cmax was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Cmax parameter values (1 for IV dosing, 1 for oral dosing). The population analyzed was all treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each age cohort, as well as the pooled age cohorts.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old) Age Cohort 2 (12 -< 18 years old Age Cohorts 1 and 2 (2 -< 18 years old)
    Number of subjects analysed
    13
    15
    28
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    3620 ( 48.5 )
    3610 ( 53.7 )
    3610 ( 51.0 )
    No statistical analyses for this end point

    Secondary: Average plasma concentration (Cavg) of POS by formulation

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    End point title
    		 Average plasma concentration (Cavg) of POS by formulation
    End point description
    Steady-state Cavg was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N > 2. The population analyzed was all treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each POS formulation.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old): IV formulation Age Cohort 1 (2 -< 12 years old): PFS formulation Age Cohort 1 (2 -< 12 years old): Tablet formulation Age Cohort 2 (12 -< 18 years old): IV formulation Age Cohort 2 (12 -< 18 years old): PFS formulation Age Cohort 2 (12 -< 18 years old): Tablet formulation
    Number of subjects analysed
    10
    6
    0 [2]
    13
    0 [3]
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    2900 ( 51.6 )
    2070 ( 38.0 )
    ( )
    2860 ( 45.8 )
    ( )
    2500 ( 72.7 )
    Notes
    [2] - Per protocol, summary statistics were not calculated where N are 2 or less values.
    [3] - Per protocol, summary statistics were not calculated where N are 2 or less values.
    No statistical analyses for this end point

    Secondary: Minimum plasma concentration (Cmin) of POS by formulation

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    End point title
    		 Minimum plasma concentration (Cmin) of POS by formulation
    End point description
    Steady-state Cmin was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N > 2. The population analyzed was all treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each POS formulation.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old): IV formulation Age Cohort 1 (2 -< 12 years old): PFS formulation Age Cohort 1 (2 -< 12 years old): Tablet formulation Age Cohort 2 (12 -< 18 years old): IV formulation Age Cohort 2 (12 -< 18 years old): PFS formulation Age Cohort 2 (12 -< 18 years old): Tablet formulation
    Number of subjects analysed
    10
    6
    0 [4]
    13
    0 [5]
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    1680 ( 74.8 )
    1410 ( 44.8 )
    ( )
    1820 ( 56.5 )
    ( )
    1910 ( 80.5 )
    Notes
    [4] - Per protocol, summary statistics were not calculated where N are 2 or less values.
    [5] - Per protocol, summary statistics were not calculated where N are 2 or less values.
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (Cmax) of POS by formulation

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    End point title
    		 Maximum plasma concentration (Cmax) of POS by formulation
    End point description
    Steady-state Cmax was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N > 2. The population analyzed was all treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each POS formulation.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old): IV formulation Age Cohort 1 (2 -< 12 years old): PFS formulation Age Cohort 1 (2 -< 12 years old): Tablet formulation Age Cohort 2 (12 -< 18 years old): IV formulation Age Cohort 2 (12 -< 18 years old): PFS formulation Age Cohort 2 (12 -< 18 years old): Tablet formulation
    Number of subjects analysed
    10
    6
    0 [6]
    13
    0 [7]
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    4530 ( 39.2 )
    2510 ( 36.3 )
    ( )
    4180 ( 38.8 )
    ( )
    2880 ( 69.3 )
    Notes
    [6] - Per protocol, summary statistics were not calculated where N are 2 or less values.
    [7] - Per protocol, summary statistics were not calculated where N are 2 or less values.
    No statistical analyses for this end point

    Secondary: Area under the concentration time curve over the dosing interval (AUCtau) of POS by formulation

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    End point title
    		 Area under the concentration time curve over the dosing interval (AUCtau) of POS by formulation
    End point description
    Steady-state AUCtau was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N > 2. The population analyzed was all treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each POS formulation.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old): IV formulation Age Cohort 1 (2 -< 12 years old): PFS formulation Age Cohort 1 (2 -< 12 years old): Tablet formulation Age Cohort 2 (12 -< 18 years old): IV formulation Age Cohort 2 (12 -< 18 years old): PFS formulation Age Cohort 2 (12 -< 18 years old): Tablet formulation
    Number of subjects analysed
    10
    6
    0 [8]
    13
    0 [9]
    10
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    69600 ( 51.6 )
    49700 ( 38.0 )
    ( )
    68600 ( 45.8 )
    ( )
    60100 ( 72.7 )
    Notes
    [8] - Per protocol, summary statistics were not calculated where N are 2 or less values.
    [9] - Per protocol, summary statistics were not calculated where N are 2 or less values.
    No statistical analyses for this end point

    Secondary: Time to reach Cmax (Tmax) of POS by formulation

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    End point title
    		 Time to reach Cmax (Tmax) of POS by formulation
    End point description
    Steady-state Tmax was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N > 2. The population analyzed was all treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each POS formulation.
    End point type
    Secondary
    End point timeframe
    Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
    End point values
    		 Age Cohort 1 (2 -< 12 years old): IV formulation Age Cohort 1 (2 -< 12 years old): PFS formulation Age Cohort 1 (2 -< 12 years old): Tablet formulation Age Cohort 2 (12 -< 18 years old): IV formulation Age Cohort 2 (12 -< 18 years old): PFS formulation Age Cohort 2 (12 -< 18 years old): Tablet formulation
    Number of subjects analysed
    10
    6
    0 [10]
    13
    0 [11]
    10
    Units: hr
        median (full range (min-max))
    1.50 (1.25 to 1.77)
    7.00 (6.50 to 7.10)
    ( to )
    1.50 (1.30 to 1.63)
    ( to )
    7.20 (6.90 to 7.40)
    Notes
    [10] - Per protocol, summary statistics were not calculated where N are 2 or less values.
    [11] - Per protocol, summary statistics were not calculated where N are 2 or less values.
    No statistical analyses for this end point

    Secondary: Percentage of participants with different categories of palatability after last day of treatment with the POS PFS formulation

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    End point title
    		 Percentage of participants with different categories of palatability after last day of treatment with the POS PFS formulation
    End point description
    Palatability was categorized on the last day (Day 85) on PFS based on responses by participants to a palatability questionnaire. Per protocol participants were pooled into a single treatment group Palatability categories for taste are as follows: Very good; Good; Very bad; Neither good nor bad. The population analyzed was participants who completed the palatability questionnaire. Per protocol participants were pooled into a single treatment group
    End point type
    Secondary
    End point timeframe
    Last day of PFS treatment (Day 85)
    End point values
    		 All participants (Ages 2 - < 18 years old)
    Number of subjects analysed
    10
    Units: Percentage of participants
    number (not applicable)
        Very Good
    10
        Good
    40
        Very bad
    10
        Neither good nor bad
    40
    No statistical analyses for this end point

    Secondary: Percentage of participants with different categories of palatability after first day of treatment with the POS PFS formulation

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    End point title
    		 Percentage of participants with different categories of palatability after first day of treatment with the POS PFS formulation
    End point description
    Palatability was categorized on the first (Day 8) and last (up to Day 84) day on PFS based on responses by participants to a palatability questionnaire. Palatability categories for taste are as follows: Very good; Good; Very bad; Neither good nor bad. The population analyzed was participants who completed the palatability questionnaire. Per protocol participants were pooled into a single treatment group.
    End point type
    Secondary
    End point timeframe
    First day of PFS treatment (Day 8)
    End point values
    		 All participants (Ages 2 - < 18 years old)
    Number of subjects analysed
    10
    Units: Percentage of participants
    number (not applicable)
        Very good First Day on PFS
    20.0
        Good First Day on PFS
    40.0
        Very bad First Day on PFS
    10.0
        Neither good nor bad First Day on PFS
    30.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality (ACM): from enrollment up to Day 114, and included those reported beyond the final Day 114 study visit. Adverse events (AEs); from treatment up to 14 days after treatment (up to Day 102).
    Adverse event reporting additional description
    ACM population analyzed was all enrolled participants. AE population analyzed was all enrolled participants who received at least 1 dose of study treatment, regardless of their IA classification.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Age Cohort 2 (12 -< 18 years old)
    Reporting group description
    		 -

    Reporting group title
    Age Cohort 1 (2 -< 12 years old)
    Reporting group description
    		 -

    Serious adverse events
    		 Age Cohort 2 (12 -< 18 years old) Age Cohort 1 (2 -< 12 years old)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 17 (47.06%)
    4 / 14 (28.57%)
         number of deaths (all causes)
    4
    2
         number of deaths resulting from adverse events
    3
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemic infiltration extramedullary
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Administration site extravasation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (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
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis bacterial
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral sepsis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Age Cohort 2 (12 -< 18 years old) Age Cohort 1 (2 -< 12 years old)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 17 (82.35%)
    12 / 14 (85.71%)
    Vascular disorders
    Vena cava thrombosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    5 / 17 (29.41%)
    3 / 14 (21.43%)
         occurrences all number
    5
    5
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 14 (7.14%)
         occurrences all number
    3
    1
    Feeling hot
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Hypothermia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Infusion site thrombosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    6 / 17 (35.29%)
    3 / 14 (21.43%)
         occurrences all number
    6
    14
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Genital pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Testicular pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 14 (14.29%)
         occurrences all number
    1
    4
    Haemoptysis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Hyperventilation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    Wheezing
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    Cough
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Depressed mood
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Delirium
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 14 (0.00%)
         occurrences all number
    7
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 14 (0.00%)
         occurrences all number
    7
    0
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Liver function test increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Platelet count decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Weight increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Infusion related reaction
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Procedural pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Spinal compression fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Bradycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    Tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Dysgeusia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 14 (0.00%)
         occurrences all number
    5
    0
    Neuralgia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    Febrile neutropenia
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 14 (7.14%)
         occurrences all number
    2
    1
    Lymphocytosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Myelosuppression
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    Oculogyric crisis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 14 (28.57%)
         occurrences all number
    2
    7
    Haematochezia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Anal fissure
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Colitis
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Constipation
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 14 (14.29%)
         occurrences all number
    1
    2
    Diarrhoea
         subjects affected / exposed
    2 / 17 (11.76%)
    3 / 14 (21.43%)
         occurrences all number
    2
    3
    Haematemesis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Lip dry
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    4 / 17 (23.53%)
    1 / 14 (7.14%)
         occurrences all number
    5
    2
    Neutropenic colitis
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    1
    2
    Rectal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 14 (7.14%)
         occurrences all number
    2
    1
    Vomiting
         subjects affected / exposed
    7 / 17 (41.18%)
    3 / 14 (21.43%)
         occurrences all number
    12
    3
    Mouth haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Cholestasis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Hepatotoxicity
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Rash papular
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    2
    Hyperhidrosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    Dysuria
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    Bladder spasm
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Acute kidney injury
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Hydronephrosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Urinary retention
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Renal tubular disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Renal haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Pyelocaliectasis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Pollakiuria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Nephropathy toxic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Nephrolithiasis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Kidney enlargement
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 14 (0.00%)
         occurrences all number
    6
    0
    Back pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Flank pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 14 (7.14%)
         occurrences all number
    3
    1
    Pain in extremity
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Urinary tract infection viral
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Adenovirus infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Adenovirus interstitial nephritis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    BK virus infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Cytomegalovirus urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Device related infection
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    Herpes zoster
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Infectious disease carrier
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Nail infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Rhinitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Sepsis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Viraemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Viral haemorrhagic cystitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Viruria
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 14 (14.29%)
         occurrences all number
    3
    2
    Hyperglycaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 14 (14.29%)
         occurrences all number
    1
    2
    Hypocalcaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    2
    Hypoproteinaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2020
    Amendment 01: To remove the device-related adverse event reporting language and the Future Biomedical Research (FBR) substudy from the protocol
    21 Jan 2021
    Amendment 02: To provide details for IV dosing requirements; to clarify procedures (ie, ECG and diagnostic imaging) in the Schedule of Activities; to clarify maximum blood volume and method for calculating creatinine clearance; to remove pregnancy exclusion to avoid potential confusion with the pregnancy criteria in the list of inclusions; and to update informed consent text to align with current informed consent/assent procedures.
    10 Nov 2022
    Amendment 04: To revise exclusion criteria to include the specific K values used in the modified Schwartz formula for males of different ages.

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

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