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    Clinical Trial Results:
    Once daily DArunavir/ritonavir in HIV-infected children 6-12 years old: a PHarmacokiNEtic validation of model-based dosing recommendations (DAPHNE)

    Summary
    EudraCT number
    		 2014-001111-39
    Trial protocol
    		 NL  
    Global end of trial date
    19 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2019
    First version publication date
    21 Sep 2019
    Other versions
    Summary report(s)
    		 DAPHNE paper

    Trial information

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    Trial identification
    Sponsor protocol code
    UMCN-AKF13.03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboudumc
    Sponsor organisation address
    Geert Grooteplein Zuid 10, Nijmegen, Netherlands,
    Public contact
    David Burger, Radboud University Medical Center, david.burger@radboudumc.nl
    Scientific contact
    David Burger, Radboud University Medical Center, david.burger@radboudumc.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To validate FDA-approved dosing recommendation for once daily DRV/r in children 6-12 years old. This will be done by evaluating the pharmacokinetics of DRV/r given once daily (according to FDA dosing guideline) to children from 6 – 12 years
    Protection of trial subjects
    The risk-classification is assessed as negligible to the patient population receiving study drug at the current regimens. The drug (darunavir) is licensed by the FDA for the use as investigated in this protocol. A rich sampling pharmacokinetic assessment, performed after switch to a once-daily regime, is part of current routine clinical practice for children who are treated with a antiretroviral drugs. There are no real risks involved. Anaemia because of PK sampling is unlikely, because the amount of blood that will be taken solely for study purposes is within the limits of international standards.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2014
    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
    Netherlands: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    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)
    12
    Adolescents (12-17 years)
    0
    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
    		 Twelve children were enrolled from four sites in the Netherlands.

    Pre-assignment
    Screening details
    		 Children (6–12 years of age) were eligible when they used darunavir/ritonavir once-daily for at least 2 weeks according to the approved dose.

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

    Arms
    Arm title
    		 DRV/rtv QD
    Arm description
    		 In this multicenter pharmacokinetic study in HIV-infected children (6–12 years of age), we validated the approved once-daily darunavir/ritonavir dosing recommendations.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    darunavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ≥ 15 kg to < 30 kg DRV 600 mg with ritonavir 100 mg ≥ 30 kg to < 40 kg DRV 675 mg with ritonavir 100 mg ≥ 40 kg DRV 800 mg with ritonavir 100 mg

    Number of subjects in period 1
    		DRV/rtv QD
    Started
    12
    Completed
    12
    Period 2
    Period 2 title
    PK sampling DRV/rtv QD
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 DRV/rtv QD
    Arm description
    		 Children were using DRV/rtv QD treatment dosed according to EMA approved SPC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    darunavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ≥ 15 kg to < 30 kg DRV 600 mg with ritonavir 100 mg ≥ 30 kg to < 40 kg DRV 675 mg with ritonavir 100 mg ≥ 40 kg DRV 800 mg with ritonavir 100 mg

    Number of subjects in period 2
    		DRV/rtv QD
    Started
    12
    Completed
    12
    Period 3
    Period 3 title
    adult data
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 daruanvir adult
    Arm description
    		 this is information from literature, therefore number of subjects is put in as 1 (start 12, as otherwise we get errors).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    darunavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    DRV 800 mg with ritonavir 100 mg, adult dose

    Number of subjects in period 3
    		daruanvir adult
    Started
    12
    Completed
    1
    Not completed
    11
         not applicable, lit data
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    screening
    Reporting group description
    		 -

    Reporting group values
    		 screening Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 8.9 (6.3 to 11.7) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 5 5

    End points

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    End points reporting groups
    Reporting group title
    DRV/rtv QD
    Reporting group description
    		 In this multicenter pharmacokinetic study in HIV-infected children (6–12 years of age), we validated the approved once-daily darunavir/ritonavir dosing recommendations.
    Reporting group title
    DRV/rtv QD
    Reporting group description
    		 Children were using DRV/rtv QD treatment dosed according to EMA approved SPC.
    Reporting group title
    daruanvir adult
    Reporting group description
    		 this is information from literature, therefore number of subjects is put in as 1 (start 12, as otherwise we get errors).

    Subject analysis set title
    DAPHNE
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients in the study

    Primary: AUC0-24

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    End point title
    		 AUC0-24
    End point description
    End point type
    Primary
    End point timeframe
    one day
    End point values
    		 DRV/rtv QD daruanvir adult
    Number of subjects analysed
    12
    1 [1]
    Units: mg*h/L
        geometric mean (geometric coefficient of variation)
    63.1 ± 33
    81 ± 30
    Notes
    [1] - literature data
    Statistical analysis title
    		 descriptive
    Statistical analysis description
    comparison of AUC values in children to adults.
    Comparison groups
    DRV/rtv QD v daruanvir adult
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.05 [3]
    Method
    		 t-test, 1-sided
    Parameter type
    		 none
    Confidence interval
    Notes
    [2] - comparison of AUC values in children to adults.
    [3] - not applicable

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    entire study
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    1
    Reporting groups
    Reporting group title
    DAPHNE
    Reporting group description
    		 -

    Serious adverse events
    		 DAPHNE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DAPHNE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 12 (8.33%)
    Psychiatric disorders
    hallucinations
    Additional description: One child suffered from anxiety starting 4 weeks after switch to drv/rtv and 2 weeks after PK assessment, resulting in hallucinations at 6 weeks after start. DRV/rtv was stopped and the child fully recovered wihtin 4 days after stop.
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29474261
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