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    Clinical Trial Results:
    Pharmacokinetic interactions between silymarin and Darunavir/Ritonavir

    Summary
    EudraCT number
    		 2010-021159-25
    Trial protocol
    		 ES  
    Global end of trial date
    20 Jul 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2018
    First version publication date
    05 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SILIDAR
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01346982
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fundació Lluita contra la SIDA
    Sponsor organisation address
    Crta de Canyet s/n, Badalona, Spain, 08916
    Public contact
    CRA, Fundació Lluita contra la SIDA, +34 93 497 84 14, sgel@flsida.org
    Scientific contact
    CRA, Fundació Lluita contra la SIDA, +34 93 497 84 14,
    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
    20 Jul 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jul 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the potential of silymarin to interact with a boosted protease inhibitor such as darunavir-ritonavir and to evaluate the risk associated of its joint intake in HIV-Infected patients.
    Protection of trial subjects
    not specific
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Mar 2011
    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
    Spain: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    0
    Adults (18-64 years)
    15
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 15 Caucasian HIV-infected males were enrolled.

    Pre-assignment
    Screening details
    		 All patients receiving antiretroviral therapy with darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were enrolled.

    Period 1
    Period 1 title
    overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Experimental arm
    Arm description
    		 darunavir-ritonavir plus one capsule containing 150 mg of silymarin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Darunavir/ritonavir (DRV/r)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600/100 mg twice daily

    Investigational medicinal product name
    silymarin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg of silymarin every 8 h from days 1 to 14

    Number of subjects in period 1
    		Experimental arm
    Started
    15
    Completed
    15

    Baseline characteristics

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

    Reporting group values
    		 overall Total
    Number of subjects
    		 15 15
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 15 15
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 48 (44 to 50) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 15 15

    End points

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    End points reporting groups
    Reporting group title
    Experimental arm
    Reporting group description
    		 darunavir-ritonavir plus one capsule containing 150 mg of silymarin

    Primary: darunavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin

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    End point title
    		 darunavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin [1]
    End point description
    End point type
    Primary
    End point timeframe
    week 12
    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: one single arm study
    End point values
    		 Experimental arm
    Number of subjects analysed
    15
    Units: area under the time-concent (mg*h/l)
    geometric mean (confidence interval 90%)
        DRV/r
    53.21 (46.03 to 61.38)
        DRV/r+silymarin
    45.6 (39.54 to 52.72)
    No statistical analyses for this end point

    Primary: darunavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin

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    End point title
    		 darunavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin [2]
    End point description
    End point type
    Primary
    End point timeframe
    week 12
    Notes
    [2] - 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: one single arm study
    End point values
    		 Experimental arm
    Number of subjects analysed
    15
    Units: maximum concentration (mg/l)
    geometric mean (confidence interval 90%)
        DRV/r
    7.08 (6.28 to 7.98)
        DRV/r+ silymarin
    5.86 (5.2 to 6.61)
    No statistical analyses for this end point

    Primary: darunavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin

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    End point title
    		 darunavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin [3]
    End point description
    End point type
    Primary
    End point timeframe
    week 12
    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: one single arm study
    End point values
    		 Experimental arm
    Number of subjects analysed
    15
    Units: concentration at the end (mg/l)
    geometric mean (confidence interval 90%)
        DRV/r
    2.58 (2.17 to 3.07)
        DRV/r+silymarin
    2.42 (2.04 to 2.87)
    No statistical analyses for this end point

    Primary: ritonavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin

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    End point title
    		 ritonavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin [4]
    End point description
    End point type
    Primary
    End point timeframe
    week 12
    Notes
    [4] - 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: one single arm study
    End point values
    		 Experimental arm
    Number of subjects analysed
    15
    Units: area under the time-concent (mg*h/l)
    geometric mean (confidence interval 90%)
        DRV/r+silymarin
    6 (5.19 to 6.93)
        DRV/r
    6.73 (5.82 to 7.8)
    No statistical analyses for this end point

    Primary: ritonavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin

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    End point title
    		 ritonavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin [5]
    End point description
    End point type
    Primary
    End point timeframe
    week 12
    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: one single arm study
    End point values
    		 Experimental arm
    Number of subjects analysed
    15
    Units: maximum concentration (mg/l)
    geometric mean (confidence interval 90%)
        DRV/r
    0.95 (0.8 to 1.12)
        DRV/r+silymarin
    0.86 (0.73 to 1.01)
    No statistical analyses for this end point

    Primary: ritonavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin

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    End point title
    		 ritonavir pharmacokinetic parameters with and without coadministration of multiple doses of silymarin [6]
    End point description
    End point type
    Primary
    End point timeframe
    week 12
    Notes
    [6] - 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: one single arm study
    End point values
    		 Experimental arm
    Number of subjects analysed
    15
    Units: concentration at the end (mg/l)
    geometric mean (confidence interval 90%)
        DRV/r
    0.24 (0.21 to 0.28)
        DRV/r+silymarin
    0.23 (0.19 to 0.26)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    week 12
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 DAIDS AE GRADING TAB
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    experimental group
    Reporting group description
    		 -

    Serious adverse events
    		 experimental group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 experimental group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 15 (6.67%)
    Gastrointestinal disorders
    mild heartburn
         subjects affected / exposed
    1 / 15 (6.67%)
         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
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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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