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    Clinical Trial Results:
    The influence of CYP3A5 and ABCB1 genotype on the pharmacokinetics of twice daily Tacrolimus and Advagraf

    Summary
    EudraCT number
    		 2009-013461-25
    Trial protocol
    		 GB  
    Global end of trial date
    16 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Dec 2021
    First version publication date
    23 Dec 2021
    Other versions
    Summary report(s)
    		 Final Report
    Presentation

    Trial information

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    Trial identification
    Sponsor protocol code
    UK-02-RG-194_09.0098
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    St Georges Univerity of London
    Sponsor organisation address
    Cranmer Terrace, London, United Kingdom, SW17 0QT
    Public contact
    Prof MacPhee, St Georges Univerity of London, imacphee@sgul.ac.uk
    Scientific contact
    Prof MacPhee, St Georges Univerity of London, imacphee@sgul.ac.uk
    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
    29 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) Determine the influence of CYP3A5 and ABCB1 genotypes on Advagraf pharmacokinetics 2) Compare the influence of these genotypes on the comparison between Prograf and Advagraf pharmacokinetics
    Protection of trial subjects
    none
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Oct 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 64
    Worldwide total number of subjects
    64
    EEA total number of subjects
    64
    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)
    64
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of 75 stable kidney transplant patients who were screened and considered eligible for participation, 11 withdrew before the study began. Therefore, 64 patients enrolled.

    Pre-assignment
    Screening details
    		 Of 75 stable kidney transplant patients who were screened and considered eligible for participation, 11 withdrew before the study began. Therefore, 64 patients enrolled.

    Period 1
    Period 1 title
    period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    open labelled study

    Arms
    Arm title
    		 Tacrolimus
    Arm description
    		 All participants received Tacrolimus for 2 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    twice a day for 2 weeks

    Number of subjects in period 1
    		Tacrolimus
    Started
    64
    Completed
    64
    Period 2
    Period 2 title
    period 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    open labelled

    Arms
    Arm title
    		 Advagraf
    Arm description
    		 All participants received Advagraf
    Arm type
    		 Experimental

    Investigational medicinal product name
    Advagraf
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    once a day for 2 weeks

    Number of subjects in period 2
    		Advagraf
    Started
    64
    Completed
    64

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    period 1
    Reporting group description
    		 -

    Reporting group values
    		 period 1 Total
    Number of subjects
    		 64 64
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 64 64
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55 ( 13 ) -
    Gender categorical
    Units: Subjects
        Female
    		 21 21
        Male
    		 43 43
    Number of participants with Immunosuppression at baseline
    Units: Subjects
        Tacrolimus_Prograf
    		 48 48
        Tacrolimus_Adoport®
    		 16 16

    End points

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    End points reporting groups
    Reporting group title
    Tacrolimus
    Reporting group description
    		 All participants received Tacrolimus for 2 weeks
    Reporting group title
    Advagraf
    Reporting group description
    		 All participants received Advagraf

    Subject analysis set title
    CYP3A5 Expressers
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Individuals possessing at least one CYP3A5*1 allele (CYP3A5-expressers)

    Subject analysis set title
    CYP3A5*1 non-expressers
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    CYP3A5*3/*3 carriers (CYP3A5 non-expressers)

    Primary: Tacrolimus PK parameters - DOSE - according to their CYP3A5*3 genotypes

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    End point title
    		 Tacrolimus PK parameters - DOSE - according to their CYP3A5*3 genotypes
    End point description
    End point type
    Primary
    End point timeframe
    2 weeks
    End point values
    		 CYP3A5 Expressers CYP3A5*1 non-expressers
    Number of subjects analysed
    30
    34
    Units: mg/kg/day
        arithmetic mean (standard deviation)
    0.11 ( 0.05 )
    0.05 ( 0.03 )
    Statistical analysis title
    		 Dose
    Comparison groups
    CYP3A5 Expressers v CYP3A5*1 non-expressers
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Primary: Tacrolimus PK parameters - Cmax - according to their CYP3A5*3 genotypes

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    End point title
    		 Tacrolimus PK parameters - Cmax - according to their CYP3A5*3 genotypes
    End point description
    End point type
    Primary
    End point timeframe
    2 weeks
    End point values
    		 CYP3A5 Expressers CYP3A5*1 non-expressers
    Number of subjects analysed
    30
    34
    Units: µg/L/mg/Kg
        arithmetic mean (standard deviation)
    19.1 ( 10.6 )
    33.5 ( 13.8 )
    Statistical analysis title
    		 Cmax
    Comparison groups
    CYP3A5 Expressers v CYP3A5*1 non-expressers
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    4 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 All participants

    Serious adverse events
    		 Overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 64 (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
    		 Overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 64 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No serious adverse event was reported

    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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