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    Clinical Trial Results:
    Pharmacokinetic study in HIV infected patient receiving 1 tenofovir disoproxil fumarate (TDF): Investigation of systemic and intracellular interaction between TDF and abacavir, lamivudine or lopinavir/ritonavir

    Summary
    EudraCT number
    		 2004-000948-25
    Trial protocol
    		 ES  
    Global end of trial date
    07 Sep 2005

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2018
    First version publication date
    04 Apr 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    INTRANUCS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00335192
    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,
    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
    07 Sep 2005
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Sep 2005
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Sep 2005
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate if the co-administration of tenofovir disoxipropil fumarate (TDF) modifies intracelular levels of abacavir (ABC) and lamivudine
    Protection of trial subjects
    not specific
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jan 2005
    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: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    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)
    27
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study enrolled subjects who had been receiving a triple HAART regimen for more than 42.2 months (±8.2) including TDF 300 mg once daily, taken with food, 3TC 300 mg once daily or ABC 300 mg twice daily and a NNRTI (NVP 400 mg once daily) or a PI (LPV/r, 400/100 mg twice daily).

    Pre-assignment
    Screening details
    		 Twenty seven patients were included in the cross-sectional part of the study. Fourteen of them also participated in the longitudinal study.

    Period 1
    Period 1 title
    cross-sectional part
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: TDF + 3TC + LPV/r
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg once daily

    Investigational medicinal product name
    lamivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg once daily

    Investigational medicinal product name
    lopinavir/ritonavir (LPV/r)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400/100 mg twice daily

    Arm title
    		 Group 2: TDF + 3TC + NVP
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg once daily

    Investigational medicinal product name
    lamivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg once daily

    Investigational medicinal product name
    nevirapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg once daily

    Arm title
    		 Group 3: TDF + ABC + LPV/r
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg once daily

    Investigational medicinal product name
    Abacavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg twice daily

    Investigational medicinal product name
    lopinavir/ritonavir (LPV/r)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400/100 mg twice daily

    Arm title
    		 Group 4: TDF + ABC + NVP
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg once daily

    Investigational medicinal product name
    Abacavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg twice daily

    Investigational medicinal product name
    nevirapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg once daily

    Number of subjects in period 1
    		Group 1: TDF + 3TC + LPV/r Group 2: TDF + 3TC + NVP Group 3: TDF + ABC + LPV/r Group 4: TDF + ABC + NVP
    Started
    7
    8
    7
    5
    Completed
    7
    8
    7
    5
    Period 2
    Period 2 title
    longitudinal study
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: 3TC + LPV/r
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    lamibudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg/24 h

    Investigational medicinal product name
    lopinavir/ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    133.3/33.3 mg, 3 tablets/12 h

    Arm title
    		 Group 3: ABC + LPV/r
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    abacavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg/12 h

    Investigational medicinal product name
    lopinavir/ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    133.3/33.3 mg, 3 tablets/12 h

    Number of subjects in period 2 [1]
    		Group 1: 3TC + LPV/r Group 3: ABC + LPV/r
    Started
    7
    7
    Completed
    7
    7
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The study design was a cross sectional study followed by a longitudinal prospective study (after 4 weeks of TDF interruption). TDF was withdrawn for 4 weeks to assess pharmacokinetic interactions between TDF and ABC or 3TC only in patients under LPV/r (group 1 and 3) in order to avoid viral rebound during the dual therapy. So, patients starting the second period (longitudinal study) were less than those who were completed the preceding period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    cross-sectional part
    Reporting group description
    		 -

    Reporting group values
    		 cross-sectional part Total
    Number of subjects
    		 27 27
    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)
    		 27 27
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.8 ± 9.5 -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    Group 1: TDF + 3TC + LPV/r
    Reporting group description
    		 -

    Reporting group title
    Group 2: TDF + 3TC + NVP
    Reporting group description
    		 -

    Reporting group title
    Group 3: TDF + ABC + LPV/r
    Reporting group description
    		 -

    Reporting group title
    Group 4: TDF + ABC + NVP
    Reporting group description
    		 -
    Reporting group title
    Group 1: 3TC + LPV/r
    Reporting group description
    		 -

    Reporting group title
    Group 3: ABC + LPV/r
    Reporting group description
    		 -

    Subject analysis set title
    group A
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    3TC with LPV/r

    Subject analysis set title
    group B
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    3TC with NVP

    Subject analysis set title
    group C
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ABC with LPV/r

    Subject analysis set title
    group D
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ABC with NVP

    Subject analysis set title
    group E
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TFV with LPV/r

    Subject analysis set title
    group F
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TFV with NVP

    Primary: Plasma pharmacokinetic parameters of lamivudine in the presence of lopinavir/ritonavir or nevirapine: area under the curve

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    End point title
    		 Plasma pharmacokinetic parameters of lamivudine in the presence of lopinavir/ritonavir or nevirapine: area under the curve
    End point description
    End point type
    Primary
    End point timeframe
    week 4
    End point values
    		 group A group B
    Number of subjects analysed
    7
    8
    Units: ng.h/ml
        median (inter-quartile range (Q1-Q3))
    5748 (3932 to 7365)
    4974 (3707 to 7414)
    Statistical analysis title
    		 Geometric Mean Ratio
    Statistical analysis description
    Ratio of the geometric mean (GMR )
    Comparison groups
    group A v group B
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.491
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Plasma pharmacokinetic parameters of lamivudine in the presence of lopinavir/ritonavir or nevirapine: maximum concentration observed

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    End point title
    		 Plasma pharmacokinetic parameters of lamivudine in the presence of lopinavir/ritonavir or nevirapine: maximum concentration observed
    End point description
    End point type
    Primary
    End point timeframe
    week 4
    End point values
    		 group A group B
    Number of subjects analysed
    7
    8
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    2241 (2014 to 2299)
    1850 (1666 to 2599)
    Statistical analysis title
    		 Geometric Mean Ratio
    Statistical analysis description
    Ratio of the geometric mean (GMR )
    Comparison groups
    group A v group B
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.121
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Plasma pharmacokinetic parameters of lamivudine in the presence of lopinavir/ritonavir or nevirapine: residual concentration at the end of the dosing interval

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    End point title
    		 Plasma pharmacokinetic parameters of lamivudine in the presence of lopinavir/ritonavir or nevirapine: residual concentration at the end of the dosing interval
    End point description
    End point type
    Primary
    End point timeframe
    week 4
    End point values
    		 group A group B
    Number of subjects analysed
    7
    8
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    161 (62.0 to 178)
    84.3 (55.6 to 99.1)
    Statistical analysis title
    		 Geometric Mean Ratio
    Statistical analysis description
    Ratio of the geometric mean (GMR )
    Comparison groups
    group A v group B
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.232
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Plasma pharmacokinetic parameters of abacavir in the presence of lopinavir/ritonavir or nevirapine: area under the curve

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    End point title
    		 Plasma pharmacokinetic parameters of abacavir in the presence of lopinavir/ritonavir or nevirapine: area under the curve
    End point description
    End point type
    Primary
    End point timeframe
    week 4
    End point values
    		 group C group D
    Number of subjects analysed
    7
    5
    Units: ng.h/ml
        median (inter-quartile range (Q1-Q3))
    3630 (2248 to 3762)
    5257 (3868 to 7802)
    Statistical analysis title
    		 Geometric Mean Ratio
    Statistical analysis description
    Ratio of the geometric mean (GMR )
    Comparison groups
    group C v group D
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.048
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Plasma pharmacokinetic parameters of abacavir in the presence of lopinavir/ritonavir or nevirapine: maximum concentration observed

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    End point title
    		 Plasma pharmacokinetic parameters of abacavir in the presence of lopinavir/ritonavir or nevirapine: maximum concentration observed
    End point description
    End point type
    Primary
    End point timeframe
    week 4
    End point values
    		 group C group D
    Number of subjects analysed
    7
    5
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    1783 (954.9 to 1992)
    2665 (2173 to 3718)
    Statistical analysis title
    		 Geometric Mean Ratio
    Statistical analysis description
    Ratio of the geometric mean (GMR )
    Comparison groups
    group C v group D
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.012
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Plasma pharmacokinetic parameters of abacavir in the presence of lopinavir/ritonavir or nevirapine: residual concentration at the end of the dosing interval

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    End point title
    		 Plasma pharmacokinetic parameters of abacavir in the presence of lopinavir/ritonavir or nevirapine: residual concentration at the end of the dosing interval
    End point description
    End point type
    Primary
    End point timeframe
    week 4
    End point values
    		 group C group D
    Number of subjects analysed
    7
    5
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    42.4 (32.7 to 181)
    76.3 (56.5 to 135)
    Statistical analysis title
    		 Geometric Mean Ratio
    Statistical analysis description
    Ratio of the geometric mean (GMR )
    Comparison groups
    group C v group D
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.343
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Plasma pharmacokinetic parameters of tenofovir in the presence of lopinavir/ritonavir or nevirapine: area under the curve: area under the curve

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    End point title
    		 Plasma pharmacokinetic parameters of tenofovir in the presence of lopinavir/ritonavir or nevirapine: area under the curve: area under the curve
    End point description
    End point type
    Primary
    End point timeframe
    week 4
    End point values
    		 group E group F
    Number of subjects analysed
    14
    13
    Units: ng.h/ml
        median (inter-quartile range (Q1-Q3))
    1006 (612 to 1344)
    582.7 (456.7 to 811.7)
    Statistical analysis title
    		 Geometric Mean Ratio
    Statistical analysis description
    Ratio of the geometric mean (GMR )
    Comparison groups
    group E v group F
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.026
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Plasma pharmacokinetic parameters of tenofovir in the presence of lopinavir/ritonavir or nevirapine: maximum concentration observed

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    End point title
    		 Plasma pharmacokinetic parameters of tenofovir in the presence of lopinavir/ritonavir or nevirapine: maximum concentration observed
    End point description
    End point type
    Primary
    End point timeframe
    week 4
    End point values
    		 group E group F
    Number of subjects analysed
    14
    13
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    349.5 (228.2 to 453.4)
    252.1 (195.6 to 306.3)
    Statistical analysis title
    		 Geometric Mean Ratio
    Statistical analysis description
    Ratio of the geometric mean (GMR )
    Comparison groups
    group E v group F
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.033
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Plasma pharmacokinetic parameters of tenofovir in the presence of lopinavir/ritonavir or nevirapine: residual concentration at the end of the dosing interval

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    End point title
    		 Plasma pharmacokinetic parameters of tenofovir in the presence of lopinavir/ritonavir or nevirapine: residual concentration at the end of the dosing interval
    End point description
    End point type
    Primary
    End point timeframe
    week 4
    End point values
    		 group E group F
    Number of subjects analysed
    14
    13
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    96.7 (54.6 to 119)
    54.4 (33.5 to 62.1)
    Statistical analysis title
    		 Geometric Mean Ratio
    Statistical analysis description
    Ratio of the geometric mean (GMR )
    Comparison groups
    group E v group F
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.013
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    from baseline to week 4
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 DAIDS AE GRADING TAB
    Dictionary version
    1.0
    Frequency threshold for reporting non-serious adverse events: 1%
    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: non-serious adverse events were reported

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Feb 2005
    TDF withdrawal period extended

    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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