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    Clinical Trial Results:
    The effect of dicloxacillin on oral absorption of drugs

    Summary
    EudraCT number
    		 2021-003814-37
    Trial protocol
    		 DK  
    Global end of trial date
    21 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jun 2023
    First version publication date
    08 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AKF-400
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05073627
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Southern Denmark
    Sponsor organisation address
    J.B. Winsløws Vej 19, 2nd floor, Odense, Denmark,
    Public contact
    Clinical Pharmacology and Pharmacy, Clinical Pharmacology, Pharmacy and Environmental Medicine, University of Southern Denmark, +45 65502352 , dbiversen@health.sdu.dk
    Scientific contact
    Clinical Pharmacology and Pharmacy, Clinical Pharmacology, Pharmacy and Environmental Medicine, University of Southern Denmark, +45 65502352 , dbiversen@health.sdu.dk
    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
    13 Apr 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim of this study is to investigate if treatment with dicloxacillin can lead to drug-drug interactions through induction of the efflux transporter P-glycoprotein (P-gp).
    Protection of trial subjects
    Trial subjects were asked about adverse events during the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 2021
    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
    Denmark: 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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    12
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 We recruited healthy men and women from January 2022 until June 2022. All trial subjects consented to participate in the trial. If in- and exclusion criteria were fulfilled trial subjects were randomized to start in period A or period B. Based on In- and exclusion criteria a medical doctor decided if trial subjects could participate in the trial

    Pre-assignment
    Screening details
    		 Trial subjects were screened based on in and exclusion criteria. A medical doctor decided if trial subjects full-filled the criteria and could enter the trial.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Baseline
    Arm description
    		 We measured the baseline level of P-gp without intake of dicloxacillin. All trial subjects worked as their own control. 5 people started in the Baseline period before entering the treatment period, and 5 people started in the treatment period before entering the Baseline period. It has been stated later that 12 people completed the trial. This is not correct. 10 people completed the trial and 2 left due to non-fatal adverse events. Due to an error message, it has not been possible to write this correctly in the boxes below.
    Arm type
    		 No administration of drugs

    Investigational medicinal product name
    Dabigatran etexilate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg of dabigatran etexilate was administered to trial subjects after fasting.

    Number of subjects in period 1
    		Baseline
    Started
    12
    Completed
    12
    Period 2
    Period 2 title
    Dicloxacillin
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Dicloxacillin
    Arm description
    		 Trial subjects ingested dicloxacillin for 30 days. We measured induction of P-gp at 10 days and 28 days. All trial subjects worked as their own control. 5 people started in the Baseline period before entering the treatment period, and 5 people started in the treatment period before entering the Baseline period. It has been stated later that 12 people completed the trial. This is not correct. 10 people completed the trial and 2 left due to non-fatal adverse events. Due to an error message, it has not been possible to write this correctly in the boxes below.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dicloxacillin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    During the trial, trial subjects ingested 1 gram dicloxacillin 3 times daily.

    Number of subjects in period 2
    		Dicloxacillin
    Started
    12
    Completed
    12

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 12 12
    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)
    		 12 12
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 24 (23 to 25) -
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 7 7

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 We measured the baseline level of P-gp without intake of dicloxacillin. All trial subjects worked as their own control. 5 people started in the Baseline period before entering the treatment period, and 5 people started in the treatment period before entering the Baseline period. It has been stated later that 12 people completed the trial. This is not correct. 10 people completed the trial and 2 left due to non-fatal adverse events. Due to an error message, it has not been possible to write this correctly in the boxes below.
    Reporting group title
    Dicloxacillin
    Reporting group description
    		 Trial subjects ingested dicloxacillin for 30 days. We measured induction of P-gp at 10 days and 28 days. All trial subjects worked as their own control. 5 people started in the Baseline period before entering the treatment period, and 5 people started in the treatment period before entering the Baseline period. It has been stated later that 12 people completed the trial. This is not correct. 10 people completed the trial and 2 left due to non-fatal adverse events. Due to an error message, it has not been possible to write this correctly in the boxes below.

    Primary: Change in AUC of dabigatran after 28 days of treatment

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    End point title
    		 Change in AUC of dabigatran after 28 days of treatment
    End point description
    Reporting group 1 is the change in AUC between baseline and 10 days of dicloxacillin Reporting group 2 is the change in AUC between baseline and 28 days of dicloxacillin
    End point type
    Primary
    End point timeframe
    At baseline and 28 days of dicloxacillin treatment
    End point values
    		 Baseline Dicloxacillin
    Number of subjects analysed
    10
    10
    Units: Geometric mean ratio
    geometric mean (confidence interval 95%)
        Dabigatran
    0.67 (0.42 to 1.1)
    0.72 (0.39 to 1.4)
        Dabigatran etexilate
    0.32 (0.13 to 0.79)
    0.62 (0.17 to 2.3)
    Statistical analysis title
    		 Geometric mean ratio
    Statistical analysis description
    There were 10 subjects in this analysis as the study was self-controlled
    Comparison groups
    Baseline v Dicloxacillin
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 > 0.05
    Method
    		 No p-value
    Confidence interval
    Notes
    [1] - We did not calculate p-values, but instead, the confidence interval 95%. If the geometric mean ration contained 1, it was not considered statistically significant.

    Secondary: Change in Cmax of the dabigatran and dabigatran etexilate

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    End point title
    		 Change in Cmax of the dabigatran and dabigatran etexilate
    End point description
    End point type
    Secondary
    End point timeframe
    Comparing data from baseline until day 10 and 28 of dicloxacillin treatment
    End point values
    		 Baseline Dicloxacillin
    Number of subjects analysed
    10
    10
    Units: Geometric mean ratio
    geometric mean (confidence interval 95%)
        Dabigatran
    0.69 (0.40 to 1.2)
    0.71 (0.31 to 1.7)
        Dabigatran etexilate
    0.43 (0.23 to 0.82)
    0.78 (0.35 to 1.8)
    Statistical analysis title
    		 Geometric mean ratio
    Statistical analysis description
    There were 10 subjects in this analysis as the study was self-controlled
    Comparison groups
    Baseline v Dicloxacillin
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05 [2]
    Method
    		 No p-value
    Confidence interval
    Notes
    [2] - We did not calculate the p-value. instead we calculated the 95% confidence interval. If the geometric mean ratio CI 95% contained 1 it was not considered statistical signific

    Secondary: Change in T1/2 of the dabigatran and dabigatran etexilate

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    End point title
    		 Change in T1/2 of the dabigatran and dabigatran etexilate
    End point description
    End point type
    Secondary
    End point timeframe
    Measuring baseline and comparing to 10 and 28 days of dicloxacillin treatment
    End point values
    		 Baseline Dicloxacillin
    Number of subjects analysed
    10
    10
    Units: Geometric mean ratio
    geometric mean (confidence interval 95%)
        Dabigatran
    0.95 (0.80 to 1.1)
    0.99 (0.72 to 1.4)
    Statistical analysis title
    		 Geometric mean ratio
    Statistical analysis description
    There were 10 subjects in this analysis as the study was self-controlled
    Comparison groups
    Baseline v Dicloxacillin
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05 [3]
    Method
    		 No p-value
    Confidence interval
    Notes
    [3] - We did not calculate the p-value. instead we calculated the 95% confidence interval. If the geometric mean ratio CI 95% contained 1 it was not considered statistical signific

    Secondary: Change in formation clearance of the dabigatran

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    End point title
    		 Change in formation clearance of the dabigatran
    End point description
    End point type
    Secondary
    End point timeframe
    Measuring baseline and comparing to 10 and 28 days of dicloxacillin treatment
    End point values
    		 Baseline Dicloxacillin
    Number of subjects analysed
    10
    10
    Units: Geometric mean ratio
    geometric mean (confidence interval 95%)
        Dabigatran
    1.5 (0.95 to 2.4)
    1.4 (0.74 to 2.6)
    Statistical analysis title
    		 Geometric mean ratio
    Statistical analysis description
    There were 10 subjects in this analysis as the study was self-controlled
    Comparison groups
    Baseline v Dicloxacillin
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05 [4]
    Method
    		 No p-value
    Confidence interval
    Notes
    [4] - We did not calculate the p-value. instead we calculated the 95% confidence interval. If the geometric mean ratio CI 95% contained 1 it was not considered statistical signific

    Secondary: change in renal clearance of the dabigatran

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    End point title
    		 change in renal clearance of the dabigatran
    End point description
    End point type
    Secondary
    End point timeframe
    Measuring baseline and comparing to 10 and 28 days of flucloxacillin treatment
    End point values
    		 Baseline Dicloxacillin
    Number of subjects analysed
    10
    10
    Units: Geometric mean ratio
    geometric mean (confidence interval 95%)
        Dabigatran
    1.0 (0.96 to 1.1)
    1.0 (0.86 to 1.2)
    Statistical analysis title
    		 Geometric mean ratio
    Statistical analysis description
    There were 10 subjects in this analysis as the study was self-controlled
    Comparison groups
    Baseline v Dicloxacillin
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05 [5]
    Method
    		 No p-value
    Confidence interval
    Notes
    [5] - We did not calculate the p-value. instead we calculated the 95% confidence interval. If the geometric mean ratio CI 95% contained 1 it was not considered statistical signific

    Secondary: Change in Ae (around in urine) of the dabigatran

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    End point title
    		 Change in Ae (around in urine) of the dabigatran
    End point description
    End point type
    Secondary
    End point timeframe
    Measuring baseline and comparing to 10 and 28 days of dicloxacillin treatment
    End point values
    		 Baseline Dicloxacillin
    Number of subjects analysed
    10
    10
    Units: Geometric mean ratio
    geometric mean (confidence interval 95%)
        Dabigatran
    0.68 (0.43 to 1.1)
    0.70 (0.34 to 1.4)
    Statistical analysis title
    		 Geometric mean ratio
    Statistical analysis description
    There were 10 subjects in this analysis as the study was self-controlled
    Comparison groups
    Baseline v Dicloxacillin
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05 [6]
    Method
    		 No p-value
    Confidence interval
    Notes
    [6] - We did not calculate the p-value. instead we calculated the 95% confidence interval. If the geometric mean ratio CI 95% contained 1 it was not considered statistical signific

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were were reported from intake of medicine in the trial and 2 weeks after the last dose
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Ingesting Dicloxacillin
    Reporting group description
    		 -

    Serious adverse events
    		 Ingesting Dicloxacillin
    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
    		 Ingesting Dicloxacillin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 12 (91.67%)
    General disorders and administration site conditions
    Pain in esophagus
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Heartburn
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 12 (58.33%)
         occurrences all number
    7
    Discomfort
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Stomach pain
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Dyspepsia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Infections and infestations
    Vaginal yeast infection
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Urinary tract infection
         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
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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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