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    Clinical Trial Results:
    An Open Label, Non-Randomised, Phase IV Clinical Trial to Determine the Transfer of Apixaban and Rivaroxaban in Breast Milk Following Oral Administration

    Summary
    EudraCT number
    		 2018-003852-19
    Trial protocol
    		 GB  
    Global end of trial date
    07 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Mar 2021
    First version publication date
    28 Mar 2021
    Other versions
    Summary report(s)
    		 Clinical Study report

    Trial information

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    Trial identification
    Sponsor protocol code
    DOAC
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Roopen Arya, King's College London, +44 02032993570, roopen.arya@nhs.net
    Scientific contact
    Roopen Arya, King's College London, +44 02032993570, roopen.arya@nhs.net
    Sponsor organisation name
    King's College Hospital NHS Foundation Trust
    Sponsor organisation address
    Denmark Hill, London, United Kingdom, SE5 9RS
    Public contact
    Roopen Arya, King's college Hospital NHS Foundation Trust, +44 02032993570, roopen.arya@nhs.net
    Scientific contact
    Roopen Arya, King's college Hospital NHS Foundation Trust, +44 02032993570, roopen.arya@nhs.net
    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
    15 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if apixaban and rivaroxaban are excreted in breastmilk following single dose oral administration to breastfeeding mothers.
    Protection of trial subjects
    Subjects had the right to withdraw from the study at any time for any reason.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jan 2020
    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: 3
    Worldwide total number of subjects
    3
    EEA total number of subjects
    3
    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)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Potential study subjects were invited to participate in this trial via multiple routes, such as advertisements post on websites, and invitation letters enclosed with PIS sent to those women who had delivered their babies at King’s College Hospital NHS Foundation Trust in the preceding year, and had been administrated LMWH during pregnancy.

    Pre-assignment
    Screening details
    		 The assessment included participant’s age, duration of gestation, date of delivery, feeding regimen (exclusive breastfeeding or mixed feeding), smoking history, alcohol history, medical history, ongoing medication, blood pressure, and pulse. Laboratory tests were performed,including haematology tests,biochemistry tests,pregnancy test, and serology.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Apixaban
    Arm description
    		 5 mg of Apixaban (Eliquis®)(twice daily)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apixaban
    Investigational medicinal product code
    Other name
    Eliquis
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 5 mg (twice daily).

    Arm title
    		 Rivaroxaban
    Arm description
    		 Rivaroxaban 20mg (once daily)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    Other name
    Xarelto
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 20mg (once daily)

    Number of subjects in period 1
    		Apixaban Rivaroxaban
    Started
    1
    2
    Completed
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Apixaban
    Reporting group description
    		 5 mg of Apixaban (Eliquis®)(twice daily)

    Reporting group title
    Rivaroxaban
    Reporting group description
    		 Rivaroxaban 20mg (once daily)

    Reporting group values
    		 Apixaban Rivaroxaban Total
    Number of subjects
    		 1 2 3
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 1 2 3
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 1 2 3
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Apixaban
    Reporting group description
    		 5 mg of Apixaban (Eliquis®)(twice daily)

    Reporting group title
    Rivaroxaban
    Reporting group description
    		 Rivaroxaban 20mg (once daily)

    Primary: Concentration in milk

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    End point title
    		 Concentration in milk [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    0 to 24 hours
    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: Due to the nature of the study, descriptive statistics will be used to analyse the data and describe the study population.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the nature of the study, descriptive statistics will be used to analyse the data and describe the study population.
    End point values
    		 Rivaroxaban
    Number of subjects analysed
    2
    Units: ng/ml
    arithmetic mean (standard deviation)
        2.5 hours
    83.29 ( 2.81 )
        6 hours
    51.14 ( 12.24 )
        10 hours
    27.47 ( 3.97 )
        12 hours
    19.78 ( 2.47 )
        24 hours
    7.09 ( 10.03 )
    No statistical analyses for this end point

    Primary: Concentration in milk

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    End point title
    		 Concentration in milk [3] [4]
    End point description
    End point type
    Primary
    End point timeframe
    0 to 24 hours
    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: Due to the nature of the study, descriptive statistics will be used to analyse the data and describe the study population.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the nature of the study, descriptive statistics will be used to analyse the data and describe the study population.
    End point values
    		 Apixaban
    Number of subjects analysed
    1
    Units: ng/ml
    number (not applicable)
        3.5 hours
    229.78
        hours
    108.99
        12 hours
    38.18
        14 hours
    219.64
        16 hours
    168.98
        24 hours
    48.89
    No statistical analyses for this end point

    Primary: Concentration in plasma

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    End point title
    		 Concentration in plasma [5] [6]
    End point description
    End point type
    Primary
    End point timeframe
    0 to 24 hours
    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: Due to the nature of the study, descriptive statistics will be used to analyse the data and describe the study population.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the nature of the study, descriptive statistics will be used to analyse the data and describe the study population.
    End point values
    		 Rivaroxaban
    Number of subjects analysed
    2
    Units: ng/ml
    arithmetic mean (standard deviation)
        2.5 hours
    325.37 ( 51.58 )
        6 hours
    153.41 ( 24.57 )
        10 hours
    101.05 ( 26.97 )
        12 hours
    92.52 ( 65.29 )
        24 hours
    30.83 ( 26.65 )
    No statistical analyses for this end point

    Primary: Concentration in plasma

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    End point title
    		 Concentration in plasma [7] [8]
    End point description
    End point type
    Primary
    End point timeframe
    0 to 24 hours
    Notes
    [7] - 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: Due to the nature of the study, descriptive statistics will be used to analyse the data and describe the study population.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the nature of the study, descriptive statistics will be used to analyse the data and describe the study population.
    End point values
    		 Apixaban
    Number of subjects analysed
    1
    Units: ng/ml
    number (not applicable)
        3.5 hours
    77.72
        7 hours
    31.89
        12 hours
    14.02
        14 hours
    115.34
        16 hours
    66.89
        24 hours
    20.50
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs will be reported from first dose until 24 hours following first dose.
    Adverse event reporting additional description
    AEs listed in the SmPC do not need to be reported.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Apixaban
    Reporting group description
    		 5 mg of Apixaban (Eliquis®)(twice daily)

    Reporting group title
    Rivaroxaban
    Reporting group description
    		 Rivaroxaban 20mg (once daily)

    Serious adverse events
    		 Apixaban Rivaroxaban
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Apixaban Rivaroxaban
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    Gastrointestinal disorders
    gum bleeding
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2019
    IMP change: Dabigatran changed to Apixaban. Change occurred prior to recruitment start.

    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.
    The final subject was unable to be recruited due to the COVID-19 pandemic.
    For support, Contact us.
    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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