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    Clinical Trial Results:
    An Open Label, Non-Randomised, Phase II study to Determine if Dabigatran and its Metabolites are Detectable in Breast Milk Following Oral Administration to Non-Breastfeeding Mothers

    Summary
    EudraCT number
    		 2014-004249-29
    Trial protocol
    		 GB  
    Global end of trial date
    31 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Nov 2017
    First version publication date
    30 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DALMATION/7212
    Additional study identifiers
    ISRCTN number
    		 ISRCTN87845776
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Newcastle upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    Regent Point, Newcastle upon Tyne, United Kingdom,
    Public contact
    Ms Jenn Walker, Newcastle University, +44 01912082520, jenn.walker@newcastle.ac.uk
    Scientific contact
    Dr Paul Ayuk, Newcastle upon Tyne Hospitals NHS Foundation Trust, +44 0191 2829325, paul.ayuk@nuth.nhs.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
    28 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to determine if dabigatran and its metabolites are detectable in breast milk following oral administration to non-breast feeding mothers. Pregnancy and the post-partum period are recognised risk factors for venous thrombo-embolism (VTE). VTE is one of the most important causes of maternal mortality. Low molecular weight heparin (LMWH) is currently recommended for post-partum VTE prophylaxis. Dabigatran has approval for the prevention of VTE in patients who have undergone elective total hip or knee replacement surgery. The study will therefore calculate the pharmacokinetics of dabigatran (Tmax, Cmax, t1/2, AUC) in maternal plasma and breast milk to explore the extent of dabigatran secretion into breast milk in women between 2 and 7 days after giving birth. The study also aimed to develop an HPLC-MS assay to measure dabigatran concentrations in both plasma and breast milk following oral dosing of dabigatran.
    Protection of trial subjects
    The trial involved an independent Trial Oversight (TOC) committee to provide overall supervision for the trial on behalf of the Trial Sponsor and Trial Funder and to safeguard the interests of trial participants, monitor the main outcome measures including safety and efficacy, and monitor the overall conduct of the trial. The maternity unit at site is an accredited UNICEF baby friendly unit and the guidelines associated with this accreditation were followed. Recruitment was also conducted in line with principles of Good Clinical Practice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Nov 2015
    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: 2
    Worldwide total number of subjects
    2
    EEA total number of subjects
    2
    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)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was an open label, non-randomised, single centre, phase 2 study approaching participants from post-natal wards and Midwifery-led Units. Participants were recruited to the study between February 2016 and December 2016.

    Pre-assignment
    Screening details
    		 Potential participants were identified through screening medical records to identify women who had made an informed decision not to feed their baby with breast milk. Women were approached a minimum of 48 hours after delivery and also those who initially breastfed but had since stopped but within 7 days of giving birth were also screened.

    Pre-assignment period milestones
    Number of subjects started
    		 2
    Number of subjects completed
    		 2

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

    Arms
    Arm title
    		 Dabigatran
    Arm description
    		 -
    Arm type
    		 IMP

    Investigational medicinal product name
    Dabigatran
    Investigational medicinal product code
    Other name
    Pradaxa
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    a single dose of two 110mg dabigatran etexilate capsules (total 220mg) within 7 days post partum

    Number of subjects in period 1
    		Dabigatran
    Started
    2
    Completed
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dabigatran
    Reporting group description
    		 A single dose of two 110mg dabigatran etexilate capsules (total 220mg).

    Reporting group values
    		 Dabigatran Total
    Number of subjects
    		 2 2
    Age categorical
    Participant HR60 was 28 years of age at baseline. Participant HR61 was 36 years of age at baseline.
    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)
    		 2 2
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 0 0
    Height (metres)
    Participant HR60 was 171m Participant HR61 was 173m
    Units: Subjects
        N/A
    		 2 2
    Weight at booking (kg)
    Participant HR60 = 67 kg Participant HR61 = 62 kg
    Units: Subjects
        N/A
    		 2 2
    BMI at booking
    Participant HR60 BMI at booking = 22.9 Participant HR61 BMI at booking = 20.7
    Units: Subjects
        N/A
    		 2 2
    Ethnicity
    1 = Caucasian
    Units: Subjects
        N/A
    		 2 2
    Days post-partum
    Participant HR60 = 6 days post partum. Participant HR61 - 5 days post partum.
    Units: Subjects
        N/A
    		 2 2
    Serum creatinine
    Participant HR60 Serum creatinine = 48µM Participant HR61 Serum creatinine = 54µM
    Units: Subjects
        N/A
    		 2 2
    Serum Alanine Transaminase
    Participant HR60 Serum Alanine Transaminase= 23 IU Participant HR61 Serum Alanine Transaminase= 11 IU
    Units: Subjects
        N/A
    		 2 2

    End points

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    End points reporting groups
    Reporting group title
    Dabigatran
    Reporting group description
    		 -

    Primary: Dabigatran pharmacokinetics in plasma and breast milk

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    End point title
    		 Dabigatran pharmacokinetics in plasma and breast milk [1]
    End point description
    Dabigatran pharmacokinetic parameters in plasma and breast milk are presented. Dabigatran was detected in plasma 1h after dosing.
    End point type
    Primary
    End point timeframe
    Time to Dabigatran detection in 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 limited data descriptive statistics are presented.
    End point values
    		 Dabigatran
    Number of subjects analysed
    2
    Units: hours
    number (not applicable)
        Participant HR60 (plasma)
    1
        Participant HR61 (plasma)
    1
        Participant HR60 (breast milk)
    3
        Participant HR61 (breast milk)
    2
    Attachments
    		 Dabigatran pharmacokinetics
    Dabigatran Concentrations
    No statistical analyses for this end point

    Primary: Peak concentration of Dabigatran in plasma and breast milk (Cmax)

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    End point title
    		 Peak concentration of Dabigatran in plasma and breast milk (Cmax) [2]
    End point description
    Dabigatran pharmacokinetic parameters in plasma and breast milk are presented. Peak plasma dabigatran concentrations of 204.6 ng/ml in HR60 and 414.9 ng/ml in HR61 were reached between 2-3 hours following dabigatran administration.
    End point type
    Primary
    End point timeframe
    Peak concentration of Dabigatran following administration of drug.
    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: Due to limited data descriptive statistics are presented.
    End point values
    		 Dabigatran
    Number of subjects analysed
    2
    Units: ng/ml
    number (not applicable)
        Participant HR60 (Plasma)
    204.6
        Participant HR61 (Plasma)
    414.9
        Participant HR60 (Breast Milk)
    8.2
        Participant HR61 (Breast Milk)
    52.6
    No statistical analyses for this end point

    Primary: Tmax (hours) of Dabigatran concentration in plasma and breast milk

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    End point title
    		 Tmax (hours) of Dabigatran concentration in plasma and breast milk [3]
    End point description
    Dabigatran pharmacokinetic parameters in plasma and breast milk are presented. Peak plasma dabigatran concentrations of 204.6 ng/ml in HR60 and 414.9 ng/ml in HR61 were reached between 2-3 hours following dabigatran administration.
    End point type
    Primary
    End point timeframe
    Tmax (hours) of dabigatran pharmacokinetics in plasma and breast milk
    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 limited data descriptive statistics are presented.
    End point values
    		 Dabigatran
    Number of subjects analysed
    2
    Units: hours
    number (not applicable)
        Participant HR60 (Plasma)
    2
        Participant HR61 (Plasma)
    3
        Participant HR60 (Breast Milk)
    7
        Participant HR61 (Breast Milk)
    7
    No statistical analyses for this end point

    Primary: Observed Exposure to Dabigatran (AUC 0-t)

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    End point title
    		 Observed Exposure to Dabigatran (AUC 0-t) [4]
    End point description
    Dabigatran pharmacokinetic parameters in plasma and breast milk are presented.
    End point type
    Primary
    End point timeframe
    Observed Exposure to Dabigatran (AUC 0-t)
    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: Due to limited data descriptive statistics are presented.
    End point values
    		 Dabigatran
    Number of subjects analysed
    2
    Units: ng/ml.h
    number (not applicable)
        Participant HR60 (Plasma)
    752.7
        Participant HR61 (Plasma)
    1523
        Participant HR60 (Breast Milk)
    16
        Participant HR61 (Breast Milk)
    171
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All non-serious AEs/ARs that occur during drug treatment will be recorded on the eCRF, in the patient medical notes and also sent to the Newcastle CTU Management team within 2 weeks. All SAEs and SARs during drug treatment will be reported to Sponsor.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 As verbatim
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Dabigatran
    Reporting group description
    		 -

    Serious adverse events
    		 Dabigatran
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Dabigatran
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 2 (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 adverse events were reported for this trial.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jan 2016
    Change made to the location within the Newcastle Hospitals NHS Foundation Trust of where IMP would be assembled. The amendment was requested by NuTHFT pharmacy for logistical reasons. The drug label was therefore updated to reflect the change in address and phone number, which was classified as a substantial amendment to the MHRA
    25 Feb 2016
    Update to study recruitment strategies. Participants could also be approached at the point of discharge and be able to return to hospital for the treatment visit. The participant information sheet(s) updated to confirm an antidote is available for dabigatran which reverses the effect of heavy bleeding. The protocol was also updated to clearly define the Reference Safety Information to be used for the Dalmation trial.
    22 Mar 2016
    Praxbind was made available for use at the Royal Victoria Infirmary (RVI) Newcastle, via approval from the Haematology department. The protocol and participant documents were updated to include this as part of substantial amendment 2 made to REC. In line with the updated, it was requested that the SmPC for Pradaxa 110mg hard capsules dated 2nd March 2016 was to be approved for use for the Dalmation study. Although the risk of bleeding is extremely small, the use of the Praxbind for participants in the Dalmation study had been agreed with the Chief Investigator, Sponsor, Trial Oversight Committee (8th March 2016) and Haematology Department at the RVI.
    02 Jun 2016
    Change to study recruitment strategy: allowing for Participant Identification Centres (PICs) to help screen, identify and refer potentially eligible women to Newcastle RVI for study participation. Change to last breast milk/blood sample collection time: allowing for the last sample to be collected at either the 8, 9 or 10 hour time point after administration of the drug.
    07 Jul 2016
    Study was temporarily suspended on 23/06/16.
    16 Aug 2016
    Request to re-start study

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Jun 2016
    Study temporarily suspended due to serious breach. Susbtantial Amendment to restart the study was made on 16th August 2017. The study received MHRA approval to restart on 31/08/2016. Favourable ethical opinion was received on the 06/09/2016.
    06 Sep 2016

    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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