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    Clinical Trial Results:
    Open label, single arm safety prospective cohort study of dabigatran etexilate for secondary prevention of venous thromboembolism in children from 0 to less than 18 years

    Summary
    EudraCT number
    2014-000583-18
    Trial protocol
    ES   FI   AT   GR   IT   LT   CZ   BE   SK   SE   BG   FR   HU   DK   DE  
    Global end of trial date
    19 Nov 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    23 May 2020
    First version publication date
    23 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1160.108
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02197416
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000081-PIP01-11
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this paediatric prospective cohort trial is to assess the safety of dabigatran etexilate for secondary prevention of venous thromboembolism in children from 0 to less than 18 years of age.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 May 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Thailand: 2
    Country: Number of subjects enrolled
    Turkey: 17
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    United States: 29
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Czech Republic: 24
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Russian Federation: 59
    Worldwide total number of subjects
    231
    EEA total number of subjects
    86
    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)
    12
    Children (2-11 years)
    45
    Adolescents (12-17 years)
    174
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This open label, single arm prospective cohort study was designed to assess the safety of dabigatran etexilate (DE) for secondary prevention of paediatric venous thromboembolism (VTE) with 12-month (365 days) treatment period followed by 28 days end of treatment follow-up. Results of participants were reported via 3 mutually exclusive age groups.

    Pre-assignment
    Screening details
    All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. 1 enrolled subject was withdrawn before treated due to unable to swallow the capsules.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    dabigatran etexilate (0 to < 2 years)
    Arm description
    Single oral dose of dabigatran etexilate (DE) oral liquid formulation (OLF) ranging from 6.25 milligram(mg) to 143.75mg was administrated twice daily in the morning and evening for participants aged less than 12 months. Single oral dose of DE pellets ranging from 20mg to 330mg was administrated twice daily in the morning and evening for participants aged less than 8 years. Dosage of DE was adjusted by age and weight of participants intending to achieve trough plasma dabigatran concentrations between 50 and <250 nanogram(ng)/mL. The DE dose limit was 22.2 mg/kilogram (kg)/day.The maximal DE single dose was 330 mg. This arm includes participants aged between 0 to <2 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Dabigatran etexilate pellets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Single oral dose of DE pellets ranging from 20mg to 330mg was administrated twice daily in the morning and evening for participants aged less than 8 years. Dosage of DE was adjusted by age and weight of participants. Granules stands for pellets.

    Investigational medicinal product name
    Dabigatran etexilate oral liquid formulation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Single oral dose of dabigatran etexilate (DE) oral liquid formulation (OLF) ranging from 6.25 milligram(mg) to 143.75mg was administrated twice daily in the morning and evening for participants aged less than 12 months .Dosage of DE was adjusted by age and weight of participants.

    Arm title
    dabigatran etexilate (2 to <12 years)
    Arm description
    Single oral dose of DE pellets ranging from 20mg to 330mg was administrated twice daily in the morning and evening for participants aged less than 8 years and who cannot take capsules between 8 to <12 years. Single oral dose of DE capsule ranging from 50 mg to 330mg was administrated twice daily in the morning and evening for participants aged at least 8 years. Dosage of DE was adjusted by age and weight of participants intending to achieve trough plasma dabigatran concentrations between 50 and <250 ng/mL. The DE dose limit was 22.2 mg/kg/day.The maximal DE single dose was 330 mg. This arm includes participants aged between 2 to <12 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Dabigatran etexilate capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Single oral dose of DE capsule ranging from 50 mg to 330mg was administrated twice daily in the morning and evening for participants aged at least 8 years. Dosage of DE was adjusted by age and weight of participants

    Investigational medicinal product name
    Dabigatran etexilate pellets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Single oral dose of DE pellets ranging from 20mg to 330mg was administrated twice daily in the morning and evening for participants aged less than 8 years and who cannot take capsules between 8 to <12 years. Dosage of DE was adjusted by age and weight of participants. Granules stands for pellets.

    Arm title
    dabigatran etexilate (12 to <18 years)
    Arm description
    Single oral dose of DE capsule ranging from 50 mg to 330mg was administrated twice daily in the morning and evening for participants aged at least 8 years. Dosage of DE was adjusted by age and weight of participants intending to achieve trough plasma dabigatran concentrations between 50 and <250 ng/mL. The DE dose limit was 22.2 mg/kg/day.The maximal DE single dose was 330 mg. This arm includes participants aged between 12 to <18 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Dabigatran etexilate capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Single oral dose of DE capsule ranging from 50 mg to 330mg was administrated twice daily in the morning and evening for participants aged at least 8 years. Dosage of DE was adjusted by age and weight of participants.

    Number of subjects in period 1 [1]
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Started
    9
    43
    161
    Completed
    8
    39
    153
    Not completed
    1
    4
    8
         Protocol deviation
    1
    -
    1
         Adverse event, non-fatal
    -
    -
    1
         Consent withdrawn by subject
    -
    2
    1
         Other reasons
    -
    2
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The enrolled set included all patients with signed informed consent. The enrolled set was used for disposition summaries. The baseline characteristic were reported on the entered set including all patients with signed informed consent who were eligible to enter the trial, regardless whether they took trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    dabigatran etexilate (0 to < 2 years)
    Reporting group description
    Single oral dose of dabigatran etexilate (DE) oral liquid formulation (OLF) ranging from 6.25 milligram(mg) to 143.75mg was administrated twice daily in the morning and evening for participants aged less than 12 months. Single oral dose of DE pellets ranging from 20mg to 330mg was administrated twice daily in the morning and evening for participants aged less than 8 years. Dosage of DE was adjusted by age and weight of participants intending to achieve trough plasma dabigatran concentrations between 50 and <250 nanogram(ng)/mL. The DE dose limit was 22.2 mg/kilogram (kg)/day.The maximal DE single dose was 330 mg. This arm includes participants aged between 0 to <2 years.

    Reporting group title
    dabigatran etexilate (2 to <12 years)
    Reporting group description
    Single oral dose of DE pellets ranging from 20mg to 330mg was administrated twice daily in the morning and evening for participants aged less than 8 years and who cannot take capsules between 8 to <12 years. Single oral dose of DE capsule ranging from 50 mg to 330mg was administrated twice daily in the morning and evening for participants aged at least 8 years. Dosage of DE was adjusted by age and weight of participants intending to achieve trough plasma dabigatran concentrations between 50 and <250 ng/mL. The DE dose limit was 22.2 mg/kg/day.The maximal DE single dose was 330 mg. This arm includes participants aged between 2 to <12 years.

    Reporting group title
    dabigatran etexilate (12 to <18 years)
    Reporting group description
    Single oral dose of DE capsule ranging from 50 mg to 330mg was administrated twice daily in the morning and evening for participants aged at least 8 years. Dosage of DE was adjusted by age and weight of participants intending to achieve trough plasma dabigatran concentrations between 50 and <250 ng/mL. The DE dose limit was 22.2 mg/kg/day.The maximal DE single dose was 330 mg. This arm includes participants aged between 12 to <18 years.

    Reporting group values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years) Total
    Number of subjects
    9 43 161 213
    Age categorical
    The treated set (TS) included all patients who were dispensed trial medication and were documented to have taken at least one dose of investigational treatment.
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    9 0 0 9
        Children (2-11 years)
    0 43 0 43
        Adolescents (12-17 years)
    0 0 161 161
        Adults (18-64 years)
    0 0 0 0
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age Continuous
    The treated set (TS) included all patients who were dispensed trial medication and were documented to have taken at least one dose of investigational treatment.
    Units: years
        arithmetic mean (standard deviation)
    0.6 ± 0.5 6.8 ± 3.1 15.1 ± 1.6 -
    Sex: Female, Male
    The treated set (TS) included all patients who were dispensed trial medication and were documented to have taken at least one dose of investigational treatment.
    Units: Participants
        Female
    4 22 70 96
        Male
    5 21 91 117
    Race (NIH/OMB)
    The treated set (TS) included all patients who were dispensed trial medication and were documented to have taken at least one dose of investigational treatment.
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    0 1 6 7
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    0 4 4 8
        White
    8 37 149 194
        More than one race
    1 1 1 3
        Unknown or Not Reported
    0 0 1 1
    Ethnicity (NIH/OMB)
    The treated set (TS) included all patients who were dispensed trial medication and were documented to have taken at least one dose of investigational treatment.
    Units: Subjects
        Hispanic or Latino
    0 2 7 9
        Not Hispanic or Latino
    9 41 153 203
        Unknown or Not Reported
    0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    dabigatran etexilate (0 to < 2 years)
    Reporting group description
    Single oral dose of dabigatran etexilate (DE) oral liquid formulation (OLF) ranging from 6.25 milligram(mg) to 143.75mg was administrated twice daily in the morning and evening for participants aged less than 12 months. Single oral dose of DE pellets ranging from 20mg to 330mg was administrated twice daily in the morning and evening for participants aged less than 8 years. Dosage of DE was adjusted by age and weight of participants intending to achieve trough plasma dabigatran concentrations between 50 and <250 nanogram(ng)/mL. The DE dose limit was 22.2 mg/kilogram (kg)/day.The maximal DE single dose was 330 mg. This arm includes participants aged between 0 to <2 years.

    Reporting group title
    dabigatran etexilate (2 to <12 years)
    Reporting group description
    Single oral dose of DE pellets ranging from 20mg to 330mg was administrated twice daily in the morning and evening for participants aged less than 8 years and who cannot take capsules between 8 to <12 years. Single oral dose of DE capsule ranging from 50 mg to 330mg was administrated twice daily in the morning and evening for participants aged at least 8 years. Dosage of DE was adjusted by age and weight of participants intending to achieve trough plasma dabigatran concentrations between 50 and <250 ng/mL. The DE dose limit was 22.2 mg/kg/day.The maximal DE single dose was 330 mg. This arm includes participants aged between 2 to <12 years.

    Reporting group title
    dabigatran etexilate (12 to <18 years)
    Reporting group description
    Single oral dose of DE capsule ranging from 50 mg to 330mg was administrated twice daily in the morning and evening for participants aged at least 8 years. Dosage of DE was adjusted by age and weight of participants intending to achieve trough plasma dabigatran concentrations between 50 and <250 ng/mL. The DE dose limit was 22.2 mg/kg/day.The maximal DE single dose was 330 mg. This arm includes participants aged between 12 to <18 years.

    Primary: Event-free probability of recurrence of venous thromboembolism (VTE) at 6 and 12 months

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    End point title
    Event-free probability of recurrence of venous thromboembolism (VTE) at 6 and 12 months [1]
    End point description
    The event-free probability of first recurrence of VTE were provided by Kaplan-Meier estimation with its 95% confidence intervals (CIs) at 6 and 12 months. Patients who did not experience recurrent VTE at the time of analysis, dropped out from the trial early, were lost to follow-up, or had died from non-VTE related cause were considered as non-events and censored. On treatment period was from first DE administration to 3 days of residual effect period after last DE administration. The treated set (TS) included all patients who were dispensed trial medication and were documented to have taken at least one dose of investigational treatment. The treated set was used to assess safety endpoints
    End point type
    Primary
    End point timeframe
    At month 6 (Week 26) and 12 (Week 52) of on treatment period
    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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    9
    43
    161
    Units: Probability
    number (confidence interval 95%)
        6 months
    1.000 (1.000 to 1.000)
    1.000 (1.000 to 1.000)
    0.979 (0.937 to 0.993)
        12 months
    1.000 (1.000 to 1.000)
    1.000 (1.000 to 1.000)
    0.979 (0.937 to 0.993)
    No statistical analyses for this end point

    Primary: Event-free probability of major or minor (including Clinically relevant non-major (CRNM)) bleeding events at 6 and 12 months

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    End point title
    Event-free probability of major or minor (including Clinically relevant non-major (CRNM)) bleeding events at 6 and 12 months [2]
    End point description
    The event-free probability of major or minor (including CRNM) bleeding event were provided by Kaplan-Meier estimation with its 95% confidence intervals (CIs) at 6 and 12 months. Patients who did not experience major or minor (including CRNM) bleeding event at the time of analysis, dropped out from the trial early, were lost to follow-up, or had died from non-bleeding related cause were considered as non-events and censored. On treatment period was from first DE administration to 3 days of residual effect period after last DE administration. The treated set (TS) included all patients who were dispensed trial medication and were documented to have taken at least one dose of investigational treatment.
    End point type
    Primary
    End point timeframe
    At month 6 (Week 26) and month 12 (Week 52) of on treatment period
    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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    9
    43
    161
    Units: Probability
    number (confidence interval 95%)
        6 months
    0.889 (0.433 to 0.984)
    0.894 (0.706 to 0.965)
    0.753 (0.675 to 0.815)
        12 months
    0.889 (0.433 to 0.984)
    0.831 (0.592 to 0.936)
    0.691 (0.603 to 0.763)
    No statistical analyses for this end point

    Primary: Event-free probability of mortality overall and related to thrombotic or thromboembolic events at 6 and 12 months

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    End point title
    Event-free probability of mortality overall and related to thrombotic or thromboembolic events at 6 and 12 months [3]
    End point description
    The event-free probability of mortality overall and related to thrombotic or thromboembolic events were provided by Kaplan-Meier estimation with its 95% confidence intervals (CIs) at 6 and 12 months. Patients who did not experience mortality overall and related to thrombotic or thromboembolic events at the time of analysis, dropped out from the trial early, were lost to follow-up, were considered as non-events and censored. On treatment period was from first DE administration to 3 days of residual effect period after last DE administration. The treated set (TS) included all patients who were dispensed trial medication and were documented to have taken at least one dose of investigational treatment.
    End point type
    Primary
    End point timeframe
    At month 6 (Week 26) and 12 (Week 52) of on treatment period
    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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    9
    43
    161
    Units: Probability
    number (confidence interval 95%)
        6 months
    1.000 (1.000 to 1.000)
    1.000 (1.000 to 1.000)
    1.000 (1.000 to 1.000)
        12 months
    1.000 (1.000 to 1.000)
    1.000 (1.000 to 1.000)
    1.000 (1.000 to 1.000)
    No statistical analyses for this end point

    Secondary: Event-free probability of occurrence of post-thrombotic syndrome (PTS) at 6 and 12 months

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    End point title
    Event-free probability of occurrence of post-thrombotic syndrome (PTS) at 6 and 12 months
    End point description
    The event-free probability of PTS were provided by Kaplan-Meier estimation with its 95% confidence intervals (CIs) at 6 and 12 months. Patients who did not experience PTS at the time of analysis, dropped out from the trial early, were lost to follow-up, or had died from non-PTS related cause were considered as non-events and censored. On treatment period was from first DE administration to 3 days of residual effect period after last DE administration. The treated set (TS) included all patients who were dispensed trial medication and were documented to have taken at least one dose of investigational treatment.
    End point type
    Secondary
    End point timeframe
    At month 6 (Week 26) and 12 (Week 52) of on treatment period
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    9
    43
    161
    Units: Probability
    number (confidence interval 95%)
        6 months
    1.000 (1.000 to 1.000)
    1.000 (1.000 to 1.000)
    0.979 (0.935 to 0.993)
        12 months
    1.000 (1.000 to 1.000)
    1.000 (1.000 to 1.000)
    0.979 (0.935 to 0.993)
    No statistical analyses for this end point

    Secondary: Percentage of participants with dabigatran etexilate (DE) dose adjustments during on treatment period

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    End point title
    Percentage of participants with dabigatran etexilate (DE) dose adjustments during on treatment period
    End point description
    On treatment period was from first DE administration to 3 days of residual effect period after last DE administration. The treated set (TS) included all patients who were dispensed trial medication and were documented to have taken at least one dose of investigational treatment.
    End point type
    Secondary
    End point timeframe
    From first DE administration to 3 days of residual effect period after last DE administration, up to 52 weeks+ 3 days
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    9
    43
    161
    Units: Percentage of participants
        number (not applicable)
    66.7
    39.5
    21.1
    No statistical analyses for this end point

    Secondary: Central measurement of Activated partial thromboplastin time (aPTT) at Visit 3 (after at least six consecutive dabigatran etexilate (DE) doses)

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    End point title
    Central measurement of Activated partial thromboplastin time (aPTT) at Visit 3 (after at least six consecutive dabigatran etexilate (DE) doses)
    End point description
    The pharmacodynamics (PD) set (PDS) included all treated patients who provided at least one evaluable PD observation and had no protocol deviations relevant to the evaluation of PD endpoints. Only those with non-missing endpoint values were included in this analysis.
    End point type
    Secondary
    End point timeframe
    At Visit 3 (day 4 after first dose of trial medication)
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    8
    23
    105
    Units: Second (s)
        arithmetic mean (standard deviation)
    46.6 ± 18.1
    57.1 ± 70.4
    56.8 ± 64.6
    No statistical analyses for this end point

    Secondary: Central measurement of Activated partial thromboplastin time (aPTT) at post-titration (after at least 3 days following any dabigatran etexilate (DE) dose adjustment)

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    End point title
    Central measurement of Activated partial thromboplastin time (aPTT) at post-titration (after at least 3 days following any dabigatran etexilate (DE) dose adjustment)
    End point description
    The pharmacodynamics (PD) set (PDS) included all treated patients who provided at least one evaluable PD observation and had no protocol deviations relevant to the evaluation of PD endpoints. Only those with non-missing endpoint values were included in this analysis.
    End point type
    Secondary
    End point timeframe
    Pharmacodynamics (PD) samples were collected from first dose of trial medication at day 1 and day 4, 22, 43, 85, 127, 183, 239, and 295 until last dose at day 365 and at post-titration (at least 3 days after dose adjustment) if needed, up to 365 days.
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    6
    16
    31
    Units: Second (s)
        arithmetic mean (standard deviation)
    49.1 ± 26.8
    57.3 ± 23.9
    59.0 ± 80.8
    No statistical analyses for this end point

    Secondary: Central measurement of Ecarin clotting time (ECT) at Visit 3 (after at least six consecutive dabigatran etexilate (DE) doses)

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    End point title
    Central measurement of Ecarin clotting time (ECT) at Visit 3 (after at least six consecutive dabigatran etexilate (DE) doses)
    End point description
    The pharmacodynamics (PD) set (PDS) included all treated patients who provided at least one evaluable PD observation and had no protocol deviations relevant to the evaluation of PD endpoints. Only those with non-missing endpoint values were included in this analysis.
    End point type
    Secondary
    End point timeframe
    At Visit 3 (day 4 after first dose of trial medication)
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    8
    24
    105
    Units: Second (s)
        arithmetic mean (standard deviation)
    52.7 ± 17.6
    64.3 ± 55.7
    69.5 ± 30.3
    No statistical analyses for this end point

    Secondary: Central measurement of Ecarin clotting time (ECT) at post-titration (after at least 3 days following any dabigatran etexilate (DE) dose adjustment)

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    End point title
    Central measurement of Ecarin clotting time (ECT) at post-titration (after at least 3 days following any dabigatran etexilate (DE) dose adjustment)
    End point description
    The pharmacodynamics (PD) set (PDS) included all treated patients who provided at least one evaluable PD observation and had no protocol deviations relevant to the evaluation of PD endpoints. Only those with non-missing endpoint values were included in this analysis.
    End point type
    Secondary
    End point timeframe
    PD samples were collected from first dose of trial medication at day 1 and day 4, 22, 43, 85, 127, 183, 239, and 295 until last dose at day 365 and at post-titration (at least 3 days after dose adjustment) if needed, up to 365 days.
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    6
    16
    32
    Units: Second (s)
        arithmetic mean (standard deviation)
    53.3 ± 19.4
    66.6 ± 23.6
    69.2 ± 28.7
    No statistical analyses for this end point

    Secondary: Central measurement of Diluted thrombin time (dTT) at Visit 3 (after at least six consecutive dabigatran etexilate (DE) doses)

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    End point title
    Central measurement of Diluted thrombin time (dTT) at Visit 3 (after at least six consecutive dabigatran etexilate (DE) doses)
    End point description
    The pharmacodynamics (PD) set (PDS) included all treated patients who provided at least one evaluable PD observation and had no protocol deviations relevant to the evaluation of PD endpoints. Only those with non-missing endpoint values were included in this analysis.
    End point type
    Secondary
    End point timeframe
    At Visit 3 (day 4 after first dose of trial medication)
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    8
    17
    64
    Units: Second (s)
        arithmetic mean (standard deviation)
    37.9 ± 19.5
    40.5 ± 14.6
    45.3 ± 17.4
    No statistical analyses for this end point

    Secondary: Central measurement of Diluted thrombin time (dTT) at post-titration (after at least 3 days following any dabigatran etexilate (DE) dose adjustment)

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    End point title
    Central measurement of Diluted thrombin time (dTT) at post-titration (after at least 3 days following any dabigatran etexilate (DE) dose adjustment)
    End point description
    The pharmacodynamics (PD) set (PDS) included all treated patients who provided at least one evaluable PD observation and had no protocol deviations relevant to the evaluation of PD endpoints. Only those with non-missing endpoint values were included in this analysis.
    End point type
    Secondary
    End point timeframe
    dTT values were collected at day 4, 22, 43, 85, 127, 183, 239, and 295 until last dose at day 365 and at post-titration (at least 3 days after dose adjustment) if needed, up to 365 days.
    End point values
    dabigatran etexilate (0 to < 2 years) dabigatran etexilate (2 to <12 years) dabigatran etexilate (12 to <18 years)
    Number of subjects analysed
    6
    12
    26
    Units: Second (s)
        arithmetic mean (standard deviation)
    40.0 ± 24.3
    46.0 ± 18.6
    43.4 ± 17.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose until end of trial + 28 days of follow-up, up to 52 weeks+28 days for all cause death. From first dose until last dose of study drug + 3 days of residual effect period, up to 52 weeks + 3 days for other adverse events.
    Adverse event reporting additional description
    The treated set (TS) included all patients who were dispensed trial medication and had taken at least 1 dose of investigational treatment, which was used to assess safety endpoints. The adverse events were reported with single arm align with the study design.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Dabigatran etexilate
    Reporting group description
    Single oral dose of dabigatran etexilate (DE) oral liquid formulation (OLF) ranging from 6.25 milligram(mg) to 143.75 mg was administrated twice daily in the morning and evening for participants aged less than 12 months. Single oral dose of DE pellets ranging from 20mg to 330mg was administrated twice daily in the morning and evening for participants aged less than 8 years. Single oral dose of DE capsule ranging from 50 mg to 330mg was administrated twice daily in the morning and evening for participants aged at least 8 years. Dosage of DE was adjusted by age and weight of participants intending to achieve trough plasma dabigatran concentrations between 50 and <250 ng/mL. The DE dose limit was 22.2 mg/kg/day.The maximal DE single dose was 330 mg.

    Serious adverse events
    Dabigatran etexilate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 213 (14.08%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Bleeding varicose vein
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lupus vasculitis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Phlebitis superficial
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ewing's sarcoma recurrent
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Post-traumatic stress disorder
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Menstrual disorder
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic adhesions
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Animal bite
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metal poisoning
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular pre-excitation
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Congenital anomaly
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic vein stenosis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Lupus nephritis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulpitis dental
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Dabigatran etexilate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    113 / 213 (53.05%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 213 (6.57%)
         occurrences all number
    17
    Epistaxis
         subjects affected / exposed
    14 / 213 (6.57%)
         occurrences all number
    17
    Nervous system disorders
    Headache
         subjects affected / exposed
    34 / 213 (15.96%)
         occurrences all number
    54
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    15 / 213 (7.04%)
         occurrences all number
    20
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    15 / 213 (7.04%)
         occurrences all number
    21
    Abdominal pain upper
         subjects affected / exposed
    13 / 213 (6.10%)
         occurrences all number
    13
    Dyspepsia
         subjects affected / exposed
    15 / 213 (7.04%)
         occurrences all number
    18
    Nausea
         subjects affected / exposed
    17 / 213 (7.98%)
         occurrences all number
    25
    Vomiting
         subjects affected / exposed
    15 / 213 (7.04%)
         occurrences all number
    17
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    11 / 213 (5.16%)
         occurrences all number
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 213 (5.16%)
         occurrences all number
    14
    Pain in extremity
         subjects affected / exposed
    13 / 213 (6.10%)
         occurrences all number
    17
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 213 (6.57%)
         occurrences all number
    14
    Nasopharyngitis
         subjects affected / exposed
    34 / 213 (15.96%)
         occurrences all number
    54

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2014
    With Global Amendment 1, recruitment of patients with a body weight >40 kg was temporarily suspended. It was projected that, because of the performed capping of the maximum single starting dose at 220 mg, a considerable proportion of patients with a body weight >40 kg will have dabigatran plasma levels falling below 50 ng/mL. Of note, with Global Amendment 2 (see below) a two times daily regimen using actual calculated dosages (according to Hayton equation) was implemented instead of capped dosages.
    28 Jan 2015
    A twice daily dosing regimen using actual calculated dosages (according to Hayton equation) was implemented. This dosing regimen also included the additional safeguard of up- or down-titration to achieve a trough plasma level of 50 to <250 ng/mL. The temporary suspension of recruitment of patients with a body weight >40 kg was terminated. It was explained that the maximal daily dose level does neither exceed a daily dose level of 22.2 mg/kg nor a single dose of 330 mg, resulting in a maximal daily dose of 660 mg in the higher age/body weight group. With this amendment, only one dose adjustment was allowed. Consequently, patients not reaching the target trough plasma concentrations after one dose adjustment were to discontinue DE and were to receive subsequently SoC at the investigator’s discretion. The extent of up-titration was modified from initially 85 - 100% to 15 -100% to not exceed maximum daily dosages based on acceptable toxicology limits. Dosing and dose adjustment nomograms were incorporated in Appendix 10.4 of the CTP. It was clarified that patients aged 6 months to <8 years and those who cannot take capsule were to receive pellets while patients aged 0 to <6 months and those who cannot take pellets at an age of 6 to <12 months were to receive OLF. For clarification, it was added to inclusion criterion 2 that patients who were switched from DE to the SoC arm during the treatment phase of trial 1160.106 for any reason were not eligible for this trial. An additional exclusion criterion was introduced: Patients in age group 0 to <2 years with gestational age at birth <37 weeks or with a body weight lower than the 3rd percentile (according to the WHO Child growth standards) were not to be entered in the trial. It was clarified that use of a specific reversal agent to counteract the antithrombotic activity of DE is allowed as soon as available in a framework of clinical investigation.
    27 Nov 2015
    The up-titration dosing nomograms for capsules and pellets were updated. It was stated that the dosing nomograms for the OLF will be revised as well in light of the errors identified for the capsule and pellet nomograms and to reflect the acceptable daily intake of tartaric acid. It was defined that this revision will be done before opening the youngest age group (0 to <2 years).
    16 Mar 2016
    The assessment of acceptability of all age-appropriate formulations (capsules, pellets, OLF) was added. Randomisation in a 1:1 ratio to an OLF with either a flavoured or an unflavoured solvent for reconstitution was introduced. A summary of the Phase I bioavailability trial 1160.194 was added to provide background information on the interchangeability of the different DE formulations. Information on the Phase IIa trial 1160.89 was updated. In the inclusion criteria, it was added that a temporary interruption of the anticoagulant therapy for the index VTE event or prior to the start of secondary VTE prophylaxis was acceptable, if one of the defined pre-requisites was met. In the exclusion criteria, it was clarified that central venous line insertion is not considered a major surgery and that patients with a history of asymptomatic petechial or microbleeds are eligible for the trial. The threshold when to remove patients from the trial because of low eGFR was decreased to <50 mL/min/1.73 m^2. The threshold for inclusion into the trial remained at ≥80 mL/min/1.73 m^2. A precise definition of the eGFR Schwarz formula was added. The 150 mg DE capsule was introduced to reduce the number of capsules taken by a patient at a single time point. The derived DE target doses based on Hayton calculations for newborns aged <1 month and with a body weight <3 kg were added. Dose adjustment step ranges for up-titration were corrected to 10-100% and for downtitration to 25-50% to reflect the respective dosing nomograms. The dosing nomograms for the OLF were updated. It was explained that as soon as a clinical trial with a specific reversal agent in paediatric patients is initiated, eligible patients from trial 1160.108 can be entered in this trial and receive the reversal agent. Cross reporting of laboratory results between trials is then allowed to limit the blood volume required for analysis.
    30 Nov 2016
    In the section on sample size, it was clarified that recruitment can be kept open after 100 patients have been recruited. The final results of the completed Phase IIa PK/PD trials 1160.89 and 1160.105, which were relevant for the patients to be included in second age group (2 to<12 years) and in the youngest age group (0 to <2 years), were provided. To reflect the sequential introduction of age-appropriate formulations (and OLF in particular), it was clarified that patients in age group 2 to <12 years are to be entered and treated considering the availability of the age-appropriate DE formulations. The 60 mg and 70 mg strengths, which were not planned to be used in the trial, were removed from the dosing nomograms for DE pellets. The eGFR threshold for exclusion from the trial was changed to <60 mL/min/1.73m^2 for patients aged 12 to <18 years. For patients aged 0 to <12 years, the eGFR threshold for exclusion from the trial remained unchanged at <80 mL/min/1.73m^2. It was clarified that patients with a heart valve prosthesis requiring anticoagulation are not to be included in the trial. The analysis set for PK analyses was defined; it was specified that this analysis set will also be used for PK/PD analyses. It was defined that multiple PK/PD and safety interim analyses for any of the age groups may be considered. It was clarified that interim analyses based on selected or partial clinical trial data may be conducted for regulatory purposes. It was added that all deaths are to be considered as non-events for occurrence of PTS and therefore are to be censored. The recommendation to use a proton pump inhibitor such as pantoprazole in case of development of gastrointestinal symptoms was replaced by the recommendation to use a proton pump inhibitor according to the local standard of care in accordance with local labelling recommendations.
    19 Jan 2018
    Active meningitis, encephalitis, and intracranial abscess at Visit 2 were added as exclusion criteria. Furthermore, patients who developed active meningitis, encephalitis, or intracranial abscess were to be discontinued from the trial medication.
    10 Sep 2018
    The option to administer pellets was expanded to patients <6 months of age. It was explained that the use of OLF is preferred over pellets in patients <12 months of age, provided that OLF supplies are available to the site. The time window from Visit 1 (screening) to Visit 2 (first administration of trial medication) was expanded to 14 days to facilitate screening procedures. It was clarified that the discontinuation from trial medication is required if a drug-related SAE occurred. Accordingly, the option to re-start DE after a major bleeding event was deleted. Reaching steady state of the currently assigned DE formulation (i.e. at least 6 consecutive DE doses taken) was introduced as a prerequisite for considering a switch to another formulation. It was deleted that the primary analysis can only be conducted after all patients have completed the 12-month evaluation or otherwise dropped out from the trial. The requirement not to publish any trial data prior to the finalisation of CTRs was deleted. The definition of the PD endpoints was modified: PD assessments at Visit 3 (after at least 6 consecutive DE doses) and after at least 3 days following any DE dose adjustment were to be considered instead of PD assessments at Visit 4. It was clarified that the PD sample Aliquot 1, if not needed for DE concentration measurement guiding dose adjustment, can be used for the central analysis of PD and PK based on dTT (Anti-Factor IIa activity), aPTT and/or ECT. An explanation was added that the secondary endpoint of ‘number of DE dose adjustments during the treatment period’ is equivalent to the number of patients with DE adjustments during the treatment period since only one dose adjustment was allowed per patient.
    07 Feb 2019
    The eGFR threshold in exclusion criterion 2 was lowered to <50 mL/min/1.73m^2 for all patients, irrespective of their age.

    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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