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    Clinical Trial Results:
    Multicenter, open-label, randomised, pharmacokinetic (PK) and pharmacodynamic (PD) dose-ranging Phase II study of ticagrelor followed by a double-blind, randomised, parallel-group, placebo-controlled 4 weeks extension phase in paediatric patients with sickle cell disease

    Summary
    EudraCT number
    2014-001006-18
    Trial protocol
    GB   IT  
    Global end of trial date
    27 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jul 2017
    First version publication date
    29 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5136C00007
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02214121
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, 431 50
    Public contact
    Brilinta Global Clinical Lead, AstraZeneca, +46 31 776 1000,
    Scientific contact
    Brilinta Global Clinical Lead, AstraZeneca, +46 31 776 1000,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000480-PIP01-08
    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
    27 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterise the relationship between ticagrelor dose and inhibition of platelet aggregation in paediatric patients with Sickle Cell Disease (SCD), using PK-PD modelling, to support dose selection for Phase III.
    Protection of trial subjects
    For safety reasons, the dosing schedule had the potential to be modified for individual patients based on their PRU at Visit 2, 3 and 4. If the response in PRU was higher than expected, subsequent doses for that patient was lowered.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Sep 2014
    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
    Canada: 2
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Kenya: 8
    Country: Number of subjects enrolled
    Lebanon: 21
    Country: Number of subjects enrolled
    United States: 19
    Country: Number of subjects enrolled
    South Africa: 8
    Worldwide total number of subjects
    73
    EEA total number of subjects
    15
    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)
    43
    Adolescents (12-17 years)
    30
    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
    The study was conducted at 24 centres, in 6 countries. The first patient was enrolled to Part A of the study on 11 Sep 2014, and the last patient completed Part B of the study on 27 Feb 2017. Recruitment was stopped due to protocol amendment between 8 September 2015 and 1 June 2016.

    Pre-assignment
    Screening details
    A total of 73 patients were enrolled to the study, 46 of which were randomised to Part A of the study (open label). Of the patients completing Part A, 25 was randomised to Part B of the study (double blind).

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

    Arms
    Arm title
    Part A - Ticagrelor
    Arm description
    Actual treatment group for Part A of the study. Relevant for the Part A period.
    Arm type
    Experimental

    Investigational medicinal product name
    Ticagrelor 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Granules for oral suspension 10 mg

    Investigational medicinal product name
    Ticagrelor 45 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Granules for oral suspension 45 mg

    Number of subjects in period 1 [1]
    Part A - Ticagrelor
    Started
    45
    Completed
    39
    Not completed
    6
         Other
             1
         Dev. of study-specific withdrawal crit.
             4
         Patient decision
             1
    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 number of patients in “Trial Information” is the number of enrolled subjects, whereas the subjects displayed here is the number actually part of Part A. There were a number of patients that were not randomised or taking IP that are not included in the arm.
    Period 2
    Period 2 title
    Part B
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part B - Ticagrelor
    Arm description
    Randomised treatment group for Part B of the study. Relevant for the Part B period.
    Arm type
    Experimental

    Investigational medicinal product name
    Ticagrelor 45 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Granules for oral suspension 45 mg

    Investigational medicinal product name
    Ticagrelor 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Granules for oral suspension 10 mg

    Arm title
    Part B - Placebo
    Arm description
    Randomised treatment group for Part B of the study. Relevant for the Part B period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo for ticagrelor

    Number of subjects in period 2 [2]
    Part B - Ticagrelor Part B - Placebo
    Started
    17
    8
    Completed
    14
    7
    Not completed
    3
    1
         Dev. of study-specific withdrawal crit.
             2
             -
         Patient decision
             1
             -
         Lost to follow-up
             -
             1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Part B period was optional, therefore the number of patients completing Part A period is not the same as the number of patients starting Part B period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A - Ticagrelor
    Reporting group description
    Actual treatment group for Part A of the study. Relevant for the Part A period.

    Reporting group values
    Part A - Ticagrelor Total
    Number of subjects
    45 45
    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)
    24 24
        Adolescents (12-17 years)
    21 21
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age Continuous
    Relevant for the Part A period of the study.
    Units: Years
        arithmetic mean (standard deviation)
    11.2 ± 3.34 -
    Gender, Male/Female
    Relevant for the Part A period of the study
    Units: Subjects
        Male
    21 21
        Female
    24 24
    Race/Ethnicity, Customized
    Relevant for the Part A period of the study
    Units: Subjects
        White
    10 10
        Black or African American
    35 35
        Asian
    0 0
        Native Hawaiian or Other Pacific Islander
    0 0
        American Indian or Alaska Native
    0 0
        Other
    0 0
    Ethnicity (NIH/OMB)
    Relevant for the Part A period
    Units: Subjects
        Hispanic or Latino
    1 1
        Not Hispanic or Latino
    44 44
        Unknown or Not Reported
    0 0
    Subject analysis sets

    Subject analysis set title
    Ticagrelor 0.125 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 2.

    Subject analysis set title
    Ticagrelor 0.75 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 2.

    Subject analysis set title
    Ticagrelor 0.375 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 3.

    Subject analysis set title
    Ticagrelor 0.563 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 3

    Subject analysis set title
    Ticagrelor 1.125 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 3.

    Subject analysis set title
    Ticagrelor 2.25 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 3.

    Subject analysis set title
    Ticagrelor 0.125 mg/kg bid
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Repeated bid treatment between Visit 3 and Visit 4.

    Subject analysis set title
    Ticagrelor 0.563 mg/kg bid
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Repeated bid treatment between Visit 3 and Visit 4.

    Subject analysis set title
    Ticagrelor 0.75 mg/kg bid
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Repeated bid treatment between Visit 3 and Visit 4.

    Subject analysis set title
    Part B - Ticagrelor 0.125 mg/kg bid
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Repeated bid treatment during Part B.

    Subject analysis set title
    Part B - Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Repeated bid treatment during Part B.

    Subject analysis set title
    Part A - Overall
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All ticagrelor-treated patients in Part A

    Subject analysis sets values
    Ticagrelor 0.125 mg/kg Ticagrelor 0.75 mg/kg Ticagrelor 0.375 mg/kg Ticagrelor 0.563 mg/kg Ticagrelor 1.125 mg/kg Ticagrelor 2.25 mg/kg Ticagrelor 0.125 mg/kg bid Ticagrelor 0.563 mg/kg bid Ticagrelor 0.75 mg/kg bid Part B - Ticagrelor 0.125 mg/kg bid Part B - Placebo Part A - Overall
    Number of subjects
    14
    31
    7
    18
    10
    9
    14
    9
    17
    9
    3
    45
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    11
    13
    6
    10
    4
    4
    11
    4
    8
    7
    2
    24
        Adolescents (12-17 years)
    3
    18
    1
    8
    6
    5
    3
    5
    9
    2
    1
    21
        Adults (18-64 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Age Continuous
    Relevant for the Part A period of the study.
    Units: Years
        arithmetic mean (standard deviation)
    9.4 ± 3.73
    12 ± 2.83
    8.9 ± 4.22
    11.2 ± 3.17
    11.9 ± 2.96
    12.2 ± 3.19
    9.4 ± 3.73
    12.4 ± 2.55
    11.8 ± 3.03
    9.4 ± 3.91
    9.7 ± 5.13
    11.2 ± 3.34
    Gender, Male/Female
    Relevant for the Part A period of the study
    Units: Subjects
        Male
    8
    13
    3
    11
    3
    4
    8
    4
    6
    5
    2
    21
        Female
    6
    18
    4
    7
    7
    5
    6
    5
    11
    4
    1
    24
    Race/Ethnicity, Customized
    Relevant for the Part A period of the study
    Units: Subjects
        White
    2
    8
    2
    2
    2
    3
    2
    1
    4
    1
    0
    10
        Black or African American
    12
    23
    5
    16
    8
    6
    12
    8
    13
    8
    3
    35
        Asian
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        American Indian or Alaska Native
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Other
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ethnicity (NIH/OMB)
    Relevant for the Part A period
    Units: Subjects
        Hispanic or Latino
    1
    0
    1
    0
    0
    0
    1
    0
    0
    1
    0
    1
        Not Hispanic or Latino
    13
    31
    6
    18
    10
    9
    13
    9
    17
    8
    3
    44
        Unknown or Not Reported
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Part A - Ticagrelor
    Reporting group description
    Actual treatment group for Part A of the study. Relevant for the Part A period.
    Reporting group title
    Part B - Ticagrelor
    Reporting group description
    Randomised treatment group for Part B of the study. Relevant for the Part B period.

    Reporting group title
    Part B - Placebo
    Reporting group description
    Randomised treatment group for Part B of the study. Relevant for the Part B period.

    Subject analysis set title
    Ticagrelor 0.125 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 2.

    Subject analysis set title
    Ticagrelor 0.75 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 2.

    Subject analysis set title
    Ticagrelor 0.375 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 3.

    Subject analysis set title
    Ticagrelor 0.563 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 3

    Subject analysis set title
    Ticagrelor 1.125 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 3.

    Subject analysis set title
    Ticagrelor 2.25 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose received at Visit 3.

    Subject analysis set title
    Ticagrelor 0.125 mg/kg bid
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Repeated bid treatment between Visit 3 and Visit 4.

    Subject analysis set title
    Ticagrelor 0.563 mg/kg bid
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Repeated bid treatment between Visit 3 and Visit 4.

    Subject analysis set title
    Ticagrelor 0.75 mg/kg bid
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Repeated bid treatment between Visit 3 and Visit 4.

    Subject analysis set title
    Part B - Ticagrelor 0.125 mg/kg bid
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Repeated bid treatment during Part B.

    Subject analysis set title
    Part B - Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Repeated bid treatment during Part B.

    Subject analysis set title
    Part A - Overall
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All ticagrelor-treated patients in Part A

    Primary: P2Y12 reaction units (PRU) - Part A

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    End point title
    P2Y12 reaction units (PRU) - Part A [1]
    End point description
    End point type
    Primary
    End point timeframe
    PRU measurements are taken in conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7) and after repeated dosing at Visit 4 (Day 14).
    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: All of the above: No statistical tests were planned or conducted, only descriptive statistics were used.
    End point values
    Ticagrelor 0.125 mg/kg Ticagrelor 0.75 mg/kg Ticagrelor 0.375 mg/kg Ticagrelor 0.563 mg/kg Ticagrelor 1.125 mg/kg Ticagrelor 2.25 mg/kg Ticagrelor 0.125 mg/kg bid Ticagrelor 0.563 mg/kg bid Ticagrelor 0.75 mg/kg bid
    Number of subjects analysed
    14
    31
    7
    18
    10
    9
    14
    9
    17
    Units: Unit
    arithmetic mean (standard deviation)
        Pre-dose
    301.6 ± 46.55
    268 ± 35.95
    295.4 ± 42.3
    287.7 ± 34.35
    283.7 ± 36.88
    277.7 ± 39.36
    320 ± 99999999
    205.4 ± 53.22
    214.7 ± 48.71
        2 hours post-dose
    278.2 ± 47.2
    138.4 ± 70.68
    229 ± 64.22
    176.2 ± 79.53
    128.9 ± 37.68
    79.9 ± 47.74
    271.2 ± 70.35
    102 ± 72.53
    152 ± 72.35
        6 hours post-dose
    276 ± 75.43
    189 ± 69.84
    266 ± 57.98
    190.4 ± 47.78
    191.2 ± 57.59
    141.7 ± 69.58
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
        8 hours post-dose
    343 ± 38.13
    99999999 ± 99999999
    318.3 ± 66.43
    318 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    No statistical analyses for this end point

    Primary: P2Y12 reaction units (PRU) - Part B

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    End point title
    P2Y12 reaction units (PRU) - Part B [2]
    End point description
    End point type
    Primary
    End point timeframe
    PRU measurements are taken after 4 weeks of double blind treatment at the end of Part B.
    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: All of the above: No statistical tests were planned or conducted, only descriptive statistics were used.
    End point values
    Part B - Ticagrelor 0.125 mg/kg bid Part B - Placebo
    Number of subjects analysed
    9
    3
    Units: Unit
    arithmetic mean (standard deviation)
        Pre-dose
    282.8 ± 19.26
    313.3 ± 20.13
        2 hours post-dose
    259.6 ± 61.95
    217.3 ± 78.34
    No statistical analyses for this end point

    Primary: Maximum plasma concentration (Cmax) - Part A

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    End point title
    Maximum plasma concentration (Cmax) - Part A [3]
    End point description
    End point type
    Primary
    End point timeframe
    PK measurements are taken in conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7) and after repeated dosing at Visit 4 (Day 14).
    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: All of the above: No statistical tests were planned or conducted, only descriptive statistics were used.
    End point values
    Ticagrelor 0.125 mg/kg Ticagrelor 0.75 mg/kg Ticagrelor 0.375 mg/kg Ticagrelor 0.563 mg/kg Ticagrelor 1.125 mg/kg Ticagrelor 2.25 mg/kg Ticagrelor 0.125 mg/kg bid Ticagrelor 0.563 mg/kg bid Ticagrelor 0.75 mg/kg bid
    Number of subjects analysed
    14
    31
    7
    18
    10
    9
    14
    9
    17
    Units: ng/mL
        geometric mean (standard deviation)
    15.24 ± 15.2709
    162.961 ± 84.923
    52.069 ± 34.4115
    96.031 ± 51.4902
    269.174 ± 162.2147
    566.55 ± 225.9447
    13.973 ± 15.3652
    111.367 ± 81.1597
    157.216 ± 114.8138
    No statistical analyses for this end point

    Primary: Maximum plasma concentration (Cmax) - Part B

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    End point title
    Maximum plasma concentration (Cmax) - Part B [4]
    End point description
    End point type
    Primary
    End point timeframe
    PK measurements are taken after 4 weeks of double blind treatment at the end of Part B.
    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: All of the above: No statistical tests were planned or conducted, only descriptive statistics were used.
    End point values
    Part B - Ticagrelor 0.125 mg/kg bid
    Number of subjects analysed
    9
    Units: ng/mL
        geometric mean (standard deviation)
    16.394 ± 13.3671
    No statistical analyses for this end point

    Primary: Area under the plasma concentration time curve (AUC) - Part A

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    End point title
    Area under the plasma concentration time curve (AUC) - Part A [5]
    End point description
    The PK parameter presented was derived using a model based analysis and not from a non-compartmental (NCA) analysis.
    End point type
    Primary
    End point timeframe
    PK measurements are taken in conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7) and after repeated dosing at Visit 4 (Day 14).
    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: All of the above: No statistical tests were planned or conducted, only descriptive statistics were used.
    End point values
    Ticagrelor 0.125 mg/kg Ticagrelor 0.75 mg/kg Ticagrelor 0.375 mg/kg Ticagrelor 0.563 mg/kg Ticagrelor 1.125 mg/kg Ticagrelor 2.25 mg/kg Ticagrelor 0.125 mg/kg bid Ticagrelor 0.563 mg/kg bid Ticagrelor 0.75 mg/kg bid
    Number of subjects analysed
    14
    31
    7
    18
    10
    9
    14
    9
    17
    Units: ng*h/mL
        geometric mean (standard deviation)
    161.9 ± 72.24
    1151.9 ± 308.39
    437.5 ± 262.24
    879.3 ± 236.12
    1638.7 ± 521.8
    2850.9 ± 1277.39
    161.9 ± 72.24
    913.5 ± 208.82
    1022.4 ± 287.32
    No statistical analyses for this end point

    Primary: Area under the plasma concentration time curve (AUC) - Part B

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    End point title
    Area under the plasma concentration time curve (AUC) - Part B [6]
    End point description
    The PK parameter presented was derived using a model based analysis and not from a non-compartmental (NCA) analysis.
    End point type
    Primary
    End point timeframe
    PK measurements are taken after 4 weeks of double blind treatment at the end of Part B.
    Notes
    [6] - 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: All of the above: No statistical tests were planned or conducted, only descriptive statistics were used.
    End point values
    Part B - Ticagrelor 0.125 mg/kg bid
    Number of subjects analysed
    9
    Units: ng*h/mL
        geometric mean (standard deviation)
    160.6 ± 88.58
    No statistical analyses for this end point

    Secondary: Assessment of Ticagrelor concentration - Part A

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    End point title
    Assessment of Ticagrelor concentration - Part A
    End point description
    End point type
    Secondary
    End point timeframe
    PK measurements are taken in conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7) and after repeated dosing at Visit 4 (Day 14).
    End point values
    Ticagrelor 0.125 mg/kg Ticagrelor 0.75 mg/kg Ticagrelor 0.375 mg/kg Ticagrelor 0.563 mg/kg Ticagrelor 1.125 mg/kg Ticagrelor 2.25 mg/kg Ticagrelor 0.125 mg/kg bid Ticagrelor 0.563 mg/kg bid Ticagrelor 0.75 mg/kg bid
    Number of subjects analysed
    14
    31
    7
    18
    10
    9
    14
    9
    17
    Units: ng/mL
    geometric mean (standard deviation)
        Pre-dose
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    2.17 ± 99999999
    31.937 ± 48.6501
    28.066 ± 27.1344
        1 hour post-dose
    12.713 ± 16.0627
    104.243 ± 103.1502
    34.069 ± 42.3746
    33.294 ± 55.4258
    182.558 ± 188.4254
    390.568 ± 294.2189
    99999999 ± 99999999
    80.414 ± 75.9675
    151.52 ± 116.0079
        2 hours post-dose
    11.465 ± 8.7427
    107.729 ± 62.8343
    37.782 ± 31.689
    74.626 ± 50.7053
    162.435 ± 161.8489
    426.804 ± 212.5385
    13.973 ± 15.3652
    102.166 ± 78.0785
    101.618 ± 65.2415
        4 hours post-dose
    6.647 ± 4.4533
    75.907 ± 31.2786
    20.122 ± 9.9383
    51.005 ± 24.6435
    118.217 ± 42.0873
    188.383 ± 111.9267
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
        6 hours post-dose
    3.663 ± 3.4061
    52.966 ± 29.0297
    19.435 ± 15.7259
    45.502 ± 17.895
    69.708 ± 44.3168
    125.279 ± 89.0005
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
        8 hours post-dose
    3.88 ± 3.3171
    99999999 ± 99999999
    15.699 ± 20.7596
    15.691 ± 15.1392
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    No statistical analyses for this end point

    Secondary: Assessment of Ticagrelor concentration - Part B

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    End point title
    Assessment of Ticagrelor concentration - Part B
    End point description
    End point type
    Secondary
    End point timeframe
    PK measurements are taken after 4 weeks of double blind treatment at the end of Part B.
    End point values
    Part B - Ticagrelor 0.125 mg/kg bid
    Number of subjects analysed
    9
    Units: ng/mL
    geometric mean (standard deviation)
        Pre-dose
    2.478 ± 3.958
        1 hour post-dose
    9.677 ± 9.4275
        2 hours post-dose
    14.144 ± 12.4711
        4 hours post-dose
    9.605 ± 14.4979
    No statistical analyses for this end point

    Secondary: Assessment of AR-C124910XX concentration - Part A

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    End point title
    Assessment of AR-C124910XX concentration - Part A
    End point description
    End point type
    Secondary
    End point timeframe
    PK measurements are taken in conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7) and after repeated dosing at Visit 4 (Day 14).
    End point values
    Ticagrelor 0.125 mg/kg Ticagrelor 0.75 mg/kg Ticagrelor 0.375 mg/kg Ticagrelor 0.563 mg/kg Ticagrelor 1.125 mg/kg Ticagrelor 2.25 mg/kg Ticagrelor 0.125 mg/kg bid Ticagrelor 0.563 mg/kg bid Ticagrelor 0.75 mg/kg bid
    Number of subjects analysed
    14
    31
    7
    18
    10
    9
    14
    9
    17
    Units: ng/mL
    geometric mean (standard deviation)
        Pre-dose
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    1.25 ± 99999999
    17.38 ± 10.0399
    20.359 ± 15.0788
        1 hour post-dose
    1.782 ± 1.6604
    16.302 ± 22.4614
    4.577 ± 7.861
    3.708 ± 13.3332
    30.07 ± 44.295
    63.088 ± 84.2091
    99999999 ± 99999999
    24.945 ± 15.6547
    43.986 ± 29.8127
        2 hours post-dose
    2.681 ± 2.0733
    33.256 ± 25.3854
    11.757 ± 13.3322
    15.918 ± 17.4849
    52.932 ± 69.1056
    149.772 ± 71.3624
    4.026 ± 4.7624
    37.013 ± 32.765
    44.69 ± 31.6577
        4 hours post-dose
    2.071 ± 1.277
    29.86 ± 13.8726
    7.63 ± 6.373
    17.015 ± 7.9272
    50.887 ± 25.6964
    101.37 ± 44.6207
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
        6 hours post-dose
    1.646 ± 1.0427
    25.276 ± 10.8318
    9.762 ± 2.3304
    16.703 ± 5.8115
    35.716 ± 22.3351
    76.941 ± 39.9167
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
        8 hours post-dose
    1.715 ± 1.0226
    99999999 ± 99999999
    6.176 ± 6.3168
    9.232 ± 2.5385
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    99999999 ± 99999999
    No statistical analyses for this end point

    Secondary: Assessment of AR-C124910XX concentration - Part B

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    End point title
    Assessment of AR-C124910XX concentration - Part B
    End point description
    End point type
    Secondary
    End point timeframe
    PK measurements are taken after 4 weeks of double blind treatment at the end of Part B.
    End point values
    Part B - Ticagrelor 0.125 mg/kg bid
    Number of subjects analysed
    9
    Units: ng/mL
    geometric mean (standard deviation)
        Pre-dose
    1.81 ± 1.1213
        1 hour post-dose
    2.865 ± 1.6443
        2 hours post-dose
    4.16 ± 3.1503
        4 hours post-dose
    3.953 ± 4.1179
    No statistical analyses for this end point

    Secondary: Oral Clearance (CL/F) - Part A

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    End point title
    Oral Clearance (CL/F) - Part A
    End point description
    The PK parameter presented were derived using a model based analysis and not from a non-compartmental (NCA) analysis.
    End point type
    Secondary
    End point timeframe
    PK measurements are taken in conjunction with single doses at Visit 2 (Day 0) and Visit 3 (Day 7) and after repeated dosing at Visit 4 (Day 14).
    End point values
    Part A - Overall
    Number of subjects analysed
    45
    Units: L/h
        geometric mean (standard deviation)
    22.5 ± 7.531
    No statistical analyses for this end point

    Secondary: Oral Clearance (CL/F) - Part B

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    End point title
    Oral Clearance (CL/F) - Part B
    End point description
    The PK parameter presented was derived using a model based analysis and not from a non-compartmental (NCA) analysis.
    End point type
    Secondary
    End point timeframe
    PK measurements are taken after 4 weeks of double blind treatment at the end of Part B.
    End point values
    Part B - Ticagrelor 0.125 mg/kg bid
    Number of subjects analysed
    9
    Units: L/h
        geometric mean (standard deviation)
    19.15 ± 6.673
    No statistical analyses for this end point

    Secondary: Number of vaso-occlusive crises - Part B

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    End point title
    Number of vaso-occlusive crises - Part B
    End point description
    End point type
    Secondary
    End point timeframe
    During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
    End point values
    Part B - Ticagrelor Part B - Placebo
    Number of subjects analysed
    15
    8
    Units: Number of events
        arithmetic mean (standard deviation)
    1 ± 2
    0.6 ± 0.74
    No statistical analyses for this end point

    Secondary: Number of vaso-occlusive crises requiring hospitalization or emergency department visits - Part B

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    End point title
    Number of vaso-occlusive crises requiring hospitalization or emergency department visits - Part B
    End point description
    End point type
    Secondary
    End point timeframe
    During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
    End point values
    Part B - Ticagrelor Part B - Placebo
    Number of subjects analysed
    15
    8
    Units: Number of events
        arithmetic mean (standard deviation)
    0.2 ± 0.41
    0.1 ± 0.35
    No statistical analyses for this end point

    Secondary: Percentage of days hospitalized for vaso-occlusice crisis or other complications of sickle cell disease - Part B

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    End point title
    Percentage of days hospitalized for vaso-occlusice crisis or other complications of sickle cell disease - Part B
    End point description
    End point type
    Secondary
    End point timeframe
    During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
    End point values
    Part B - Ticagrelor Part B - Placebo
    Number of subjects analysed
    15
    8
    Units: Percentage of days
        arithmetic mean (standard deviation)
    4.52 ± 11.816
    1.34 ± 3.788
    No statistical analyses for this end point

    Secondary: Percentage of days with pain (age >=4) - Part B

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    End point title
    Percentage of days with pain (age >=4) - Part B
    End point description
    End point type
    Secondary
    End point timeframe
    During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
    End point values
    Part B - Ticagrelor Part B - Placebo
    Number of subjects analysed
    14
    8
    Units: Percentage of days
        arithmetic mean (standard deviation)
    27.01 ± 34.065
    31.78 ± 23.731
    No statistical analyses for this end point

    Secondary: Mean intensity of pain (age >=4) - Part B

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    End point title
    Mean intensity of pain (age >=4) - Part B
    End point description
    End point type
    Secondary
    End point timeframe
    During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
    End point values
    Part B - Ticagrelor Part B - Placebo
    Number of subjects analysed
    14
    8
    Units: Mean intensity of pain
    arithmetic mean (standard deviation)
        Overall - Part B
    1.4 ± 2.027
    0.87 ± 0.493
        1st week
    1.64 ± 2.603
    1.36 ± 0.827
        2nd week
    1.11 ± 2.236
    0.38 ± 0.525
        3rd week
    1.06 ± 1.881
    0.67 ± 1.116
        4th week
    1.46 ± 2.624
    0.83 ± 0.901
    No statistical analyses for this end point

    Secondary: Percentage of days of analgesic use (age >= 4) - Part B

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    End point title
    Percentage of days of analgesic use (age >= 4) - Part B
    End point description
    End point type
    Secondary
    End point timeframe
    During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
    End point values
    Part B - Ticagrelor Part B - Placebo
    Number of subjects analysed
    14
    8
    Units: Percentage of days
        arithmetic mean (standard deviation)
    16.79 ± 20.838
    18.56 ± 19.11
    No statistical analyses for this end point

    Secondary: Percentage of days of opioid analgesic use (age >=4) - Part B

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    End point title
    Percentage of days of opioid analgesic use (age >=4) - Part B
    End point description
    End point type
    Secondary
    End point timeframe
    During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
    End point values
    Part B - Ticagrelor Part B - Placebo
    Number of subjects analysed
    14
    8
    Units: Percentage of days
        arithmetic mean (standard deviation)
    12.46 ± 22.502
    0.54 ± 1.537
    No statistical analyses for this end point

    Secondary: Percentage of days of absence from school or work (age >=6) - Part B

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    End point title
    Percentage of days of absence from school or work (age >=6) - Part B
    End point description
    End point type
    Secondary
    End point timeframe
    During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
    End point values
    Part B - Ticagrelor Part B - Placebo
    Number of subjects analysed
    11
    6
    Units: Percentage of days
        arithmetic mean (standard deviation)
    4.87 ± 10.865
    5.95 ± 9.494
    No statistical analyses for this end point

    Other pre-specified: Haemorrhagic events - Part A

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    End point title
    Haemorrhagic events - Part A
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From randomisation to Part A (week 0) through Visit 4 (week 2)
    End point values
    Part A - Ticagrelor
    Number of subjects analysed
    45
    Units: Number of events
    0
    No statistical analyses for this end point

    Other pre-specified: Haemorrhagic events - Part B

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    End point title
    Haemorrhagic events - Part B
    End point description
    End point type
    Other pre-specified
    End point timeframe
    During 4 weeks of study treatment starting from randomization in Part B (week 2) up to 4 weeks (week 6).
    End point values
    Part B - Ticagrelor Part B - Placebo
    Number of subjects analysed
    16
    7
    Units: Number of events
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs were collected from Visit 1 and AEs from Visit 2. SAEs and Other AEs are presented by study period, where Part A consists of the time from randomization to Part A through Visit 4. Part B starts the day after Visit 4 and continues until Visit 8.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Part A - Ticagrelor
    Reporting group description
    Randomised treatment group for Part A of the study. Relevant for the Part A period.

    Reporting group title
    Part B - Ticagrelor
    Reporting group description
    Randomised treatment group for Part B of the study. Relevant for the Part B period.

    Reporting group title
    Part B - Placebo
    Reporting group description
    Randomised treatment group for Part B of the study. Relevant for the Part B period.

    Serious adverse events
    Part A - Ticagrelor Part B - Ticagrelor Part B - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 45 (11.11%)
    4 / 16 (25.00%)
    1 / 7 (14.29%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute chest syndrome
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Sickle cell anemia with crisis
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 16 (18.75%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 16 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part A - Ticagrelor Part B - Ticagrelor Part B - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 45 (48.89%)
    12 / 16 (75.00%)
    5 / 7 (71.43%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 16 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 16 (18.75%)
    0 / 7 (0.00%)
         occurrences all number
    1
    3
    0
    Blood and lymphatic system disorders
    Sickle cell anemia with crisis
         subjects affected / exposed
    6 / 45 (13.33%)
    1 / 16 (6.25%)
    1 / 7 (14.29%)
         occurrences all number
    8
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 16 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    7
    0
    2
    Dizziness
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Facial pain
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 16 (6.25%)
    1 / 7 (14.29%)
         occurrences all number
    4
    1
    2
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 16 (6.25%)
    1 / 7 (14.29%)
         occurrences all number
    2
    2
    1
    Pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 16 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    0
    Ear and labyrinth disorders
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 45 (13.33%)
    3 / 16 (18.75%)
    2 / 7 (28.57%)
         occurrences all number
    6
    6
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 16 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Gastritis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 16 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 16 (18.75%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 16 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 45 (11.11%)
    4 / 16 (25.00%)
    2 / 7 (28.57%)
         occurrences all number
    7
    4
    2
    Back pain
         subjects affected / exposed
    3 / 45 (6.67%)
    2 / 16 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    3
    2
    3
    Musculoskeletal pain
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 16 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    2
    1
    Neck pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    5 / 45 (11.11%)
    3 / 16 (18.75%)
    2 / 7 (28.57%)
         occurrences all number
    8
    4
    2
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 16 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis media
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Tinea infection
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 16 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2014
    CSP Amendment 1: The purpose of this amendment was to address changes in the CSP related to the FDA’s identified potential hold issues and non-hold comments for IND 120,366, dated 11 April 2014. An additional haematology and chemistry assessment was included at Visit 4. The stopping rules in Section 3.11 of the CSP were revised. Patients will be discontinued from study drug if any major bleeding should occur, not at the discretion of the PI. The time of the study follow-up visit (Visit 9) was changed to 30-35 days after last dose. Severity of AEs will be collected by maximum intensity. The intensity ratings are mild, moderate and severe. The Faces Pain Scale - Revised will be administered to patients aged ≥4 years instead of all patients. Inclusion criterion 2 was amended to read: “Experienced at least 2 vaso-occlusive crises requiring medical intervention during the past 12 months”. The study was amended to a double-blind design. In addition clarifications on exclusion criterion 1, order of study procedures during study visits and recording of study drug intake in dosing diary have been made. First dose after each visit in the repeated dosing phase will be administered in the evening to simplify for the patients. Exclusion criterion 12; Males were deleted and 1 variable collected for AE was deleted due to error in writing. The time of the study enrolment visit (Visit 1) was changed, and is ≤30 days before Visit 2. TCD exams and ophthalmological exams were added as study procedures, for any patients who had not had the exams within the specified time periods, the new maximum time between Visit 1 and 2 allowed for these exams to be scheduled if needed.
    22 Dec 2014
    CSP Amendment 3: Analysis of the first 12 randomised patients showed that the exposure to ticagrelor was lower than predicted and the platelet inhibitory effect was also lower than intended. Protocol was therefore amended to increase to better characterise the PK-PD relationship for ticagrelor. The following is a description of changes: Initial doses of 0.125 mg/kg, followed 7 days later by 0.375 mg/kg or 0.563 mg/kg were amended to initial doses of 0.75 mg/kg, followed 7 days later by 1.125 mg/kg or 2.25 mg/kg. Inclusion criterion 2 concerning the history of VOC in the prior 12 months was removed. Inclusion criterion 4: The requirement for stable hydroxyurea dosing was changed from 3 months to 1 month. The amended protocol allowed for patients to opt out of participation in Part B to reduce study burden on patients/families. Since Part B was now optional, the PK-PD determinations previously scheduled for Visit 8 were moved to Visit 4 in order to assure that steady state PK-PD was obtained in all study patients. The pregnancy urine testing was moved from Visit 3 to Visit 2 to ensure that all patients were tested prior to first dose. A pregnancy test was added to Visit 4 for the patients only completing Part A to insure that all patients were tested following repeated dosing. If most of the remaining patients declined participation in Part B, the patients in the EAS were prone to selection bias. Results of statistical tests conducted under such circumstances were not generalisable and hence only descriptive statistics were used. The minimum number of days between Visit 1 and Visit 2 was increased from 7 days to 14 days to ensure that 30 days elapsed between Visit 1 and Visit 4. This ensured that the volume of blood to be drawn within 30 days was not higher than 3% of blood volume. The visit window between the treatment visits was shortened to better fit the visit schedule and to avoid requiring patients to take home large volumes of study drug.
    05 Mar 2015
    CSP Amendment 2: AstraZeneca Study Team initiated the amendment to clarify wording, decrease patient burden, and to incorporate requests from the PDCO of the European Medicines Agency and the MHRA. The following is a description of notable changes: Updated the secondary objective to include the PK properties of the active metabolite of ticagrelor. Re-worded some inclusion/exclusion criteria for clarification and consistency with other parts of the CSP. Stated that randomisation would take place 7 to 30 days after enrolment. Changed collection of haematology and clinical chemistry sample at Visit 4 to 2 hours post-dose. Shortened the PK and PRU sampling time for Visit 2 and Visit 3 as last measurement occurred at 6 hours post-dose and corrected the volume of blood collection for patients with a weight of 16 to 21 kg. Confirmed that Visit 5 and Visit 7 could optionally be performed as telephone contacts rather than centre visits if the PI deemed this acceptable. Updated the criteria for interruption or discontinuation of study drug. Stated that laboratory testing performed prior to enrolment as part of usual clinical care did not need to be repeated as long as the values were obtained no more than 30 days prior to Visit 2. Added a new section specify ECG parameters collected for the study. Stated that NSAIDs could not be administered more frequently than 3 days per week during the study. Added a new section to clarify that any blood transfusion during the study will be recorded in the eCRF. Stated the maximum dose of ticagrelor in this study was 45 mg, regardless of the weight of a patient . Added pain assessment for SCD pain for children aged 2 to <4 years. FLACC form and instructions for completion of the form were added. This was studied as exploratory objectives. Added description of how PD (VerifyNow P2Y12) samples were collected and handled. Clarified that definition of VOC included medical intervention at short-stay unit.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Sep 2015
    Analysis of the first 12 randomised patients showed that the exposure to ticagrelor was lower than predicted and the platelet inhibitory effect was also lower than intended. Protocol was therefore amended to increase to better characterise the PK-PD relationship for ticagrelor. Recruitment was halted as the CSP was amended.
    01 Jun 2016

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Whenever 99999999 is displayed in the End Point tables it indicates that data is missing for this cell. This is due to changes in protocol which modified the scheme for PRU measurements and concentration measurements of ticagrelor and AR-C124910XX.
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