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    Clinical Trial Results:
    A Randomised, Double-Blind, Parallel-Group, Multicentre, Phase III Study to Evaluate the Effect of Ticagrelor versus Placebo in Reducing the Rate of Vaso-Occlusive Crises in Paediatric Patients with Sickle Cell Disease (HESTIA3)

    Summary
    EudraCT number
    		 2017-002421-38
    Trial protocol
    		 GB   ES   BE   GR   IT  
    Global end of trial date
    13 Aug 2020

    Results information
    Results version number
    		 v1
    This version publication date
    22 Feb 2021
    First version publication date
    22 Feb 2021
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    D5136C00009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03615924
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Karlebyhusentren, B674 Astraallen, Södertälje, Sweden, SE-151 85
    Public contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Sep 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the effect of ticagrelor versus (Vs) placebo for the reduction of vaso-occlusive crisis (VOC), which is the composite of painful crisis and/or acute chest syndrome (ACS), in paediatric participants with sickle cell disease (SCD).
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements (including those for conducting trials with paediatric populations) and the AstraZeneca policy on Bioethics. The data monitoring committee was responsible for safeguarding the interests of the participants in the study by assessing the safety of the intervention during the study, and for reviewing the overall conduct of the clinical study.
    Background therapy
    		 Participants were to receive standard of care for SCD adjusted to the individual participant at the discretion of the Investigator. If a participant was treated with hydroxyurea, the weight-adjusted dose had to be stable for 3 months before enrolment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Sep 2018
    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
    Kenya: 55
    Country: Number of subjects enrolled
    India: 30
    Country: Number of subjects enrolled
    Uganda: 26
    Country: Number of subjects enrolled
    Egypt: 18
    Country: Number of subjects enrolled
    Lebanon: 15
    Country: Number of subjects enrolled
    Ghana: 5
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Tanzania, United Republic of: 1
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    193
    EEA total number of subjects
    12
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    115
    Adolescents (12-17 years)
    78
    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 Phase III study was conducted in paediatric participants with SCD at 53 sites in 16 countries between 26 September 2018 and 13 August 2020. Paediatric participants who experienced at least two VOC events in the past 12 months prior to screening and who fulfilled the eligibility criteria were enrolled.

    Pre-assignment
    Screening details
    		 Participants randomized to ticagrelor received doses based on weight band (at randomization): ≥12 to ≤24 kilogram (kg)=15 milligram (mg), >24 to ≤48 kg=30 mg, >48 kg=45 mg. A total of 193 participants were randomized in this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ticagrelor 15/30/45 mg bd
    Arm description
    		 Paediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally twice daily (bd) for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: • Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. • Participants with a body weight >24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. • Participants with a body weight >48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ticagrelor
    Investigational medicinal product code
    Other name
    BRILINTA™, BRILIQUE™
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with a body weight ≥12 to ≤24 kg: 1 tablet of ticagrelor 15 mg orally bd. Participants with a body weight >24 to ≤48 kg: 2 tablets of ticagrelor 15 mg orally bd. Participants with a body weight >48 kg: 3 tablets of ticagrelor 15 mg orally bd.

    Arm title
    		 Placebo
    Arm description
    		 Paediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: • Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. • Participants with a body weight >24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. • Participants with a body weight >48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with a body weight ≥12 to ≤24 kg: 1 tablet of placebo matching with ticagrelor 15 mg orally bd. Participants with a body weight >24 to ≤48 kg: 2 tablets of placebo matching with ticagrelor 30 mg orally bd. Participants with a body weight >48 kg: 3 tablets of placebo matching with ticagrelor 45 mg orally bd.

    Number of subjects in period 1
    		Ticagrelor 15/30/45 mg bd Placebo
    Started
    101
    92
    Received treatment
    101
    92
    Completed
    0
    0
    Not completed
    101
    92
         Adverse event, serious fatal
    3
    1
         Randomized in error
    1
    -
         Study termination by Sponsor
    94
    86
         Consent withdrawn by subject
    2
    5
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ticagrelor 15/30/45 mg bd
    Reporting group description
    		 Paediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally twice daily (bd) for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: • Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. • Participants with a body weight >24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. • Participants with a body weight >48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.

    Reporting group title
    Placebo
    Reporting group description
    		 Paediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: • Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. • Participants with a body weight >24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. • Participants with a body weight >48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.

    Reporting group values
    		 Ticagrelor 15/30/45 mg bd Placebo Total
    Number of subjects
    		 101 92 193
    Age Categorical
    Units: participants
        ≥2 to <12 years
    		 61 54 115
        >=12 to <18 years
    		 40 38 78
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.40 ± 4.128 10.12 ± 3.799 -
    Sex: Female, Male
    Units: participants
        Female
    		 48 43 91
        Male
    		 53 49 102
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 25 21 46
        Black or African American
    		 60 51 111
        Asian
    		 15 15 30
        Other
    		 1 5 6
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 7 5 12
        Not Hispanic or Latino
    		 94 87 181

    End points

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    End points reporting groups
    Reporting group title
    Ticagrelor 15/30/45 mg bd
    Reporting group description
    		 Paediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally twice daily (bd) for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: • Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. • Participants with a body weight >24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. • Participants with a body weight >48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.

    Reporting group title
    Placebo
    Reporting group description
    		 Paediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: • Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. • Participants with a body weight >24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. • Participants with a body weight >48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.

    Primary: Number of Vaso-Occlusive Crisis Events

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    End point title
    		 Number of Vaso-Occlusive Crisis Events
    End point description
    A VOC is the composite of a painful crisis and/or an acute chest syndrome (ACS) event. The number of VOC events is defined as the count of VOC events experienced by a participant throughout the treatment period. The FAS included all randomized participants regardless of treatment received.
    End point type
    Primary
    End point timeframe
    From randomization (Day 0) up to end of study (EOS) visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: VOC events
    249
    202
    Statistical analysis title
    		 Treatment comparison: Ticagrelor Vs Placebo
    Statistical analysis description
    Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
    Comparison groups
    Ticagrelor 15/30/45 mg bd v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7597
    Method
    		 Negative binomial model
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.5

    Secondary: Number of Painful Crisis Events

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    End point title
    		 Number of Painful Crisis Events
    End point description
    A painful crisis is an onset or worsening of pain that lasts at least 2 hours, for which there is no explanation other than vaso-occlusion and which requires therapy with oral or parenteral opioids, parenteral non-steroidal anti-inflammatory drugs, or other analgesics prescribed by a healthcare provider in a medical setting (such as a hospital, clinic or emergency room visit) or at home. Events with an onset date <=7 days of the previous event onset date are not counted as new events. The FAS included all randomized participants regardless of treatment received.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: painful crisis events
    248
    209
    Statistical analysis title
    		 Treatment comparison: Ticagrelor Vs Placebo
    Statistical analysis description
    Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
    Comparison groups
    Ticagrelor 15/30/45 mg bd v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9037
    Method
    		 Negative binomial model
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.45

    Secondary: Number of Acute Chest Syndrome Events

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    End point title
    		 Number of Acute Chest Syndrome Events
    End point description
    The ACS is an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray. Events with an onset date <=7 days of the previous event onset date are not counted as new events. The FAS included all randomized participants regardless of treatment received.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: ACS events
    6
    6
    Statistical analysis title
    		 Treatment comparison: Ticagrelor Vs Placebo
    Statistical analysis description
    Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
    Comparison groups
    Ticagrelor 15/30/45 mg bd v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7136
    Method
    		 Negative binomial model
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 3.3

    Secondary: Duration of Painful Crises

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    End point title
    		 Duration of Painful Crises
    End point description
    The duration of painful crises is defined as the sum of the duration of painful crises experienced by a participant over the defined treatment period. If two or more events have overlapping durations, the overlapping days were counted only once. The FAS included all randomized participants regardless of treatment received.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: days
    1476
    1441
    Statistical analysis title
    		 Treatment comparison: Ticagrelor Vs Placebo
    Statistical analysis description
    Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
    Comparison groups
    Ticagrelor 15/30/45 mg bd v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.497
    Method
    		 Negative binomial model
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.4

    Secondary: Number of Vaso-Occlusive Crisis Events Requiring Hospitalization or Emergency Department Visits

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    End point title
    		 Number of Vaso-Occlusive Crisis Events Requiring Hospitalization or Emergency Department Visits
    End point description
    The number of VOC events requiring hospitalization or emergency department visits is defined as the count of VOC events experienced by a participant over the treatment period, for which the primary setting for VOC treatment was in-patient hospitalization or emergency department. Events with an onset date <=7 days of the previous event onset date are not counted as new events. The FAS included all randomized participants regardless of treatment received.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: VOC events requiring hospitalization
    87
    51
    Statistical analysis title
    		 Treatment comparison: Ticagrelor Vs Placebo
    Statistical analysis description
    Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
    Comparison groups
    Ticagrelor 15/30/45 mg bd v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1636
    Method
    		 Negative binomial model
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 2.36

    Secondary: Number of Days Hospitalized for Vaso-Occlusive Crisis Events

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    End point title
    		 Number of Days Hospitalized for Vaso-Occlusive Crisis Events
    End point description
    The number of days hospitalized for all individual VOC events experienced by a participant during the treatment period is defined as the sum of the duration of all individual hospitalizations (taking into account potential overlapping hospitalization days of VOC components) during VOC events experienced by a participant over the treatment period for which the primary setting for VOC treatment was in-patient hospitalization. The FAS included all randomized participants regardless of treatment received.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: days
    526
    256
    Statistical analysis title
    		 Treatment comparison: Ticagrelor Vs Placebo
    Statistical analysis description
    Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
    Comparison groups
    Ticagrelor 15/30/45 mg bd v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2011
    Method
    		 Negative binomial model
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 3.75

    Secondary: Number of Acute Sickle Cell Disease Complications

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    End point title
    		 Number of Acute Sickle Cell Disease Complications
    End point description
    The number of acute SCD complications is defined as the count of all individual acute SCD complications experienced by a participant over the treatment period. Acute SCD complications are defined as any one or more of the following individual complications: Transient ischaemic attack/ischaemic stroke, hepatic sequestration, splenic sequestration, priapism, and dactylitis. The statistical analysis was performed but the incidence rate of event and therefore incidence rate ratio did not converge. The FAS included all randomized participants regardless of treatment received.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: acute SCD complications
    6
    3
    No statistical analyses for this end point

    Secondary: Number of Days Hospitalized for Acute Sickle Cell Disease Complications

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    End point title
    		 Number of Days Hospitalized for Acute Sickle Cell Disease Complications
    End point description
    The number of days hospitalized for acute SCD complications is defined as the sum of the duration of all individual hospitalizations (taking into account potential overlapping hospitalization days) due to acute SCD complications experienced by a participant over the treatment period, for which hospitalization was reported. The FAS included all randomized participants regardless of treatment received. Here, 9999 = Upper limit of confidence interval was not calculable due to 0 events in Ticagrelor 15/30/45 mg bd reporting group.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: days
    0
    6
    Statistical analysis title
    		 Treatment comparison: Ticagrelor Vs Placebo
    Statistical analysis description
    Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
    Comparison groups
    Ticagrelor 15/30/45 mg bd v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.994
    Method
    		 Negative binomial model
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 9999

    Secondary: Number of Sickle Cell-Related Red Blood Cell (RBC) Transfusions

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    End point title
    		 Number of Sickle Cell-Related Red Blood Cell (RBC) Transfusions
    End point description
    The number of participants with at least one sickle cell-related RBC transfusion reported. Adverse events resulting in the need for RBC transfusions were captured prior to database lock to determine if the transfusion was sickle cell-related or not. The FAS included all randomized participants regardless of treatment received.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: RBC transfusions
    39
    49
    Statistical analysis title
    		 Treatment comparison: Ticagrelor Vs Placebo
    Statistical analysis description
    Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
    Comparison groups
    Ticagrelor 15/30/45 mg bd v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4822
    Method
    		 Negative binomial model
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.58

    Secondary: Health-Related Quality of Life Total Score Using the Paediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module

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    End point title
    		 Health-Related Quality of Life Total Score Using the Paediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module
    End point description
    The PedsQL SCD module instrument developed using a 5-point Likert scale (where 0= never and 4= almost always) for the participant self-report forms for ages ≥5 to <8 years, ≥8 to <13 years, and ≥13 to ≤18 years and the caregiver proxy-report form specific for ≥2 to <5 years was used. The PedsQL SCD module measures problems in the following categories: • Pain: 3 sub-scales • Worry: 2 sub-scales • Emotions: 1 sub-scale • Treatment: 1 sub-scale • Communication: 2 sub-scales • Total score PedsQL SCD module items were reverse-scored and linearly transformed to a 0 to 100 scale (0= 100, 1= 75, 2= 50, 3= 25, 4= 0) so that higher scores indicate better quality of life. Baseline values are closest observation prior to and including randomization visit. The FAS population. Here, n= number of participants analyzed at specific time point; 9999= Standard deviation could not be calculated as only 1 participant had analyzable data; 99999= No participants were analyzed at that specific time point.
    End point type
    Secondary
    End point timeframe
    For ages ≥2 to <5 years and ≥5 to <8 years: Baseline (observation prior to and including the randomization visit) and Months 6, and 12; For ages ≥8 to <13 years and ≥13 to ≤18 years: Baseline and Months 6, 12, and 18
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: score on a scale
    arithmetic mean (standard deviation)
        >=2 to <5 years: Baseline (n=5,10)
    88.81 ± 14.107
    67.02 ± 20.041
        >=2 to <5 years: Month 6 (n=6,10)
    80.75 ± 20.779
    81.37 ± 14.125
        >=2 to <5 years: Month 12 (n=0,1)
    99999 ± 99999
    88.10 ± 9999
        >=5 to <8 years: Baseline (n=24,14)
    75.05 ± 20.147
    74.04 ± 21.646
        >=5 to <8 years: Month 6 (n=23,14)
    83.04 ± 15.332
    84.91 ± 18.117
        >=5 to <8 years: Month 12 (n=2,1)
    65.63 ± 48.614
    97.50 ± 9999
        >=8 to <13 years: Baseline (n=31,46)
    62.35 ± 24.725
    67.98 ± 24.338
        >=8 to <13 years: Month 6 (n=28,43)
    76.52 ± 17.189
    75.76 ± 21.749
        >=8 to <13 years: Month 12 (n=6,7)
    83.20 ± 13.479
    64.12 ± 27.253
        >=8 to <13 years: Month 18 (n=1,0)
    86.05 ± 9999
    99999 ± 99999
        >=13 to <=18 years: Baseline (n=37,22)
    64.45 ± 18.746
    60.81 ± 24.979
        >=13 to <=18 years: Month 6 (n=36,20)
    68.13 ± 16.811
    74.42 ± 19.146
        >=13 to <=18 years: Month 12 (n=9,5)
    63.05 ± 19.810
    73.26 ± 22.589
        >=13 to <=18 years: Month 18 (n=1,0)
    65.12 ± 9999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Fatigue Total Score Using Paediatric Quality of Life Inventory Multidimensional Fatigue Scale

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    End point title
    		 Fatigue Total Score Using Paediatric Quality of Life Inventory Multidimensional Fatigue Scale
    End point description
    The PedsQL multidimensional fatigue scale instrument developed using a 5-point Likert scale (where 0= never and 4= almost always) for participant self-report forms for ages ≥5 to <8 years, ≥8 to <13 years, and ≥13 to ≤18 years and caregiver proxy-report form specific for ≥2 to <5 years was used. PedsQL multidimensional fatigue scale measures problems in following categories: • General (6 items) • Sleep/rest (6 items) • Cognitive fatigue (6 items) • Total score (18 items) PedsQL multidimensional fatigue scale items were reverse-scored and linearly transformed to a 0 to 100 scale (0= 100, 1= 75, 2= 50, 3= 25, 4= 0) so that higher scores indicate better quality of life. Baseline values are closest observation prior to and including randomization visit. FAS population. Here, n= number of participants analyzed at specific time point; 9999= Standard deviation could not be calculated as only 1 participant had analyzable data; 99999= No participants were analyzed at that specific time point.
    End point type
    Secondary
    End point timeframe
    For ages ≥2 to <5 years and ≥5 to <8 years: Baseline (observation prior to and including the randomization visit) and Months 6, and 12; For ages ≥8 to <13 years and ≥13 to ≤18 years: Baseline and Months 6, 12, and 18
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    101
    92
    Units: score on a scale
    arithmetic mean (standard deviation)
        >=2 to <5 years: Baseline (n=5,10)
    88.06 ± 16.304
    70.56 ± 23.220
        >=2 to <5 years: Month 6 (n=5,10)
    84.44 ± 15.541
    81.94 ± 22.775
        >=2 to <5 years: Month 12 (n=0,1)
    99999 ± 99999
    94.44 ± 9999
        >=5 to <8 years: Baseline (n=25,14)
    82.33 ± 11.450
    84.13 ± 16.139
        >=5 to <8 years: Month 6 (n=22,14)
    87.12 ± 10.553
    87.70 ± 16.076
        >=5 to <8 years: Month 12 (n=2,1)
    95.83 ± 5.893
    100.00 ± 9999
        >=8 to <13 years: Baseline (n=30,44)
    64.72 ± 26.779
    69.51 ± 25.261
        >=8 to <13 years: Month 6 (n=28,43)
    75.65 ± 18.571
    77.89 ± 22.283
        >=8 to <13 years: Month 12 (n=6,7)
    81.48 ± 17.866
    65.87 ± 25.495
        >=8 to <13 years: Month 18 (n=1,0)
    73.61 ± 9999
    99999 ± 99999
        >=13 to <=18 years: Baseline (n=36,22)
    68.06 ± 21.781
    67.17 ± 18.223
        >=13 to <=18 years: Month 6 (n=35,20)
    73.53 ± 19.138
    75.21 ± 14.913
        >=13 to <=18 years: Month 12 (n=9,5)
    67.13 ± 22.556
    60.28 ± 23.664
        >=13 to <=18 years: Month 18 (n=1,0)
    72.22 ± 9999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Percentage of Days of Absence From School or Work due to Sickle Cell Disease

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    End point title
    		 Percentage of Days of Absence From School or Work due to Sickle Cell Disease
    End point description
    For participants attending school/work at randomization, absence from school/work due to SCD was recorded weekly by the participant in the eDevice with the help of the caregiver if needed. The percentage of days absent from school/work due to SCD in the defined treatment period was calculated as follows: Percentage of absent days = (total number of days reported)/(total number of questionnaires answered ×7). The FAS included all randomized participants regardless of treatment received. Only participants going to school or work at randomization are reported.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    94
    82
    Units: percentage of days
        arithmetic mean (standard deviation)
    5.24 ± 8.942
    4.24 ± 4.964
    No statistical analyses for this end point

    Secondary: Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants <5 years of Age

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    End point title
    		 Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants <5 years of Age
    End point description
    The Face, Legs, Activity, Cry, Consolability (FLACC) scale is caregiver-reported and used to assess pain daily during the VOC event for those participants <5 years of age as determined at randomization. Each of the 5 behaviours observed are assigned a score of 0, 1 or 2. The total FLACC score ranges between 0 and 10, with 0 representing “no pain” and 10 representing “very much pain”. Lower score indicate better outcome. Worst pain ratings were collected once daily throughout the duration of the VOC event using an eDevice. The FAS included all randomized participants regardless of treatment received. Only participants <5 years of age who had experienced at least one individual VOC event and analyzed for pain assessment are reported.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    3
    5
    Units: score on a scale
        arithmetic mean (standard deviation)
    3.4 ± 2.51
    2.9 ± 1.99
    No statistical analyses for this end point

    Secondary: Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants ≥5 years of Age

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    End point title
    		 Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants ≥5 years of Age
    End point description
    The Faces Pain Scale-revised (FPS-R) was administered to assess pain daily during the VOC event by those participants aged ≥5 years as determined at randomization. The FPS-R consists of 6 faces and scoring ranges between 0 and 10 (with an increase in numeric value by 2), where 0 is “no pain” and 10 is “very much pain”. Lower score indicate better outcome. Worst pain ratings were collected once daily throughout the duration of the VOC event using an eDevice. The FAS included all randomized participants regardless of treatment received. Only participants ≥5 years of age who had experienced at least one individual VOC event and analyzed for pain assessment are reported.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    44
    40
    Units: score on a scale
        arithmetic mean (standard deviation)
    4.5 ± 2.71
    4.1 ± 2.02
    No statistical analyses for this end point

    Secondary: Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events

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    End point title
    		 Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events
    End point description
    Analgesics use (opioid and non-opioid) during VOC events. The FAS included all randomized participants regardless of treatment received. Only participants who had at least one VOC and took an analgesic are reported.
    End point type
    Secondary
    End point timeframe
    From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    70
    58
    Units: participants
        Opioids: Yes
    46
    22
        Opioids: No
    57
    50
        Non-opioids: Yes
    69
    57
        Non-opioids: No
    14
    7
    No statistical analyses for this end point

    Secondary: Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 years of Age

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    End point title
    		 Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 years of Age
    End point description
    Response to palatability was assessed through the SMPA question “Was any behaviour observed when the study medication was given to this participant that would be indicative of a negative response to the palatability of the study medication?”. This was presented as a binary outcome (that is, where “No” is no negative response and “Yes” is negative response). No negative response was considered as a positive outcome. Participants included in the Safety Analysis Set were analyzed for this endpoint. Here, n= number of participants ≤4 years of age who completed the assessment for study treatment palatability at the specific time point. NRP= Negative response to palatability.
    End point type
    Secondary
    End point timeframe
    Baseline (randomization visit) and Month 6
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    100
    92
    Units: participants
        Baseline: Whole tablet; NRP - No (n=5,8)
    5
    8
        Baseline: Whole tablet; NRP - Yes (n=5,8)
    0
    0
        Baseline: Dispersed tablet; NRP - No (n=1,2)
    1
    2
        Baseline: Dispersed tablet; NRP - Yes (n=1,2)
    0
    0
        Month 6: Whole tablet; NRP - No (n=4,9)
    4
    9
        Month 6: Whole tablet; NRP - Yes (n=4,9)
    0
    0
        Month 6: Dispersed tablet; NRP - No (n=1,1)
    1
    1
        Month 6: Dispersed tablet; NRP - Yes (n=1,1)
    0
    0
    No statistical analyses for this end point

    Secondary: Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 years of Age

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    End point title
    		 Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 years of Age
    End point description
    An observer’s assessment of the participant’s behaviour using the SMPA was performed for all participants taking the study treatment who are 2 to 4 years of age. Willingness to swallow was assessed and categorized as follows: • Swallowed without a problem • Some resistance but did swallow • Spit out some/all of the medication • Vomited up the medication. The category "swallowed without a problem" was considered as positive outcome. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available. Here, n= number of participants ≤4 years of age who completed the assessment for study treatment swallowability at the specific time point. WT= Whole tablet and DT= Dispersed tablet.
    End point type
    Secondary
    End point timeframe
    Baseline (randomization visit) and Month 6
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    100
    92
    Units: participants
        Baseline: WT; Swallow without problem (n=5,8)
    5
    8
        Baseline:WT;Some resistance but did swallow(n=5,8)
    0
    0
        Baseline: WT; Spit out some/all medication (n=5,8)
    0
    0
        Baseline: WT; Vomited up medication (n=5,8)
    0
    0
        Baseline: DT; Swallow without problem (n=1,2)
    1
    2
        Baseline:DT;Some resistance but did swallow(n=1,2)
    0
    0
        Baseline: DT; Spit out some/all medication (n=1,2)
    0
    0
        Baseline: DT; Vomited up medication (n=1,2)
    0
    0
        Month 6: WT; Swallow without problem (n=4,9)
    4
    9
        Month 6: WT;Some resistance but did swallow(n=4,9)
    0
    0
        Month 6: WT; Spit out some/all medication (n=4,9)
    0
    0
        Month 6: WT; Vomited up medication (n=4,9)
    0
    0
        Month 6: DT; Swallow without problem (n=1,1)
    1
    1
        Month 6: DT;Some resistance but did swallow(n=1,1)
    0
    0
        Month 6: DT; Spit out some/all medication (n=1,1)
    0
    0
        Month 6: DT; Vomited up medication (n=1,1)
    0
    0
    No statistical analyses for this end point

    Secondary: Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 years of Age

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    End point title
    		 Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 years of Age
    End point description
    The FHS method was used for all participants taking the study treatment who are ≥5 years of age. The FHS consists of 5 faces with descriptions ranging from “Dislike very much” to “Like very much”. The face with description "Like very much" was considered as positive outcome. The way in which the study treatment was taken, that is, whether the tablet is whole or dispersed, was captured. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available. Here, n= number of participants ≥5 years of age who completed the assessment for study treatment palatability at the specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline (randomization visit) and Month 6
    End point values
    		 Ticagrelor 15/30/45 mg bd Placebo
    Number of subjects analysed
    100
    92
    Units: participants
        Baseline: Whole tablet; Dislike very much(n=92,80)
    3
    2
        Baseline: Whole tablet; Dislike a little (n=92,80)
    4
    2
        Baseline: Whole tablet; Not sure (n=92,80)
    12
    8
        Baseline: Whole tablet; Like a little (n=92,80)
    25
    23
        Baseline: Whole tablet; Like very much (n=92,80)
    48
    45
        Baseline:Dispersed tablet;Dislike very much(n=1,2)
    0
    0
        Baseline:Dispersed tablet; Dislike a little(n=1,2)
    0
    0
        Baseline: Dispersed tablet; Not sure (n=1,2)
    1
    0
        Baseline: Dispersed tablet; Like a little (n=1,2)
    0
    1
        Baseline: Dispersed tablet; Like very much (n=1,2)
    0
    1
        Month 6: Whole tablet; Dislike very much(n=83,74)
    0
    0
        Month 6: Whole tablet; Dislike a little (n=83,74)
    5
    3
        Month 6: Whole tablet; Not sure (n=83,74)
    4
    4
        Month 6: Whole tablet; Like a little (n=83,74)
    30
    20
        Month 6: Whole tablet; Like very much (n=83,74)
    44
    47
        Month 6: Dispersed tablet;Dislike very much(n=1,0)
    0
    0
        Month 6: Dispersed tablet; Dislike a little(n=1,0)
    0
    0
        Month 6: Dispersed tablet; Not sure (n=1,0)
    1
    0
        Month 6: Dispersed tablet; Like a little (n=1,0)
    0
    0
        Month 6: Dispersed tablet; Like very much (n=1,0)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months.
    Adverse event reporting additional description
    The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Ticagrelor 15/30/45 mg bd
    Reporting group description
    		 Paediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: • Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. • Participants with a body weight >24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. • Participants with a body weight >48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.

    Reporting group title
    Placebo
    Reporting group description
    		 Paediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: • Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. • Participants with a body weight >24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. • Participants with a body weight >48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.

    Serious adverse events
    		 Ticagrelor 15/30/45 mg bd Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 100 (44.00%)
    29 / 92 (31.52%)
         number of deaths (all causes)
    3
    1
         number of deaths resulting from adverse events
    1
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Jaw fracture
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 100 (6.00%)
    7 / 92 (7.61%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersplenism
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 92 (3.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sickle cell anaemia with crisis
         subjects affected / exposed
    39 / 100 (39.00%)
    24 / 92 (26.09%)
         occurrences causally related to treatment / all
    0 / 75
    0 / 41
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 92 (3.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pemphigoid
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaria
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 100 (4.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 100 (6.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ticagrelor 15/30/45 mg bd Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 100 (82.00%)
    71 / 92 (77.17%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 100 (24.00%)
    18 / 92 (19.57%)
         occurrences all number
    44
    33
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    6 / 100 (6.00%)
    3 / 92 (3.26%)
         occurrences all number
    6
    3
    Sickle cell anaemia with crisis
         subjects affected / exposed
    60 / 100 (60.00%)
    49 / 92 (53.26%)
         occurrences all number
    190
    176
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    7 / 100 (7.00%)
    5 / 92 (5.43%)
         occurrences all number
    10
    5
    Pain
         subjects affected / exposed
    5 / 100 (5.00%)
    8 / 92 (8.70%)
         occurrences all number
    18
    9
    Pyrexia
         subjects affected / exposed
    11 / 100 (11.00%)
    10 / 92 (10.87%)
         occurrences all number
    15
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    15 / 100 (15.00%)
    10 / 92 (10.87%)
         occurrences all number
    35
    16
    Diarrhoea
         subjects affected / exposed
    3 / 100 (3.00%)
    5 / 92 (5.43%)
         occurrences all number
    5
    5
    Vomiting
         subjects affected / exposed
    6 / 100 (6.00%)
    2 / 92 (2.17%)
         occurrences all number
    8
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 100 (17.00%)
    7 / 92 (7.61%)
         occurrences all number
    22
    11
    Epistaxis
         subjects affected / exposed
    6 / 100 (6.00%)
    8 / 92 (8.70%)
         occurrences all number
    9
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 100 (14.00%)
    14 / 92 (15.22%)
         occurrences all number
    17
    21
    Back pain
         subjects affected / exposed
    21 / 100 (21.00%)
    12 / 92 (13.04%)
         occurrences all number
    28
    16
    Pain in extremity
         subjects affected / exposed
    28 / 100 (28.00%)
    23 / 92 (25.00%)
         occurrences all number
    58
    39
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    6 / 100 (6.00%)
    4 / 92 (4.35%)
         occurrences all number
    7
    5
    Malaria
         subjects affected / exposed
    12 / 100 (12.00%)
    7 / 92 (7.61%)
         occurrences all number
    15
    8
    Nasopharyngitis
         subjects affected / exposed
    4 / 100 (4.00%)
    6 / 92 (6.52%)
         occurrences all number
    7
    7
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 100 (19.00%)
    24 / 92 (26.09%)
         occurrences all number
    28
    33
    Urinary tract infection
         subjects affected / exposed
    2 / 100 (2.00%)
    5 / 92 (5.43%)
         occurrences all number
    3
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Apr 2020
    New subsection was added to allow modification of study conduct during COVID-19 pandemic including visits, Investigational Product administration, and procedures.

    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.
    AstraZeneca took the decision to terminate the study early, following a recommendation from the independent Data Monitoring Committee. This early termination was not considered to have had an impact on the robustness of the study results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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