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    Clinical Trial Results:
    Study of the Effect of Ticagrelor and Clopidogrel on the Immune Response of Healthy Volunteers

    Summary
    EudraCT number
    		 2012-005514-18
    Trial protocol
    		 GB  
    Global end of trial date
    10 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2022
    First version publication date
    14 Oct 2022
    Other versions
    Summary report(s)
    		 End of Trial Report

    Trial information

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    Trial identification
    Sponsor protocol code
    STH17062
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01846559
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sheffield Teaching Hospitals NHS Foundation Trust
    Sponsor organisation address
    Trust Headquarters, 8 Beech Hill Road, Sheffield, United Kingdom, S10 2SB
    Public contact
    Dr Dipak Patel, Sheffield Teaching Hospitals NHS Foundation Trust, sth.ResearchAdministration@nhs.net
    Scientific contact
    Dr Dipak Patel, Sheffield Teaching Hospitals NHS Foundation Trust, sth.ResearchAdministration@nhs.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Do the anti-clotting medications, ticagrelor and clopidogrel, also have an effect on the immune response?
    Protection of trial subjects
    Careful monitoring with prompt appropriate treatment for symptoms caused by endotoxaemia e.g. nausea or pain.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Feb 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 44 healthy volunteers consented and screened, of which 30 proceeded to randomisation and are therefore included in this report.

    Pre-assignment
    Screening details
    		 Healthy volunteers were recruited by local advertising using approved posters and email wording. Eligibility criteria was as follows: aged between 18- 65 years, non smokers, BMI 18- 28, body weight 60-100 kg, in good health, providing informed consent, females not of child bearing potential. Screen fails did not meet the above criteria.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 No study medication
    Arm description
    		 No study medication
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Ticagrelor
    Arm description
    		 Loading dose of ticagrelor 180 mg on day 1 followed by ticagrelor 90 mg BD for 6 days prior to endotoxin injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ticagrelor
    Investigational medicinal product code
    274693-27-5
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    180 mg loading dose of ticagrelor on d1 followed by 90 mg BD for the following 6 days.

    Arm title
    		 Clopidogrel
    Arm description
    		 300 mg loading dose of clopidogrel on day 1 followed by 6 days of 75 mg clopidogrel OD
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    113665-84-2
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of 300 mg clopidogrel on day 1 followed by 6 days of clopidogrel 75 mg OD

    Number of subjects in period 1
    		No study medication Ticagrelor Clopidogrel
    Started
    10
    10
    10
    Screening
    10
    10
    10
    Randomisation
    10
    10
    10
    IMP administration
    10
    10
    10
    Completed
    10
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    No study medication
    Reporting group description
    		 No study medication

    Reporting group title
    Ticagrelor
    Reporting group description
    		 Loading dose of ticagrelor 180 mg on day 1 followed by ticagrelor 90 mg BD for 6 days prior to endotoxin injection.

    Reporting group title
    Clopidogrel
    Reporting group description
    		 300 mg loading dose of clopidogrel on day 1 followed by 6 days of 75 mg clopidogrel OD

    Reporting group values
    		 No study medication Ticagrelor Clopidogrel Total
    Number of subjects
    		 10 10 10 30
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 10 10 10 30
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0
        Male
    		 10 10 10 30
    Subject analysis sets

    Subject analysis set title
    Randomised Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised participants

    Subject analysis sets values
    		 Randomised Participants
    Number of subjects
    30
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    30
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
    0
        Male
    30

    End points

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    End points reporting groups
    Reporting group title
    No study medication
    Reporting group description
    		 No study medication

    Reporting group title
    Ticagrelor
    Reporting group description
    		 Loading dose of ticagrelor 180 mg on day 1 followed by ticagrelor 90 mg BD for 6 days prior to endotoxin injection.

    Reporting group title
    Clopidogrel
    Reporting group description
    		 300 mg loading dose of clopidogrel on day 1 followed by 6 days of 75 mg clopidogrel OD

    Subject analysis set title
    Randomised Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised participants

    Primary: TNF alpha

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    End point title
    		 TNF alpha
    End point description
    End point type
    Primary
    End point timeframe
    Measured at 2 hours post endotoxin administration.
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: pg/ml
        arithmetic mean (standard error)
    107.7 ( 27.8 )
    41.9 ( 16.3 )
    43.0 ( 11.9 )
    Statistical analysis title
    		 Dunnetts test
    Statistical analysis description
    Multiple comparison between groups at 2 hours post endotoxin administration.
    Comparison groups
    No study medication v Ticagrelor
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.0001
    Method
    		 Dunnetts test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -65.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -87.59
         upper limit
    		 -44.02
    Variability estimate
    Standard error of the mean

    Secondary: High sensitivity C-reactive protein

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    End point title
    		 High sensitivity C-reactive protein
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours after endotoxin administration
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: mg/L
        arithmetic mean (standard deviation)
    32.7 ( 13.9 )
    27.6 ( 4.3 )
    28.3 ( 10.4 )
    No statistical analyses for this end point

    Secondary: Leucocyte count

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    End point title
    		 Leucocyte count
    End point description
    End point type
    Secondary
    End point timeframe
    2 hours after endotoxin administration
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: x10^9/L
        arithmetic mean (standard deviation)
    5.9 ( 1.1 )
    8.5 ( 3.6 )
    7.6 ( 2.2 )
    No statistical analyses for this end point

    Secondary: Neutrophil count

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    End point title
    		 Neutrophil count
    End point description
    End point type
    Secondary
    End point timeframe
    2 hours after endotoxin administration
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: x10^9/L
        arithmetic mean (standard deviation)
    5.2 ( 1.3 )
    7.6 ( 3.5 )
    6.7 ( 2.1 )
    No statistical analyses for this end point

    Secondary: Platelet count

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    End point title
    		 Platelet count
    End point description
    End point type
    Secondary
    End point timeframe
    2 hours after endotoxin administration
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: x10^9/L
        arithmetic mean (standard deviation)
    198.6 ( 31.1 )
    209.4 ( 47.7 )
    203.5 ( 29.1 )
    No statistical analyses for this end point

    Secondary: Monocyte count

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    End point title
    		 Monocyte count
    End point description
    End point type
    Secondary
    End point timeframe
    2 hours after endotoxin administration
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: x10^9/L
        arithmetic mean (standard deviation)
    0.03 ( 0.01 )
    0.05 ( 0.03 )
    0.04 ( 0.02 )
    No statistical analyses for this end point

    Secondary: Macrophage chemoattractant protein 1

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    End point title
    		 Macrophage chemoattractant protein 1
    End point description
    End point type
    Secondary
    End point timeframe
    4 hours after endotoxin administration
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: pg/mL
        arithmetic mean (standard deviation)
    4934.5 ( 1938.7 )
    3043.2 ( 2027.8 )
    4023.6 ( 2775.5 )
    No statistical analyses for this end point

    Secondary: Granulocyte colony stimulating factor

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    End point title
    		 Granulocyte colony stimulating factor
    End point description
    End point type
    Secondary
    End point timeframe
    4 hours after endotoxin administration
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: pg/mL
        arithmetic mean (standard deviation)
    102.1 ( 28.2 )
    55.6 ( 15.0 )
    83.8 ( 20.6 )
    No statistical analyses for this end point

    Secondary: Interleukin-10

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    End point title
    		 Interleukin-10
    End point description
    End point type
    Secondary
    End point timeframe
    2 hours after endotoxin administration
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: pg/mL
        arithmetic mean (standard deviation)
    20.3 ( 20.9 )
    31.9 ( 44.0 )
    22.8 ( 10.4 )
    No statistical analyses for this end point

    Secondary: Interleukin-8

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    End point title
    		 Interleukin-8
    End point description
    End point type
    Secondary
    End point timeframe
    2 hours after endotoxin administration
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: pg/mL
        arithmetic mean (standard deviation)
    583.7 ( 187.4 )
    463.2 ( 252.2 )
    550.3 ( 262.2 )
    No statistical analyses for this end point

    Secondary: Platelet monocyte aggregates

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    End point title
    		 Platelet monocyte aggregates
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours after endotoxin administration, with ADP stimulation
    End point values
    		 No study medication Ticagrelor Clopidogrel
    Number of subjects analysed
    10
    10
    10
    Units: MFI
        arithmetic mean (standard deviation)
    5862.1 ( 2756.5 )
    2301.1 ( 457.2 )
    3002.4 ( 1851.4 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for EudraCT report: enrolment to 30 days after last administration of IMP
    Adverse event reporting additional description
    Adverse events were collected as per protocol from the time of informed consent to until 30 days after last administration of the IMP, EudraCT allows for entering AEs for enrolled participants only.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    All randomised participants
    Reporting group description
    		 -

    Serious adverse events
    		 All randomised participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 30 (3.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Musculoskeletal and connective tissue disorders
    Fracture of tibia
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All randomised participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 30 (93.33%)
    Investigations
    Monocyte count decreased
         subjects affected / exposed
    24 / 30 (80.00%)
         occurrences all number
    24
    Lymphocyte count low
         subjects affected / exposed
    24 / 30 (80.00%)
         occurrences all number
    24
    Neutrophils increased
         subjects affected / exposed
    24 / 30 (80.00%)
         occurrences all number
    24
    Hemoglobin low
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Eosinophil count decreased
         subjects affected / exposed
    18 / 30 (60.00%)
         occurrences all number
    18
    Eosinophil count increased
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Neutrophil count low
         subjects affected / exposed
    10 / 30 (33.33%)
         occurrences all number
    10
    White blood cell count low
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    6
    Raised bilirubin
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Platelet count low
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    ALT increased
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    4
    Red blood cell count low
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    T wave inversion
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Cardiac disorders
    Light-headed
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Sinus bradycardia
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Nervous system disorders
    Tingling feet/hands
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Restless
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    9 / 30 (30.00%)
         occurrences all number
    9
    Shivering
         subjects affected / exposed
    14 / 30 (46.67%)
         occurrences all number
    14
    Hot
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Cold
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Eye disorders
    Photophobia
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Yawn
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Muscle ache
         subjects affected / exposed
    8 / 30 (26.67%)
         occurrences all number
    8
    Aches & pains in legs
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Aug 2013
    Change of brand of clopidogrel during the trial period.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26515417
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    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
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