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    Clinical Trial Results:
    Safety and efficacy of clopidogrel when added to aspirin and dipyridamole in high risk patients with recent ischaemic stroke or TIA: a randomised controlled trial

    Summary
    EudraCT number
    		 2007-006749-42
    Trial protocol
    		 GB   DK  
    Global end of trial date
    30 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    31350
    Additional study identifiers
    ISRCTN number
    		 ISRCTN47823388
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Nottingham
    Sponsor organisation address
    Kings Meadow Campus, Lenton Lane, Nottingham, United Kingdom, NG7 2NR
    Public contact
    TARDIS Trial Office, University of Nottingham, +44 01158230210, tardis@nottingham.ac.uk
    Scientific contact
    TARDIS Trial Office, University of Nottingham, +44 01158230210, tardis@nottingham.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    15 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the safety of short-term administration (1 month) of intensive antiplatelet therapy (aspirin, dipyridamole and clopidogrel) versus current guideline therapy (dual aspirin and dipyridamole, or clopidogrel monotherapy) in patients with very recent ischaemic stroke or TIA.
    Protection of trial subjects
    N/A
    Background therapy
    		 Standard NHS care
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    01 Apr 2009
    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
    United Kingdom: 2955
    Country: Number of subjects enrolled
    Denmark: 51
    Country: Number of subjects enrolled
    New Zealand: 7
    Country: Number of subjects enrolled
    Georgia: 83
    Worldwide total number of subjects
    3096
    EEA total number of subjects
    3006
    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)
    1093
    From 65 to 84 years
    1798
    85 years and over
    205

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment commenced in UK on 01/04/09, followed by Denmark on 01/07/13, New Zealand 18/10/13 and Georgia on 19/06/14.

    Pre-assignment
    Screening details
    		 Adults at high risk of recurrent ischaemic stroke. Stroke type confirmed by CT/MRI scan.

    Period 1
    Period 1 title
    Randomisation
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intensive
    Arm description
    		 Clopidogrel, Aspirin and Dipyridamole
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Loading dose of 300mg followed by 30 days of 75mg per day

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Loading dose of 300mg at randomisation followed by 75mg for 30 days

    Investigational medicinal product name
    Dipyridamole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    200mg tablet twice per day for 30 days

    Arm title
    		 Guideline
    Arm description
    		 Guideline therapy either clopidogrel alone or aspirin and dipyridamole
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Loading dose of 300mg followed by 30 days of 75mg per day

    Investigational medicinal product name
    aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Loading dose of 300mg followed by daily dose of 75mg for 28 days

    Investigational medicinal product name
    Dipyridamole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    200mg twice daily

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Final assessment completed by blinded assessor
    Number of subjects in period 1
    		Intensive Guideline
    Started
    1556
    1540
    Completed
    1556
    1540
    Period 2
    Period 2 title
    Baseline
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [2]
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intensive
    Arm description
    		 Clopidogrel, Aspirin and Dipyridamole
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Loading dose of 300mg followed by 30 days of 75mg per day

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Loading dose of 300mg at randomisation followed by 75mg for 30 days

    Investigational medicinal product name
    Dipyridamole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    200mg tablet twice per day for 30 days

    Arm title
    		 Guideline
    Arm description
    		 Clopidogrel or Aspirin and Dipyridamole
    Arm type
    		 Guideline therapy

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Loading dose of 300mg followed by 30 days of 75mg per day

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Loading dose of 300mg at randomisation followed by 75mg for 30 days

    Investigational medicinal product name
    Dipyridamole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    200mg tablet twice per day for 30 days

    Notes
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Final assessment completed by blinded assessor
    Number of subjects in period 2
    		Intensive Guideline
    Started
    1556
    1540
    Completed
    1556
    1540
    Period 3
    Period 3 title
    Day 7 face to face follow up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intensive
    Arm description
    		 Clopidogrel, Aspirin and Dipyridamole
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Loading dose of 300mg followed by 30 days of 75mg per day

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Loading dose of 300mg at randomisation followed by 75mg for 30 days

    Investigational medicinal product name
    Dipyridamole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    200mg tablet twice per day for 30 days

    Arm title
    		 Guideline
    Arm description
    		 Clopidogrel or Aspirin and Dipyridamole
    Arm type
    		 Guideline therapy

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Loading dose of 300mg followed by 30 days of 75mg per day

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Loading dose of 300mg at randomisation followed by 75mg for 30 days

    Investigational medicinal product name
    Dipyridamole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    200mg tablet twice per day for 30 days

    Number of subjects in period 3
    		Intensive Guideline
    Started
    1556
    1540
    Recurrent stroke/TIA
    41 [3]
    57 [4]
    Completed
    1525
    1502
    Not completed
    31
    38
         Adverse event, serious fatal
    6
    6
         Consent withdrawn by subject
    19
    18
         Logistical problem
    6
    14
    Notes
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants were able to withdraw from a particular follow up without having to withdraw fully from the trial. Patients who suffered from a recurrent stroke or TIA were also asked to complete further follow ups. This meant they were still able to complete future follow ups if they wished.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants were able to withdraw from a particular follow up without having to withdraw fully from the trial. Patients who suffered from a recurrent stroke or TIA were also asked to complete further follow ups. This meant they were still able to complete future follow ups if they wished.
    Period 4
    Period 4 title
    Day 35 face to face follow up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [5]
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intensive
    Arm description
    		 Clopidogrel, Aspirin and Dipyridamole
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Loading dose of 300mg followed by 30 days of 75mg per day

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Loading dose of 300mg at randomisation followed by 75mg for 30 days

    Investigational medicinal product name
    Dipyridamole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    200mg tablet twice per day for 30 days

    Arm title
    		 Guideline
    Arm description
    		 Clopidogrel or Aspirin and Dipyridamole
    Arm type
    		 Guideline therapy

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Loading dose of 300mg followed by 30 days of 75mg per day

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Loading dose of 300mg at randomisation followed by 75mg for 30 days

    Investigational medicinal product name
    Dipyridamole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    200mg tablet twice per day for 30 days

    Notes
    [5] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Final assessment completed by blinded assessor
    Number of subjects in period 4
    		Intensive Guideline
    Started
    1525
    1502
    Recurrent stroke/TIA
    70 [6]
    83 [7]
    Completed
    1490
    1483
    Not completed
    66
    57
         Adverse event, serious fatal
    14
    14
         Consent withdrawn by subject
    32
    27
         Logistical problem
    20
    16
    Joined
    31
    38
         Agreed to complete follow up
    31
    38
    Notes
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants were able to withdraw from a particular follow up without having to withdraw fully from the trial. Patients who suffered from a recurrent stroke or TIA were also asked to complete further follow ups. This meant they were still able to complete future follow ups if they wished.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants were able to withdraw from a particular follow up without having to withdraw fully from the trial. Patients who suffered from a recurrent stroke or TIA were also asked to complete further follow ups. This meant they were still able to complete future follow ups if they wished.
    Period 5
    Period 5 title
    Day 90 telephone follow up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [8]
    Blinding implementation details
    Follow up coordinator not involved with participant prior to follow up call and unaware of randomisation

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intensive
    Arm description
    		 Clopidogrel, Aspirin and Dipyridamole
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Loading dose of 300mg followed by 30 days of 75mg per day

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Loading dose of 300mg at randomisation followed by 75mg for 30 days

    Investigational medicinal product name
    Dipyridamole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    200mg tablet twice per day for 30 days

    Arm title
    		 Guideline
    Arm description
    		 Clopidogrel or Aspirin and Dipyridamole
    Arm type
    		 Guideline therapy

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Loading dose of 300mg followed by 30 days of 75mg per day

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Loading dose of 300mg at randomisation followed by 75mg for 30 days

    Investigational medicinal product name
    Dipyridamole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    200mg tablet twice per day for 30 days

    Notes
    [8] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Final assessment completed by blinded assessor
    Number of subjects in period 5
    		Intensive Guideline
    Started
    1490
    1483
    Recurrent stroke/TIA
    93 [9]
    105 [10]
    Completed
    1514
    1502
    Not completed
    42
    38
         Adverse event, serious fatal
    26
    28
         Consent withdrawn by subject
    15
    5
         Reason unknown
    1
    -
         Lost to follow-up
    -
    5
    Joined
    66
    57
         Agreed to complete follow up
    66
    57
    Notes
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants were able to withdraw from a particular follow up without having to withdraw fully from the trial. Patients who suffered from a recurrent stroke or TIA were also asked to complete further follow ups. This meant they were still able to complete future follow ups if they wished.
    [10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants were able to withdraw from a particular follow up without having to withdraw fully from the trial. Patients who suffered from a recurrent stroke or TIA were also asked to complete further follow ups. This meant they were still able to complete future follow ups if they wished.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Randomisation
    Reporting group description
    		 Number of participants recruited in to the trial

    Reporting group values
    		 Randomisation Total
    Number of subjects
    		 3096 3096
    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)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 973 973
        From 65-84 years
    		 1918 1918
        85 years and over
    		 205 205
    Age continuous
    Average age
    Units: years
        arithmetic mean (standard deviation)
    		 69 ± 10.1 -
    Gender categorical
    Female
    Units: Subjects
        Female
    		 1151 1151
        Male
    		 1945 1945
    Subject analysis sets

    Subject analysis set title
    All participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Analysis of baseline characteristics of all participants

    Subject analysis set title
    Stroke
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants randomised with non-cardio embolic ischaemic stroke

    Subject analysis set title
    TIA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants randomised with Transient ischaemic attack

    Subject analysis sets values
    		 All participants Stroke TIA
    Number of subjects
    3096
    2143
    953
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    973
    723
    250
        From 65-84 years
    1918
    1281
    637
        85 years and over
    205
    139
    66
    Age continuous
    Average age
    Units: years
        arithmetic mean (standard deviation)
    69 ± 10.1
    68.5 ± 10.1
    70.2 ± 9.9
    Gender categorical
    Female
    Units: Subjects
        Female
    1151
    787
    364
        Male
    1945
    1356
    589

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Intensive
    Reporting group description
    		 Clopidogrel, Aspirin and Dipyridamole

    Reporting group title
    Guideline
    Reporting group description
    		 Guideline therapy either clopidogrel alone or aspirin and dipyridamole
    Reporting group title
    Intensive
    Reporting group description
    		 Clopidogrel, Aspirin and Dipyridamole

    Reporting group title
    Guideline
    Reporting group description
    		 Clopidogrel or Aspirin and Dipyridamole
    Reporting group title
    Intensive
    Reporting group description
    		 Clopidogrel, Aspirin and Dipyridamole

    Reporting group title
    Guideline
    Reporting group description
    		 Clopidogrel or Aspirin and Dipyridamole
    Reporting group title
    Intensive
    Reporting group description
    		 Clopidogrel, Aspirin and Dipyridamole

    Reporting group title
    Guideline
    Reporting group description
    		 Clopidogrel or Aspirin and Dipyridamole
    Reporting group title
    Intensive
    Reporting group description
    		 Clopidogrel, Aspirin and Dipyridamole

    Reporting group title
    Guideline
    Reporting group description
    		 Clopidogrel or Aspirin and Dipyridamole

    Subject analysis set title
    All participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Analysis of baseline characteristics of all participants

    Subject analysis set title
    Stroke
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants randomised with non-cardio embolic ischaemic stroke

    Subject analysis set title
    TIA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants randomised with Transient ischaemic attack

    Primary: Primary outcome recurrent stroke and TIA by severity

    		 Close Top of page
    End point title
    		 Primary outcome recurrent stroke and TIA by severity
    End point description
    Ordered categorical scale
    End point type
    Primary
    End point timeframe
    By Day 90 follow up
    End point values
    		 Intensive Guideline
    Number of subjects analysed
    1540
    1530
    Units: 3096
    number (not applicable)
        No event
    1447
    1425
        TIA
    32
    48
        Stroke MRS 0/1
    15
    18
        Stroke MRS 2/3
    22
    23
        Stroke MRS 4/5
    11
    9
        Fatal stroke MRS 6
    13
    7
    Statistical analysis title
    		 Primary outcome analysis
    Statistical analysis description
    This analysis has been adjusted for country, index event, guideline comparator choice, age, sex, pre-morbid mRS, time from onset to randomisation, number of antiplatelets on before index event, stroke syndrome, systolic BP, use of gastroprotection medication, use of heparin (low dose), stroke severity (NIHSS), use of rt-PA treatment, ABCD2 score and number of TIAs in the last week.
    Comparison groups
    Intensive v Guideline
    Number of subjects included in analysis
    3070
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 Ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.2

    Secondary: Safety outcome, bleeding by severity

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    End point title
    		 Safety outcome, bleeding by severity
    End point description
    Ordered categorical scale of bleeding events
    End point type
    Secondary
    End point timeframe
    By day 90 follow up
    End point values
    		 Intensive Guideline
    Number of subjects analysed
    1541
    1531
    Units: Number
        Fatal bleed
    8
    3
        Major bleed
    31
    14
        Moderate bleed
    25
    13
        Minor bleed
    241
    109
        No bleeding event
    1236
    1392
    Statistical analysis title
    		 Safety outcome analysis
    Statistical analysis description
    This analysis has been adjusted for country, index event, guideline comparator choice, age, sex, pre-morbid mRS, time from onset to randomisation, number of antiplatelets on before index event, stroke syndrome, systolic BP, use of gastroprotection medication, use of heparin (low dose), stroke severity (NIHSS), use of rt-PA treatment, ABCD2 score and number of TIAs in the last week.
    Comparison groups
    Intensive v Guideline
    Number of subjects included in analysis
    3072
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.05
         upper limit
    		 3.16

    Secondary: Composite outcome, Stroke or major bleed

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    End point title
    		 Composite outcome, Stroke or major bleed
    End point description
    Composite binary outcome of stroke and major (including fatal) bleeding
    End point type
    Secondary
    End point timeframe
    By day 90 followup
    End point values
    		 Intensive Guideline
    Number of subjects analysed
    1540
    1530
    Units: Number
        Stroke or Major bleed
    87
    69
        No event
    1453
    1461
    Statistical analysis title
    		 Composite outcome analysis
    Statistical analysis description
    This analysis has been adjusted for country, index event, guideline comparator choice, age, sex, pre-morbid mRS, time from onset to randomisation, number of antiplatelets on before index event, stroke syndrome, systolic BP, use of gastroprotection medication, use of heparin (low dose), stroke severity (NIHSS), use of rt-PA treatment, ABCD2 score and number of TIAs in the last week.
    Comparison groups
    Intensive v Guideline
    Number of subjects included in analysis
    3070
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.7

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    01/04/09 - 30/06/16
    Adverse event reporting additional description
    Clinician assessed during hospitalisation and researcher/patient assessed during follow ups
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Excel spreadsheet
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Intensive
    Reporting group description
    		 Clopidogrel, Aspirin and Dipyridamole

    Reporting group title
    Guideline
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: All adverse events were adjudicated as serious adverse events
    Serious adverse events
    		 Intensive Guideline
    Total subjects affected by serious adverse events
         subjects affected / exposed
    592 / 1556 (38.05%)
    496 / 1540 (32.21%)
         number of deaths (all causes)
    26
    28
         number of deaths resulting from adverse events
    7
    5
    Cardiac disorders
    Cardiovascular disorder
    Additional description: Grouping of all cardiovascular events
         subjects affected / exposed
    130 / 1556 (8.35%)
    153 / 1540 (9.94%)
         occurrences causally related to treatment / all
    7 / 143
    4 / 172
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    191 / 1556 (12.28%)
    183 / 1540 (11.88%)
         occurrences causally related to treatment / all
    99 / 219
    58 / 216
         deaths causally related to treatment / all
    5 / 14
    5 / 12
    Blood and lymphatic system disorders
    Haematological disorders
         subjects affected / exposed
    13 / 1556 (0.84%)
    14 / 1540 (0.91%)
         occurrences causally related to treatment / all
    10 / 13
    12 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Miscellaneous
         subjects affected / exposed
    52 / 1556 (3.34%)
    51 / 1540 (3.31%)
         occurrences causally related to treatment / all
    16 / 52
    10 / 55
         deaths causally related to treatment / all
    1 / 5
    0 / 9
    Immune system disorders
    Immune system disorder
         subjects affected / exposed
    4 / 1556 (0.26%)
    1 / 1540 (0.06%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye disorder
         subjects affected / exposed
    12 / 1556 (0.77%)
    6 / 1540 (0.39%)
         occurrences causally related to treatment / all
    9 / 12
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal events
         subjects affected / exposed
    91 / 1556 (5.85%)
    49 / 1540 (3.18%)
         occurrences causally related to treatment / all
    67 / 97
    31 / 49
         deaths causally related to treatment / all
    1 / 3
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    87 / 1556 (5.59%)
    67 / 1540 (4.35%)
         occurrences causally related to treatment / all
    62 / 100
    32 / 75
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Skin and subcutaneous tissue disorders
    Cutaneous
         subjects affected / exposed
    159 / 1556 (10.22%)
    58 / 1540 (3.77%)
         occurrences causally related to treatment / all
    167 / 180
    46 / 62
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Genito-urinary
         subjects affected / exposed
    46 / 1556 (2.96%)
    25 / 1540 (1.62%)
         occurrences causally related to treatment / all
    34 / 56
    7 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    9 / 1556 (0.58%)
    14 / 1540 (0.91%)
         occurrences causally related to treatment / all
    5 / 9
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolic disorder
         subjects affected / exposed
    5 / 1556 (0.32%)
    8 / 1540 (0.52%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intensive Guideline
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 1556 (0.00%)
    0 / 1540 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Feb 2012
    Guideline group changed from aspirin and dipyridamole to aspirin and dipyridamole or clopidogrel

    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.
    N/A
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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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