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    Clinical Trial Results:
    Dual Antiplatelet Therapy to Inhibit Coronary Atherosclerosis and Myocardial Injury in Patients with Necrotic High-risk Coronary Plaque Disease

    Summary
    EudraCT number
    2014-000952-26
    Trial protocol
    GB  
    Global end of trial date
    03 Apr 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Mar 2019
    First version publication date
    27 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14/SS/0089
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02110303
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Edinburgh & NHS Lothian
    Sponsor organisation address
    Old College, South Bridge, Edinburgh, United Kingdom, EH8 9YL
    Public contact
    Professor David Newby, University of Edinburgh, d.e.newby@ed.ac.uk
    Scientific contact
    Professor David Newby, University of Edinburgh, d.e.newby@ed.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
    Final
    Date of interim/final analysis
    31 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if ticagrelor (a blood thinning medication) reduces the levels of plasma high-sensitivity cardiac troponin I (a protein in the blood that is associated with increased risk of heart attacks in the future) in patients with stable heart disease but evidence of high-risk features on heart scans.
    Protection of trial subjects
    This clinical trial was carried out with the approval of the national research ethics committee in accordance with the Declaration of Helsinki (2000), under a Clinical Trial Authorisation from the Medicine and Healthcare Products Regulatory Authority (MHRA, United Kingdom), and the written informed consent of all participants. The CT and PET scans involved the administration of contrast 'dye' which can cause kidney problems or allergic reactions so patients who had significant kidney disease or a history of allergic reactions to contrast dye were excluded from the trial. The PET scan involved the administration of a injected radioactive tracer chemical (18F-NaF). This type of chemical tracer is routinely used in PET-CT scans and a well developed protocol was in place to minimise radiation exposure to the patient and to ensure safe handling and administration of the tracer. To avoid an excessive risk of bleeding patients who were already taking blood thinning medications other than aspirin (e.g. warfarin, clopidogrel) were excluded from the study. There is a small bleeding risk associated with taking ticagrelor so patients who were at high risk or had a history of serious bleeding problems were also excluded from the trial.
    Background therapy
    All subjects in both arms were receiving aspirin on recruitment to the trial. They were mandated in the protocol to be maintained on aspirin 75 mg once daily during the trial and were also to be maintained on the maximally tolerated dose of statin. Subjects were encouraged to be maintained on maximally tolerated doses of angiotensin-converting enzyme inhibition and beta-blocker therapy as clinically indicated and in accordance with local guidelines.
    Evidence for comparator
    A matched placebo comparator was used to ensure blinding in the trial and so avoid potential for systematic biases in outcome measures.
    Actual start date of recruitment
    13 Mar 2015
    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: 202
    Worldwide total number of subjects
    202
    EEA total number of subjects
    202
    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)
    79
    From 65 to 84 years
    123
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients with stable coronary disease were recruited from Royal Infirmary of Edinburgh, Scotland. Recruitment to the study commenced on the 13th March 2015. The first participant was randomised on the 30th March 2015 and the last patient was randomised on 25th April 2017.

    Pre-assignment
    Screening details
    A total of 361 patients were approached to participate in the study and 220 were consented. The other 141 patients declined to participate, were ineligible, or were already taking part in another CTIMP. Eighteen of those who were consented subsequently changed their mind about participating or became ineligible, so 202 patients were randomised.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    A matched placebo comparator was supplied by the drug manufacturer to ensure the subject and clinical research team were blinded to the allocated treatment. An indication of treatment allocation could have potentially been apparent from the platelet-monocyte aggregate testing, so this testing was performed by an unblinded technician who was distinct from the clinical team and the results were not released to the research team until the end of the trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ticagrelor
    Arm description
    Ticagrelor 90 mg tablet twice daily for 12 months
    Arm type
    Experimental

    Investigational medicinal product name
    Ticagrelor
    Investigational medicinal product code
    ATC Code: B01AC24
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 90 mg tablet twice daily for 12 months

    Arm title
    Placebo
    Arm description
    Matched placebo tablet twice daily for 12 months
    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
    One tablet twice daily for 12 months

    Number of subjects in period 1
    Ticagrelor Placebo
    Started
    101
    101
    Completed
    94
    95
    Not completed
    7
    6
         Physician decision
    2
    2
         Deceased
    1
    -
         Consent withdrawn by subject
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ticagrelor
    Reporting group description
    Ticagrelor 90 mg tablet twice daily for 12 months

    Reporting group title
    Placebo
    Reporting group description
    Matched placebo tablet twice daily for 12 months

    Reporting group values
    Ticagrelor Placebo Total
    Number of subjects
    101 101 202
    Age categorical
    Units: Subjects
        18-64 years
    41 38 79
        65-84 years
    60 63 123
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.5 ± 8.3 66.4 ± 8.1 -
    Gender categorical
    Units: Subjects
        Female
    20 20 40
        Male
    81 81 162
    Increased coronary 18F-NaF uptake on PET-CT scan
    Units: Subjects
        Yes
    63 65 128
        No
    38 36 74
    Plasma high sensitivity cardiac troponin I concentration
    Units: ng/L
        median (inter-quartile range (Q1-Q3))
    3.5 (2.0 to 6.0) 3.0 (1.7 to 6.0) -
    Subject analysis sets

    Subject analysis set title
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in sub-group of the per protocol population who had increased coronary 18F-NaF uptake on baseline PET-CT scan and received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis set title
    Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in sub-group of the per protocol population who had increased coronary 18F-NaF uptake on baseline PET-CT scan and received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis set title
    Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in sub-group of the per protocol population who did not have increased coronary 18F-NaF uptake on baseline PET-CT scan and received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis set title
    Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in sub-group of the per protocol population who did not have increased coronary 18F-NaF uptake on baseline PET-CT scan and received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis set title
    Ticagrelor (Per Protocol)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in per protocol population who received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis set title
    Placebo (Per Protocol)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in per protocol population who received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis sets values
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) Placebo (Per Protocol With Coronary 18F-NaF Uptake) Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake) Placebo (Per Protocol Without Coronary 18F-NaF Uptake) Ticagrelor (Per Protocol) Placebo (Per Protocol)
    Number of subjects
    59
    61
    35
    36
    94
    97
    Age categorical
    Units: Subjects
        18-64 years
    38
    36
        65-84 years
    56
    61
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    65.5 ± 8.4
    66.3 ± 8.1
    Gender categorical
    Units: Subjects
        Female
    20
    19
        Male
    74
    78
    Increased coronary 18F-NaF uptake on PET-CT scan
    Units: Subjects
        Yes
    59
    61
    0
    0
    59
    61
        No
    0
    0
    35
    36
    35
    36
    Plasma high sensitivity cardiac troponin I concentration
    Units: ng/L
        median (inter-quartile range (Q1-Q3))
    4.0 (2.2 to 6.6)
    4.0 (1.8 to 7.0)
    2.6 (1.4 to 4.0)
    2.2 (1.5 to 4.1)
    3.5 (2.0 to 6.0)
    3.0 (1.7 to 6.0)

    End points

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    End points reporting groups
    Reporting group title
    Ticagrelor
    Reporting group description
    Ticagrelor 90 mg tablet twice daily for 12 months

    Reporting group title
    Placebo
    Reporting group description
    Matched placebo tablet twice daily for 12 months

    Subject analysis set title
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in sub-group of the per protocol population who had increased coronary 18F-NaF uptake on baseline PET-CT scan and received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis set title
    Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in sub-group of the per protocol population who had increased coronary 18F-NaF uptake on baseline PET-CT scan and received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis set title
    Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in sub-group of the per protocol population who did not have increased coronary 18F-NaF uptake on baseline PET-CT scan and received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis set title
    Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in sub-group of the per protocol population who did not have increased coronary 18F-NaF uptake on baseline PET-CT scan and received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis set title
    Ticagrelor (Per Protocol)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in per protocol population who received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Subject analysis set title
    Placebo (Per Protocol)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in per protocol population who received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.

    Primary: Plasma high sensitivity cardiac troponin I concentration at 30 days

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    End point title
    Plasma high sensitivity cardiac troponin I concentration at 30 days
    End point description
    Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
    End point type
    Primary
    End point timeframe
    Concentration from blood sample at 30 day visit
    End point values
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects analysed
    59
    61
    Units: ng/L
        geometric mean (standard deviation)
    4.05 ± 2.50
    3.23 ± 2.94
    Statistical analysis title
    Troponin at 30 days (PP with 18F-NaF uptake)
    Statistical analysis description
    General linear model for log transformed troponin concentrations at 30 days with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values at 30 days.
    Comparison groups
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.32
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.36

    Secondary: Plasma high sensitivity cardiac troponin I concentration at 30 days

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    End point title
    Plasma high sensitivity cardiac troponin I concentration at 30 days
    End point description
    Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
    End point type
    Secondary
    End point timeframe
    Concentration from blood sample at 30 day visit
    End point values
    Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake) Placebo (Per Protocol Without Coronary 18F-NaF Uptake) Ticagrelor (Per Protocol) Placebo (Per Protocol)
    Number of subjects analysed
    35
    36
    94
    97
    Units: ng/L
        geometric mean (standard deviation)
    2.43 ± 2.82
    2.31 ± 2.58
    3.35 ± 2.69
    2.85 ± 2.83
    Statistical analysis title
    Troponin at 30 days (PP without 18F-NaF uptake)
    Statistical analysis description
    general linear model for log transformed troponin concentrations at 30 days with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values at 30 days.
    Comparison groups
    Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake) v Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.87
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.31
    Statistical analysis title
    Troponin at 30 days (PP)
    Statistical analysis description
    General linear model for log transformed troponin concentrations at 30 days with age, sex, log transformed troponin concentration, increased coronary 18F-NaF uptake, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values at 30 days.
    Comparison groups
    Ticagrelor (Per Protocol) v Placebo (Per Protocol)
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.37
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    1.26

    Secondary: Area under plasma high sensitivity cardiac troponin I concentration curve over 1 year

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    End point title
    Area under plasma high sensitivity cardiac troponin I concentration curve over 1 year
    End point description
    Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
    End point type
    Secondary
    End point timeframe
    Concentrations from blood samples at 30 day, 3 month, 6 month, 9 month, and 12 month visits
    End point values
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) Placebo (Per Protocol With Coronary 18F-NaF Uptake) Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake) Placebo (Per Protocol Without Coronary 18F-NaF Uptake) Ticagrelor (Per Protocol) Placebo (Per Protocol)
    Number of subjects analysed
    58
    57
    33
    35
    91
    92
    Units: ng.year/L
        geometric mean (standard deviation)
    3.93 ± 2.25
    4.16 ± 3.36
    2.46 ± 2.51
    2.31 ± 2.22
    3.31 ± 2.41
    3.33 ± 3.02
    Statistical analysis title
    AUC over 1 year (PP with 18F-NaF uptake)
    Statistical analysis description
    General linear model for log transformed area under troponin concentration curve over 1 year with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values of AUC.
    Comparison groups
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.33
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    1.17
    Statistical analysis title
    AUC over 1 year (PP without 18F-NaF uptake)
    Statistical analysis description
    General linear model for log transformed area under troponin concentration curve over 1 year with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values of AUC.
    Comparison groups
    Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake) v Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1.28
    Statistical analysis title
    AUC over 1 year (PP)
    Statistical analysis description
    General linear model for log transformed area under troponin concentration curve over 1 year with age, sex, log transformed baseline troponin concentration, increased coronary 18F-NaF uptake, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values of AUC.
    Comparison groups
    Ticagrelor (Per Protocol) v Placebo (Per Protocol)
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.42
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.74
         upper limit
    1.13

    Secondary: Ratio of total calcium mass in coronary arteries at 1 year to baseline

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    End point title
    Ratio of total calcium mass in coronary arteries at 1 year to baseline
    End point description
    Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
    End point type
    Secondary
    End point timeframe
    Calcium mass from CT scans at baseline and 12 month visits
    End point values
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) Placebo (Per Protocol With Coronary 18F-NaF Uptake) Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake) Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
    Number of subjects analysed
    57
    55
    33
    34
    Units: Ratio
        geometric mean (standard deviation)
    1.22 ± 1.23
    1.29 ± 1.24
    1.29 ± 1.42
    1.45 ± 1.62
    Statistical analysis title
    Total calcium mass (PP with 18F-NaF uptake)
    Statistical analysis description
    General linear model for log transformed ratio of mass at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
    Comparison groups
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.87
         upper limit
    1.02
    Statistical analysis title
    Total calcium mass (PP without 18F-NaF uptake)
    Statistical analysis description
    General linear model for log transformed ratio of mass at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
    Comparison groups
    Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake) v Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.26
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    1.09

    Secondary: Ratio of calcium mass at 1 year to baseline in coronary artery segment with increased 18F-NaF uptake at baseline

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    End point title
    Ratio of calcium mass at 1 year to baseline in coronary artery segment with increased 18F-NaF uptake at baseline
    End point description
    Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
    End point type
    Secondary
    End point timeframe
    Calcium mass from CT scans at baseline and 12 month visits
    End point values
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects analysed
    53
    54
    Units: Ratio
        geometric mean (standard deviation)
    1.55 ± 1.40
    1.68 ± 1.78
    Statistical analysis title
    Calcium mass in segment with 18F-NaF uptake
    Statistical analysis description
    General linear model for log transformed ratio of mass at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
    Comparison groups
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.11

    Secondary: Ratio of calcium mass at 1 year to baseline in coronary artery segment without increased 18F-NaF uptake at baseline

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    End point title
    Ratio of calcium mass at 1 year to baseline in coronary artery segment without increased 18F-NaF uptake at baseline
    End point description
    Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
    End point type
    Secondary
    End point timeframe
    Calcium mass on CT scans at baseline and 12 month visits
    End point values
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects analysed
    57
    53
    Units: Ratio
        geometric mean (standard deviation)
    1.10 ± 1.48
    1.09 ± 1.57
    Statistical analysis title
    Calcium mass in segment without 18F-NaF uptake
    Statistical analysis description
    General linear model for log transformed ratio of mass at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
    Comparison groups
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.95
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.18

    Secondary: Ratio of calcium volume at 1 year to baseline in coronary artery segment with increased 18F-NaF uptake at baseline

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    End point title
    Ratio of calcium volume at 1 year to baseline in coronary artery segment with increased 18F-NaF uptake at baseline
    End point description
    Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
    End point type
    Secondary
    End point timeframe
    Calcium volume from CT scans at baseline and 12 month visits
    End point values
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects analysed
    53
    54
    Units: Ratio
        geometric mean (standard deviation)
    1.47 ± 1.39
    1.59 ± 1.69
    Statistical analysis title
    Calcium volume in segment with 18F-NaF uptake
    Statistical analysis description
    General linear model for log transformed ratio of volume at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
    Comparison groups
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.27
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    1.08

    Secondary: Ratio of calcium volume at 1 year to baseline in coronary artery segment without increased 18F-NaF uptake at baseline

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    End point title
    Ratio of calcium volume at 1 year to baseline in coronary artery segment without increased 18F-NaF uptake at baseline
    End point description
    Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
    End point type
    Secondary
    End point timeframe
    Calcium volume from CT scans at baseline and 12 month visits
    End point values
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects analysed
    57
    53
    Units: Ratio
        geometric mean (standard deviation)
    1.08 ± 1.44
    1.05 ± 1.53
    Statistical analysis title
    Calcium volume in segment without 18F-NaF uptake
    Statistical analysis description
    General linear model for log transformed ratio of volume at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
    Comparison groups
    Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 77
    Method
    ANCOVA
    Parameter type
    Ratio of geometric means
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    1.19

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occurred from consent until the last study visit were reported on the case report forms, but only those which started after randomisation have been included in these results.
    Adverse event reporting additional description
    Subjects were asked about the occurrence of AEs at each study visit through open-ended and non-leading verbal questioning. Any AEs which were identified via information from support departments, e.g. safety blood results, were also reported. All reported AEs were followed up until resolution of the event or until no longer medically indicated.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Ticagrelor (Safety)
    Reporting group description
    Subjects who received any ticagrelor study medication, regardless of the group they were originally allocated to.

    Reporting group title
    Placebo (Safety)
    Reporting group description
    Subjects who received some study medication but this was all placebo, regardless of the group they were originally allocated to.

    Serious adverse events
    Ticagrelor (Safety) Placebo (Safety)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 100 (7.00%)
    12 / 101 (11.88%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    All vascular disorders
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    All surgical and medical procedures
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    All cardiac disorders
         subjects affected / exposed
    4 / 100 (4.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    All respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    All general disorders and administration site conditions
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    All psychiatric disorders
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    All gastrointestinal disorders
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    All hepatobiliary disorders
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    All musculoskeletal and connective tissue disorders
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    All infections and infestations
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 101 (2.97%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Ticagrelor (Safety) Placebo (Safety)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    86 / 100 (86.00%)
    75 / 101 (74.26%)
    Vascular disorders
    All vascular disorders
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 101 (2.97%)
         occurrences all number
    2
    3
    Surgical and medical procedures
    All surgical and medical procedures
         subjects affected / exposed
    6 / 100 (6.00%)
    2 / 101 (1.98%)
         occurrences all number
    7
    2
    General disorders and administration site conditions
    All general disorders and administrative site conditions
         subjects affected / exposed
    10 / 100 (10.00%)
    13 / 101 (12.87%)
         occurrences all number
    12
    14
    Reproductive system and breast disorders
    All reproductive system and breast disorders
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 101 (0.99%)
         occurrences all number
    2
    1
    Injury, poisoning and procedural complications
    All injury, poisoning and procedural complications
         subjects affected / exposed
    61 / 100 (61.00%)
    14 / 101 (13.86%)
         occurrences all number
    79
    15
    Investigations
    All investigations
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 101 (0.99%)
         occurrences all number
    3
    1
    Cardiac disorders
    All cardiac disorders
         subjects affected / exposed
    4 / 100 (4.00%)
    8 / 101 (7.92%)
         occurrences all number
    4
    9
    Respiratory, thoracic and mediastinal disorders
    All respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    34 / 100 (34.00%)
    11 / 101 (10.89%)
         occurrences all number
    43
    11
    Blood and lymphatic system disorders
    All blood and lymphatic system disorders
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 101 (1.98%)
         occurrences all number
    2
    2
    Nervous system disorders
    All nervous system disorders
         subjects affected / exposed
    3 / 100 (3.00%)
    10 / 101 (9.90%)
         occurrences all number
    3
    12
    Eye disorders
    All eye disorders
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 101 (0.99%)
         occurrences all number
    3
    1
    Ear and labyrinth disorders
    All ear and labyrinth disorders
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 101 (1.98%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    All gastrointestinal disorders
         subjects affected / exposed
    18 / 100 (18.00%)
    14 / 101 (13.86%)
         occurrences all number
    20
    15
    Renal and urinary disorders
    All renal and urinary disorders
         subjects affected / exposed
    4 / 100 (4.00%)
    2 / 101 (1.98%)
         occurrences all number
    4
    2
    Skin and subcutaneous tissue disorders
    All skin and subcutaneous tissue disorders
         subjects affected / exposed
    6 / 100 (6.00%)
    5 / 101 (4.95%)
         occurrences all number
    6
    5
    Musculoskeletal and connective tissue disorders
    All musculoskeletal and connective tissue disorders
         subjects affected / exposed
    11 / 100 (11.00%)
    11 / 101 (10.89%)
         occurrences all number
    13
    11
    Metabolism and nutrition disorders
    All metabolism and nutrition disorders
         subjects affected / exposed
    3 / 100 (3.00%)
    7 / 101 (6.93%)
         occurrences all number
    3
    7
    Infections and infestations
    All infections and infestations
         subjects affected / exposed
    30 / 100 (30.00%)
    26 / 101 (25.74%)
         occurrences all number
    35
    33

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2016
    Substantial Amendment 5: The Ticagrelor SPC was updated on 18 February 2016 to include new information from a large clinical trial involving the use of ticagrelor in patients with a history of prior myocardial infarction. The changes to the SPC resulted in an update to the reference safety information for the DIAMOND study. The study protocol was updated to remove the SPC link from Appendix 1.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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