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    Clinical Trial Results:
    Pharmacokinetics and Pharmacodynamics of Platelet P2Y12 Inhibitors in Patients Undergoing Percutaneous Coronary Intervention (PCI) for Acute Myocardial Infarction: A Pilot Study

    Summary
    EudraCT number
    		 2014-004238-25
    Trial protocol
    		 GB  
    Global end of trial date
    30 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2019
    First version publication date
    11 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2012-004-0402-CARD
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02376283
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Royal Wolverhampton NHS Trust
    Sponsor organisation address
    New Cross Hospital, Wolverhampton, United Kingdom, WV10 0QP
    Public contact
    James Cotton, The Royal Wolverhampton NHS Trust, 01902 307999, jamescotton@nhs.net
    Scientific contact
    James Cotton, The Royal Wolverhampton NHS Trust, 01902 307999, jamescotton@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
    31 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) To demonstrate the degree of platelet inhibition by clopidogrel, prasugrel and ticagrelor given acutely before emergency primary angioplasty for ST-elevation myocardial infarction (STEMI), during the procedure and in the following 4 hours, to determine whether the condition of STEMI per se reduces the efficacy of orally administered P2Y12 inhibitors. 2) To determine the degree and time-course of platelet inhibition of an oral P2Y12 inhibitor (clopidogrel/prasugrel/ticagrelor) given acutely before emergency primary angioplasty for STEMI, during the procedure and in the following 4 hours. This will be compared with a cohort of patients presenting with non-ST elevation myocardial infarction (NSTEMI) treated with either oral P2Y12 inhibitor to determine whether the condition of STEMI per se reduces the efficacy of ticagrelor treatment.
    Protection of trial subjects
    All drugs were prescribed and administered in line with their licensed indications, and in accordance with local and national guideline recommendations. All patients were monitored for adverse events as per routine clinical practice. Patients were not considered for inclusion if they were unable to provide written or verbal informed consent, were under 18 years of age, had a documented allergy to aspirin or clopidogrel/prasugrel/ticagrelor.
    Background therapy
    		 All patients were administered oral aspirin 300mg as a single dose following by a maintenance dose of 75mg daily. The oral P2Y12 inhibitor dose was in line with licensed/guideline recommendations; clopidogrel 600mg loading followed by 75mg daily maintenance, prasugrel 60mg loading followed by 10mg daily and ticagrelor 180mg loading followed by 90mg twice daily thereafter. Background antithrombotic therapy with unfractionated heparin was administered during the procedure.
    Evidence for comparator
    		 The comparative efficacy of orally administered P2Y12 inhibitors was determined using the point of care VerifyNow assay and expressed as a measure of P2Y12 reaction unit (PRU). The PRU measurement provides an indication of the degree of platelet inhibition achieved following the administration of a P2Y12 inhibitor loading dose on admission.
    Actual start date of recruitment
    10 Jun 2013
    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: 87
    Worldwide total number of subjects
    87
    EEA total number of subjects
    87
    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)
    38
    From 65 to 84 years
    42
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 Location: Cardiology catheter laboratory and cardiology ward, Heart and Lung Centre, The Royal Wolverhampton Hospital NHS Trust, Wolverhampton, UK Recruitment period: 2 years and 10 months (34 months)

    Pre-assignment
    Screening details
    		 Clopidogrel and prasugrel were included only as the P2Y12 inhibitors under investigation initially. Amendment incorporated ticagrelor as addition. Recruitment to the prasugrel NSTEMI arm was unusually slow; therefore indications for use were changed to reflect the manufacturers recommendations and not NICE guidance.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Clopidogrel
    Arm description
    		 All STEMI and NSTEMI patients were administered a clopidogrel 600mg loading dose following confirmation of their diagnosis and receipt of verbal assent/informed consent prior to whole blood samples being collected for pharmacodynamic and pharmacokinetic assessment of the degree and time course of platelet inhibition.
    Arm type
    		 pharmacological drug handling

    Investigational medicinal product name
    Clopidogrel hydrogen sulphate
    Investigational medicinal product code
    B01AC-04
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600mg one off, loading dose, followed by 75mg daily maintenance dose for 12 months

    Arm title
    		 Prasugrel
    Arm description
    		 All STEMI and NSTEMI patients were administered a prasugrel 60mg loading dose following confirmation of their diagnosis and receipt of verbal assent/informed consent prior to whole blood samples being collected for pharmacodynamic and pharmacokinetic assessment of the degree and time course of platelet inhibition.
    Arm type
    		 drug handling of prasugrel

    Investigational medicinal product name
    Prasugrel hydrochloride
    Investigational medicinal product code
    B01AC22
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prasugrel 60mg one-off loading dose following by a 10mg daily maintenance dose for 12 months (For the purposes of our protocol, prasugrel was prescribed and administered only in those patients over 60kg and under the age of 75 years, as per the manufacturers recommendations)

    Arm title
    		 Ticagrelor
    Arm description
    		 All STEMI and NSTEMI patients were administered a prasugrel 60mg loading dose following confirmation of their diagnosis and receipt of verbal assent/informed consent prior to whole blood samples being collected for pharmacodynamic and pharmacokinetic assessment of the degree and time course of platelet inhibition.
    Arm type
    		 pharmacological drug handling of ticagrelor

    Investigational medicinal product name
    Ticagrelor
    Investigational medicinal product code
    B01AC24
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ticagrelor 180mg one-off loading dose, followed by 90mg twice daily maintenance dose for 12 months.

    Number of subjects in period 1
    		Clopidogrel Prasugrel Ticagrelor
    Started
    27
    30
    30
    Completed
    27
    30
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Clopidogrel
    Reporting group description
    		 All STEMI and NSTEMI patients were administered a clopidogrel 600mg loading dose following confirmation of their diagnosis and receipt of verbal assent/informed consent prior to whole blood samples being collected for pharmacodynamic and pharmacokinetic assessment of the degree and time course of platelet inhibition.

    Reporting group title
    Prasugrel
    Reporting group description
    		 All STEMI and NSTEMI patients were administered a prasugrel 60mg loading dose following confirmation of their diagnosis and receipt of verbal assent/informed consent prior to whole blood samples being collected for pharmacodynamic and pharmacokinetic assessment of the degree and time course of platelet inhibition.

    Reporting group title
    Ticagrelor
    Reporting group description
    		 All STEMI and NSTEMI patients were administered a prasugrel 60mg loading dose following confirmation of their diagnosis and receipt of verbal assent/informed consent prior to whole blood samples being collected for pharmacodynamic and pharmacokinetic assessment of the degree and time course of platelet inhibition.

    Reporting group values
    		 Clopidogrel Prasugrel Ticagrelor Total
    Number of subjects
    		 27 30 30 87
    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)
    		 9 19 13 41
        From 65-84 years
    		 15 11 16 42
        85 years and over
    		 3 0 1 4
    Gender categorical
    Units: Subjects
        Female
    		 8 5 6 19
        Male
    		 19 25 24 68
    Pharmacodynamic assessment of degree of platelet inhibition
    Pharmacodynamic assessment of degree of platelet inhibition as determined by VerifyNow point of care assay and expressed as P2Y12 reaction units (PRU)
    Units: Subjects
        STEMI
    		 13 15 15 43
        NSTEMI
    		 14 15 15 44

    End points

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    End points reporting groups
    Reporting group title
    Clopidogrel
    Reporting group description
    		 All STEMI and NSTEMI patients were administered a clopidogrel 600mg loading dose following confirmation of their diagnosis and receipt of verbal assent/informed consent prior to whole blood samples being collected for pharmacodynamic and pharmacokinetic assessment of the degree and time course of platelet inhibition.

    Reporting group title
    Prasugrel
    Reporting group description
    		 All STEMI and NSTEMI patients were administered a prasugrel 60mg loading dose following confirmation of their diagnosis and receipt of verbal assent/informed consent prior to whole blood samples being collected for pharmacodynamic and pharmacokinetic assessment of the degree and time course of platelet inhibition.

    Reporting group title
    Ticagrelor
    Reporting group description
    		 All STEMI and NSTEMI patients were administered a prasugrel 60mg loading dose following confirmation of their diagnosis and receipt of verbal assent/informed consent prior to whole blood samples being collected for pharmacodynamic and pharmacokinetic assessment of the degree and time course of platelet inhibition.

    Subject analysis set title
    Ticagrelor parent compound
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    STEMI/NSTEMI patients. Ticagrelor was used in our centre only after the use of prasugrel was discontinued. Other analysis with active metabolite.

    Primary: Pharmacodynamic assessment of degree of platelet inhibition as determined by VerifyNow point of care assay and expressed as P2Y12 reaction units (PRU)

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    End point title
    		 Pharmacodynamic assessment of degree of platelet inhibition as determined by VerifyNow point of care assay and expressed as P2Y12 reaction units (PRU)
    End point description
    Pharmacodynamic assessment of degree of platelet inhibition as determined by VerifyNow point of care assay and expressed as P2Y12 reaction units (PRU)
    End point type
    Primary
    End point timeframe
    240 minutes
    End point values
    		 Clopidogrel Prasugrel Ticagrelor
    Number of subjects analysed
    27
    30
    30
    Units: PRU
    arithmetic mean (standard deviation)
        STEMI at 20 mins
    270.23 ( 38.56 )
    247.73 ( 48.78 )
    256.73 ( 50.81 )
        STEMI at balloon inflation
    286.46 ( 33.12 )
    253.73 ( 57.17 )
    257.93 ( 61.12 )
        STEMI at 60 mins
    293.46 ( 31.68 )
    262.87 ( 43.43 )
    225.20 ( 82.70 )
        STEMI at 240 mins
    226.42 ( 69.44 )
    128.64 ( 89.16 )
    176.27 ( 84.92 )
        NSTEMI at 20 mins
    213.21 ( 51.74 )
    125.80 ( 89.34 )
    172.80 ( 92.54 )
        NSTEMI at 60 mins
    227.36 ( 61.19 )
    76.93 ( 99.24 )
    114.20 ( 122.22 )
        NSTEMI at 240 mins
    214.00 ( 69.98 )
    31.87 ( 45.52 )
    23.00 ( 18.94 )
    Statistical analysis title
    		 Pharmacodynamic assessment - VerifyNow
    Statistical analysis description
    Continuous variables were expressed as mean ± SD and categorical variables as frequencies (%). Continuous variables were analysed individually using student’s independent sample t-tests. Categorical variables were assessed using separate Fisher’s exact (Chi-sqaure) test.
    Comparison groups
    Clopidogrel v Prasugrel v Ticagrelor
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 < 0.05 [2]
    Method
    		 t-test, 2-sided
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [1] - A p value < 0.05 was considered to be statistically significant. Comparison of means between groups was assessed using analysis of variance (ANOVA) technique. ANOVA allowed for a comparison of more than two means and enabled an assessment to be made of the relationship between, different drugs (clopidogrel vs prasugrel vs ticagrelor), different clinical states (STEMI vs NSTEMI/UA) and different time points.
    [2] - Considered significant

    Primary: Pharmacokinetic quantification of the plasma concentration of clopidogrel and prasugrel active metabolite and ticagrelor parent compound and active metabolite

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    End point title
    		 Pharmacokinetic quantification of the plasma concentration of clopidogrel and prasugrel active metabolite and ticagrelor parent compound and active metabolite
    End point description
    Pharmacokinetic quantification of the plasma concentration of clopidogrel and prasugrel active metabolite and ticagrelor parent compound and active metabolite assessed using liquid chromatography in tandem with mass spectrometry (LC-MS/MS) and expressed as ng/ml
    End point type
    Primary
    End point timeframe
    240 minutes
    End point values
    		 Clopidogrel Prasugrel Ticagrelor Ticagrelor parent compound
    Number of subjects analysed
    27
    30
    30
    30
    Units: ng/ml
    arithmetic mean (standard deviation)
        STEMI at 20 mins
    39.12 ( 16.17 )
    14.27 ( 8.80 )
    0.16 ( 0.16 )
    9.04 ( 4.12 )
        STEMI at balloon inflation
    107.83 ( 44.08 )
    24.20 ( 13.07 )
    1.64 ( 1.17 )
    28.56 ( 12.58 )
        STEMI at 60 mins
    71.02 ( 27.21 )
    36.86 ( 13.27 )
    14.43 ( 7.28 )
    47.13 ( 24.09 )
        STEMI at 240 mins
    32.41 ( 6.71 )
    38.44 ( 7.59 )
    53.38 ( 25.21 )
    84.92 ( 42.00 )
        NSTEMI at 20 mins
    41.99 ( 25.27 )
    515.80 ( 126.84 )
    7.72 ( 5.10 )
    22.78 ( 10.27 )
        NSTEMI at 60 mins
    93.35 ( 49.65 )
    194.59 ( 29.97 )
    58.40 ( 25.41 )
    84.13 ( 34.02 )
        NSTEMI at 240 mins
    27.71 ( 6.90 )
    36.80 ( 4.59 )
    113.59 ( 19.20 )
    140.61 ( 36.31 )
    Statistical analysis title
    		 Pharmacokinetic quantification
    Statistical analysis description
    Pharmacokinetic quantification of the plasma concentration of clopidogrel and prasugrel active metabolite and ticagrelor parent compound and active metabolite assessed using liquid chromatography in tandem with mass spectrometry (LC-MS/MS) and expressed as ng/ml. Continuous variables expressed as mean ± SEM and categorical variables as frequencies (%). Continuous variables were analysed individually using student’s independent sample t-tests.
    Comparison groups
    Clopidogrel v Prasugrel v Ticagrelor v Ticagrelor parent compound
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 < 0.05 [4]
    Method
    		 t-test, 2-sided
    Confidence interval
    Variability estimate
    Standard error of the mean
    Notes
    [3] - Categorical variables assessed using separate Fisher’s exact (Chi-sqaure) test. A p value < 0.05 considered to be statistically significant. Comparison of means between groups assessed using ANOVA technique. ANOVA allowed comparison of more than two means and enabled assessment of the relationship between different drugs (clopidogrel active metabolite vs prasugrel active metabolite vs ticagrelor parent compound & active metabolite), different clinical states and different time points.
    [4] - Considered significant

    Secondary: Pharmacodynamic assessment of degree of platelet inhibition as determined by VASP flow cytometry and expressed as %PRI (platelet reactivity index)

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    End point title
    		 Pharmacodynamic assessment of degree of platelet inhibition as determined by VASP flow cytometry and expressed as %PRI (platelet reactivity index)
    End point description
    Pharmacodynamic assessment of degree of platelet inhibition as determined by VASP flow cytometry and expressed as %PRI (platelet reactivity index)
    End point type
    Secondary
    End point timeframe
    240 minutes
    End point values
    		 Clopidogrel Prasugrel Ticagrelor
    Number of subjects analysed
    27
    30
    30
    Units: %PRI
    arithmetic mean (standard deviation)
        STEMI at 20 mins
    76.29 ( 8.77 )
    46.25 ( 13.91 )
    79.75 ( 9.20 )
        STEMI at balloon inflation
    74.86 ( 9.00 )
    41.13 ( 12.71 )
    74.63 ( 11.42 )
        STEMI at 60 mins
    71.57 ( 11.68 )
    50.50 ( 11.88 )
    76.25 ( 11.12 )
        STEMI at 240 mins
    63.14 ( 13.26 )
    57.00 ( 10.39 )
    51.38 ( 14.06 )
        NSTEMI at 20 mins
    75.17 ( 2.74 )
    33.27 ( 10.66 )
    62.00 ( 8.79 )
        NSTEMI at 60 mins
    76.75 ( 4.35 )
    21.91 ( 9.72 )
    33.17 ( 17.73 )
        NSTEMI at 240 mins
    61.83 ( 5.82 )
    15.18 ( 5.85 )
    20.17 ( 10.48 )
    Statistical analysis title
    		 Pharmacodynamic assessment - VASP
    Statistical analysis description
    Continuous variables were expressed as mean ± SD and categorical variables as frequencies (%). Continuous variables were analysed individually using student’s independent sample t-tests. Categorical variables were assessed using separate Fisher’s exact (Chi-sqaure) test.
    Comparison groups
    Clopidogrel v Prasugrel v Ticagrelor
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    P-value
    		 < 0.05 [6]
    Method
    		 t-test, 2-sided
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [5] - A p value < 0.05 was considered to be statistically significant. Comparison of means between groups was assessed using analysis of variance (ANOVA) technique. ANOVA allowed for a comparison of more than two means and enabled an assessment to be made of the relationship between, different drugs (clopidogrel vs prasugrel vs ticagrelor), different clinical states (STEMI vs NSTEMI/UA) and different time points.
    [6] - Considered significant

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    24 hours
    Adverse event reporting additional description
    An SAE form will be completed and submitted to R&D by the chief investigator within 24 hours of an event being noted.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    UK
    Reporting groups
    Reporting group title
    Clopidogrel
    Reporting group description
    		 STEMI/NSTEMI treatment in patients who are not eligible for treatment with prasugrel/ticagrelor (based on clinical characteristics and as per study protocol)

    Reporting group title
    Prasugrel
    Reporting group description
    		 STEMI/NSTEMI patients over the 60kg in weight and under 75 years of age. (Prasugrel use was discontinued in our centre following a change in protocol to ticagrelor)

    Reporting group title
    Ticagrelor
    Reporting group description
    		 STEMI/NSTEMI patients. (Ticagrelor was used in our centre only after the use of prasugrel was discontinued)

    Serious adverse events
    		 Clopidogrel Prasugrel Ticagrelor
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Clopidogrel Prasugrel Ticagrelor
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    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: Due to the short reporting time of 4 hours, no adverse events took place during this time.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2014
    Due to difficulties in recruitment to the prasugrel NSTEMI group, a substantial amendment was submitted and approved, REC ref no: 14/WM/1236

    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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