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    Clinical Trial Results:
    A Single Center, Phase II, Assessor-Blinded, RaNdomized, Active Controlled, Parallel-Group Trial to COmpare Ticagrelor Versus Clopidogrel on the REduction of ArteriaL STiffness and Wave Reflections in Patients with CoronarY Artery Disease. The ‘NOVELTY’ Study

    Summary
    EudraCT number
    		 2013-004376-35
    Trial protocol
    		 GR  
    Global end of trial date
    20 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISSBRILO176
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hellenic Cardiovascular Research Society
    Sponsor organisation address
    Ethnikis Antistaseos 61, Halandri, Greece, 15231
    Public contact
    Charalambos Vlachopoulos, 1st Department of Cardiology, University of Athens Medical School, Hippokration Hospital, 0030 2132088099, cvlachop@otenet.gr
    Scientific contact
    Charalambos Vlachopoulos, 1st Department of Cardiology, University of Athens Medical School, Hippokration Hospital, 0030 2132088099, cvlachop@otenet.gr
    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
    11 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Τo compare ticagrelor versus clopidogrel regarding their effect on arterial stiffness as assessed by PWV, at 3 hours after the loading dose of each regimen, in eligible subjects with CAD.
    Protection of trial subjects
    Treated in routine care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Feb 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Greece: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    20
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 60 subjects fulfilling all study-specific eligibility criteria were initially recruited for the ‘acute’ study period of 24-hour duration. Subjects that underwent ad hoc PCI continued in the subsequent ‘chronic’ study period of 30-day duration.

    Pre-assignment
    Screening details
    		 Inclusion criteria: Provision of informed consent prior to any study specific procedures, Male and female subjects > 18 and < 79 years of age, Indication for elective coronary angiography with or without PCI for inclusion in the ‘acute’ study period, Indication for ad hoc or elective PCI for inclusion in the ‘chronic’ study period.

    Period 1
    Period 1 title
    Acute period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ticagrelor
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ticagrelor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A single 180 mg oral loading dose (two tablets of 90 mg) plus one additional oral dose (first maintenance dose) of 90 mg, 12 hours after randomisation.

    Arm title
    		 Clopidogrel
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A single 600 mg loading dose (two tablets of 300 mg or 8 tablets of 75 mg).

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Patients, Principal Investigator, study personnel and safety assessors will not be blinded to treatment allocation. Blinding participants would be difficult, as there is an obvious difference in the frequency of administration between clopidogrel and ticagrelor. It was decided that an assessor-blinded RCT design represents the most cost-efficient approach to better accommodating the purposes of this study.
    Number of subjects in period 1
    		Ticagrelor Clopidogrel
    Started
    30
    30
    Completed
    29
    29
    Not completed
    1
    1
         Consent withdrawn by subject
    1
    1
    Period 2
    Period 2 title
    Chronic period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [2]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Clopidogrel
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The subjects of the ‘acute’ period population that will eventually undergo ad hoc PCI, will continue with clopidogrel maintenance oral dose of 75 mg QD, starting with the administration of the first maintenance dose 24 hours after randomisation (administration of the loading dose). Subjects planned for elective PCI that will be recruited for the ‘chronic’ period, will be initiated on a single 600 mg oral loading dose (two tablets of 300 mg or 8 tablets of 75 mg) and continue on maintenance dosing of 75 mg QD.

    Arm title
    		 Ticagrelor
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ticagrelor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    • The subjects of the ‘acute’ period population that will eventually undergo ad hoc PCI, will continue with ticagrelor maintenance oral dose of 90 mg BID, starting with the administration of the second maintenance dose 24 hours after randomisation (12 hours after the administration of the first loading dose during the ‘acute’ period). • Subjects planned for elective PCI that will be recruited for the ‘chronic’ period, will be initiated on a single 180 mg oral loading dose (two tablets of 90 mg) and continue on maintenance dosing of 90 mg BID.

    Notes
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Patients, Principal Investigator, study personnel and safety assessors will not be blinded to treatment allocation. Blinding participants would be difficult, as there is an obvious difference in the frequency of administration between clopidogrel and ticagrelor. It was decided that an assessor-blinded RCT design represents the most cost-efficient approach to better accommodating the purposes of this study.
    Number of subjects in period 2
    		Clopidogrel Ticagrelor
    Started
    29
    29
    Completed
    28
    31
    Not completed
    2
    1
         Lost to follow-up
    2
    1
    Joined
    1
    3
         to reach at least 30 subjects at randomization
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Acute period
    Reporting group description
    		 58

    Reporting group values
    		 Acute period Total
    Number of subjects
    		 60 60
    Age categorical
    Units: Subjects
        18-79 yo
    		 60 60
    Gender categorical
    Units: Subjects
        Female
    		 22 22
        Male
    		 38 38

    End points

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    End points reporting groups
    Reporting group title
    Ticagrelor
    Reporting group description
    		 -

    Reporting group title
    Clopidogrel
    Reporting group description
    		 -
    Reporting group title
    Clopidogrel
    Reporting group description
    		 -

    Reporting group title
    Ticagrelor
    Reporting group description
    		 -

    Primary: difference in the mean change in the cfPWV

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    End point title
    		 difference in the mean change in the cfPWV
    End point description
    End point type
    Primary
    End point timeframe
    The primary outcome is the between treatment difference in the mean change in the cfPWV from baseline (0 hours) at 3 hours after the loading dose of each regimen, in ticagrelor and clopidogrel acute period populations.
    End point values
    		 Ticagrelor Clopidogrel Clopidogrel Ticagrelor
    Number of subjects analysed
    29
    29
    28
    31
    Units: m/s
        arithmetic mean (standard deviation)
    8.3 ( 1.2 )
    8.3 ( 1.8 )
    9.1 ( 1.3 )
    9.6 ( 1.6 )
    Statistical analysis title
    		 Acute phase analysis
    Statistical analysis description
    Ticagrelor and clopidogrel had no statistically significant effect adjusted for age and BP level cfPWV at baseline (9.61.6 versus 9.11.3 m/s, P=0.19).
    Comparison groups
    Clopidogrel v Ticagrelor
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.27
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Chronic phase
    Comparison groups
    Clopidogrel v Ticagrelor
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05 [1]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - At 30-day follow-up, cfPWV decreased significantly in the ticagrelor group (by 0.430.57 m/s, P<0.001, by paired t test), whereas treatment with clopidogrel was associated with a mild, nonsignificant (by 0.120.14 m/s, P=0.47) increase in cfPWV.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events will be collected from the time of signature of informed consent throughout the treatment period and including the 30-day follow-up period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Ticagrelor randomized
    Reporting group description
    		 -

    Serious adverse events
    		 Ticagrelor randomized
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ticagrelor randomized
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 30 (10.00%)
    Respiratory, thoracic and mediastinal disorders
    mild dyspnea
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2014
    change of timetable
    11 Mar 2016
    change of timetable

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31165663
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