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    Clinical Trial Results:
    Prediction of Recurrent Events with 18F-Fluoride to Identify Ruptured and High-risk Coronary Artery Plaques in Patients with Myocardial Infarction - the PREFFIR study

    Summary
    EudraCT number
    		 2014-004021-41
    Trial protocol
    		 GB  
    Global end of trial date
    20 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Dec 2023
    First version publication date
    09 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15-SS-0059
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02278211
    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, +44 0131 242 6515 , d.e.newby@ed.ac.uk
    Scientific contact
    Professor David Newby, University of Edinburgh, +44 0131 242 6515 , 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
    20 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    20 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether coronary 18F-fluoride uptake is associated with major adverse cardiac events in patients with multi-vessel coronary artery disease and recent myocardial infarction.
    Protection of trial subjects
    The study was overseen by the Edinburgh Clinical Trials Unit and an independent trial steering committee. The study was performed under a clinical trial authorization from the Medicines and Healthcare products Regulatory Agency, with approval from the South East Scotland Research Ethics Committee in accordance with the Declaration of Helsinki24 and with the written informed consent of each participant.
    Background therapy
    		 The study population consisted of patients aged 50 years or older with a recent (within 21 days) type 1 MI and multivessel coronary artery disease shown on invasive coronary angiography, defined as at least 2 major epicardial vessels with either more than 50% luminal stenosis or previous coronary revascularization(percutaneous coronary intervention or coronary artery bypass graft surgery).
    Evidence for comparator
    		 No Comparator
    Actual start date of recruitment
    28 Sep 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: 694
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Australia: 5
    Worldwide total number of subjects
    704
    EEA total number of subjects
    0
    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)
    393
    From 65 to 84 years
    305
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was an international, multicenter, prospective longitudinal cohort study conducted in 9 centres across 4 countries between September 2015 and February 2020.

    Pre-assignment
    Screening details
    		 Among 2684 patients screened, 995 were eligible, a total of 712 participants were recruited and attended for baseline 18Fsodium fluoride PET and CT scans. Of these, 6 participants received the radiotracer but were unable to complete the scan, and 2 patients were scanned but image reconstruction could not be completed. The study population was 704.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Overall Trial
    Arm description
    		 This was a cohort study, not a randomised trial.
    Arm type
    		 Overall Trial

    Investigational medicinal product name
    [18F] Sodium Fluoride
    Investigational medicinal product code
    18FNaF
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    250 MBq

    Number of subjects in period 1
    		Overall Trial
    Started
    704
    Completed
    704

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Analysis Population

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 704 704
    Age categorical
    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)
    		 393 393
        From 65-84 years
    		 305 305
        85 years and over
    		 6 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.8 ± 8.2 -
    Gender categorical
    Units: Subjects
        Female
    		 103 103
        Male
    		 601 601
    Subject analysis sets

    Subject analysis set title
    Analysis Population Overall
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All Patients analysed

    Subject analysis set title
    Low coronary atherosclerotic plaque activity
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Low coronary atherosclerotic plaque activity was defined as coronary microcalcification activity [CMA] of 0.

    Subject analysis set title
    High coronary atherosclerotic plaque activity
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    High coronary atherosclerotic plaque activity was defined as a coronary microcalcification activity (CMA) greater than 0.

    Subject analysis sets values
    		 Analysis Population Overall Low coronary atherosclerotic plaque activity High coronary atherosclerotic plaque activity
    Number of subjects
    704
    283
    421
    Age categorical
    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)
    393
    189
    204
        From 65-84 years
    305
    93
    212
        85 years and over
    6
    1
    5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.8 ± 8.2
    61.8 ± 7.4
    65.1 ± 8.4
    Gender categorical
    Units: Subjects
        Female
    103
    61
    42
        Male
    601
    222
    379

    End points

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    End points reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 This was a cohort study, not a randomised trial.

    Subject analysis set title
    Analysis Population Overall
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All Patients analysed

    Subject analysis set title
    Low coronary atherosclerotic plaque activity
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Low coronary atherosclerotic plaque activity was defined as coronary microcalcification activity [CMA] of 0.

    Subject analysis set title
    High coronary atherosclerotic plaque activity
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    High coronary atherosclerotic plaque activity was defined as a coronary microcalcification activity (CMA) greater than 0.

    Primary: Primary Endpoint

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    End point title
    		 Primary Endpoint
    End point description
    Primary outcome of cardiac death, non-fatal recurrent myocardial infarction, or unscheduled (late) coronary revascularisation for patients in analysis population
    End point type
    Primary
    End point timeframe
    Participants were followed up by site investigators until the last recruited patient had completed their 2-year follow-up visit.
    End point values
    		 Overall Trial Low coronary atherosclerotic plaque activity High coronary atherosclerotic plaque activity
    Number of subjects analysed
    704
    283
    421
    Units: Number
        Yes
    141
    51
    90
    Statistical analysis title
    		 Hazard ratio for primary outcome
    Statistical analysis description
    Time to event analysis, Cox regression.
    Comparison groups
    Low coronary atherosclerotic plaque activity v High coronary atherosclerotic plaque activity
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.76

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events within 48 hours of baseline visit
    Adverse event reporting additional description
    Performance of PET and coronary CT angiography was associated with 15 adverse events, which were predominantly iodinated contrast reactions. Two events were graded as serious: palpitation and β-blocker–induced bradycardia
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Site Investigator Reported Adverse Events. The total number of subjects exposed to IMP is 712. The denominator is 712, not 704. Eight subjects had IMP but didn't progress into the study.

    Serious adverse events
    		 Overall Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 704 (0.28%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Beta-blocker induced bradycardia
    Additional description: Admitted with Heart failure to CCU, exacerbated by beta blocker.
    alternative dictionary used: MedDRA 21
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 704 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Palpitations
    Additional description: Subject admitted to hospital with palpitations following caffeine intake.
    alternative dictionary used: MedDRA 21
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 704 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 704 (1.85%)
    Surgical and medical procedures
    Venous cannula issue
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 704 (0.71%)
         occurrences all number
    5
    Immune system disorders
    Contrast reaction
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 704 (1.14%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 May 2019
    IB updated to include a stand-alone RSI section
    14 Apr 2020
    Update to the primary and secondary endpoints. Removal of PREFFIR-TIME 6 week timepoint from protocol. Protocol window on 1 yr and subsequent annual reviews amended from -/+2weeks to -2/+26 weeks. Protocol window on 2 year visits amended from -/+2 weeks to 0 to +52 weeks. Protocol wording updated to allow 2 year CTCA scan to be performed on a separate date from other 2 year assessments if it is not possible for the scan to be performed on the same date. Data protection wording updated to reflect sponsor's approved wording. Typographical errors corrected throughout protocol. Data management section added to the protocol to reflect the Sponsor's current protocol template.

    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.
    There was a lower event rate in the study population despite recruiting patients with MI and multivessel disease. There was a low inclusion of women . We did not undertake end point adjudication because there was strict blinding of study imaging.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37379010
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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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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