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    Clinical Trial Results:
    Low-dose colchicine for secondary prevention of cardiovascular disease

    Summary
    EudraCT number
    		 2015-005568-40
    Trial protocol
    		 NL  
    Global end of trial date
    28 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jun 2021
    First version publication date
    30 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LoDoCo2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    WCN
    Sponsor organisation address
    Moreelsepark 1, Utrecht, Netherlands,
    Public contact
    Chair WCN, Werkgroep Cardiologische centra Nederland, secretariaat@wcnnet.nl
    Scientific contact
    Chair WCN, Werkgroep Cardiologische centra Nederland, secretariaat@wcnnet.nl
    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
    01 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Feb 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate clinical efficacy of treatment with colchicine 0.5mg once daily as compared to placebo in patients with stable coronary artery disease on the incidence of first occurrence of the composite of cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven revascularization.
    Protection of trial subjects
    Colchicine 0.5mg once daily is the reduced dosage recommended by the 2012 American College of Rheumatology Guidelines for Management of Gout and the FDA prescription information for Colcrys in patients with impaired renal function and for patients with concomitant use of CYP3A4 or P-glycoprotein inhibitors. (70, 71) A 30-day open label colchicine run-in period will largely filter out those with side effects occurring after initiating colchicine. By only including patients with normal renal function (eGFR ≥ 50 ml/min/1.73m2 or a serum creatinine > 150 μmol/L) and by using low-dose colchicine, adverse effects are likely to be reduced to a minimum as in the pilot LoDoCo trial. General practitioners and pharmacies will be informed on the study participation of their patients. They will be asked to report events or adverse reactions to the trial medication. Second, they will be asked to interrupt the trial medication during administration of known CYP3A4 inhibitors and monitor renal function closely in situations where it is expected that this might be impaired (e.g. diarrhoea or the start of nephrotoxic medicine).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2014
    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
    Netherlands: 4084
    Country: Number of subjects enrolled
    Australia: 2444
    Worldwide total number of subjects
    6528
    EEA total number of subjects
    4084
    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)
    3678
    From 65 to 84 years
    2850
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started in August 2014 in Australia and October 2016 in The Netherlands. Recruitment ended December 3rd 2018 when the 5522th participant was randomized in The Netherlands.

    Pre-assignment
    Screening details
    		 On the assumption that 10% of participants would report early intolerance to therapy, the trial aimed to enrol 6053 screened patients, expecting 5447 to be randomized (divided over both continents) and then followed for a median of 3 years.

    Period 1
    Period 1 title
    Run in
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    30 day open label run-in.

    Arms
    Arm title
    		 colchicine 0.5mg
    Arm description
    		 Open label run-in
    Arm type
    		 Experimental

    Investigational medicinal product name
    Colchichine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg once daily

    Number of subjects in period 1
    		colchicine 0.5mg
    Started
    6528
    Completed
    5522
    Not completed
    1006
         intolerance or compliance issues
    1006
    Period 2
    Period 2 title
    Randomised
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    double blind placebo controlled

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    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
    once daily

    Arm title
    		 colchicine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Colchichine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg once daily

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    once daily

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics and study details are reported on the randomized population (intention to treat). Randomisation was proceded by an open-label run-in.
    Number of subjects in period 2 [2]
    		Placebo colchicine
    Started
    2760
    2762
    Completed
    2760
    2762
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics and study details are reported on the randomized population (intention to treat). Randomisation was proceded by an open-label run-in

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Randomised
    Reporting group description
    		 -

    Reporting group values
    		 Randomised Total
    Number of subjects
    		 5522 5522
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 3098 3098
        Adults (65-82 years)
    		 2424 2424
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.8 ( 8.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 846 846
        Male
    		 4676 4676

    End points

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    End points reporting groups
    Reporting group title
    colchicine 0.5mg
    Reporting group description
    		 Open label run-in
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    colchicine
    Reporting group description
    		 -

    Primary: death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization

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    End point title
    		 death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization [1]
    End point description
    End point type
    Primary
    End point timeframe
    time from randomisation to first primary event.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis can be found in the appendix of the main paper
    End point values
    		 Placebo colchicine
    Number of subjects analysed
    187
    164
    Units: first events
    187
    164
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    per protocol targeted AE collection from signing of ICF until final visit
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    2020
    Frequency threshold for reporting non-serious adverse events: 0%
    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: reporting and description can be found in the mainpaper

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jan 2020
    all amendments have been specified in the protocol. Version 2.7 is the final version of the protocol.

    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/31706144
    http://www.ncbi.nlm.nih.gov/pubmed/32865380
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