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    Summary
    EudraCT Number:2015-004505-16
    Sponsor's Protocol Code Number:CON-001
    National Competent Authority:Lithuania - SMCA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-04-09
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedLithuania - SMCA
    A.2EudraCT number2015-004505-16
    A.3Full title of the trial
    CONVINCE - (COlchicine for preventioN of Vascular Inflammation in Non- CardioEmbolic stroke) – a randomised clinical trial of low-dose colchicine
    for secondary prevention after stroke
    („COlchicine“ prevencijai nuo kraujagyslių uždegimo NekardioEmbolinio priepuolio atveju) – atsitiktinės atrankos klinikinis tyrimas, naudojant mažos dozės „colchicine“ antrinei prevencijai po insulto
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The Use of Colchicine (an anti-inflammatory drug) in Prevention of Recurrent Stroke or heart attack after first Stroke; a randomised controlled trial
    A.4.1Sponsor's protocol code numberCON-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College Dublin
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHealth Research Board of Ireland
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe Irish Stroke Clinical Trials Network
    B.5.2Functional name of contact pointProf Peter Kelly
    B.5.3 Address:
    B.5.3.1Street AddressUCD Clinical Research Centre, Nelson Street,
    B.5.3.2Town/ cityDublin 7
    B.5.3.3Post codeD07 A8NN
    B.5.3.4CountryIreland
    B.5.4Telephone number35318301122
    B.5.5Fax number35317164557
    B.5.6E-mailpjkelly@mater.ie
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Colchicine 500microgram tablets
    D.2.1.1.2Name of the Marketing Authorisation holderMorningside Healthcare Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameColchicine
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Colchicine 500microgram tablets
    D.2.1.1.2Name of the Marketing Authorisation holderWockhardt UK Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameColchicine
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Colchicine Tiofarma 500 microgram Tablets
    D.2.1.1.2Name of the Marketing Authorisation holderTiofarma
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameColchicine
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Colchicine Tiofarma 0,5 mg, tabletten
    D.2.1.1.2Name of the Marketing Authorisation holderTiofarma
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameColchicine
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tiofarma B.V. Colchicin Tiofarma 0,5 mg Tabletten
    D.2.1.1.2Name of the Marketing Authorisation holderTiofarma
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameColchicine
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    The prevention of recurrent stroke and coronary events (fatal and non- fatal) after ischaemic stroke and transient ischaemic attack (TIA) not
    caused by cardiac embolism or other causes unrelated to atherosclerosis.
    E.1.1.1Medical condition in easily understood language
    Further stroke or cardiac events after stroke or TIA (like stroke but symptoms resolve quickly) not caused by a clot in the heart or other
    identifiable causes unrelated to fat deposition in arteries.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10044376
    E.1.2Term Transient cerebrovascular events
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10008205
    E.1.2Term Cerebrovascular embolism and thrombosis
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.1
    E.1.2Level LLT
    E.1.2Classification code 10023027
    E.1.2Term Ischaemic stroke NOS
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10051615
    E.1.2Term Atherosclerotic cardiovascular disease
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10007962
    E.1.2Term Central nervous system vascular disorders NEC
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLGT
    E.1.2Classification code 10007963
    E.1.2Term Central nervous system vascular disorders
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the efficacy of low dose colchicine (0.5mg/day) plus usual care (antiplatelet, lipid-lowering, antihypertensive treatment, and appropriate lifestyle advice) compared with usual care alone to prevent non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, hospitalisation for unstable angina and vascular death after ischaemic stroke or transient ischaemic attack (TIA) not caused by cardiac embolism or other defined causes unrelated to atherosclerosis.
    Ištirti mažos „Colchicine“ dozės (0,5 mg / dieną) plius įprastinės priežiūros (apibrėžtas kaip antitrombocitų, lipidų mažinimo, antihipertenzinio gydymo ir atitinkamos gyvensenos parinkimo konsultavimas) efektyvumą, lyginant tik su įprastine priežiūrą, kad būtų apsisaugota nuo nemirtino pasikartojančio išeminio insulto, miokardo infarkto, širdies sustojimo, hospitalizavimo dėl nestabilios anginos ir kraujagyslių mirties po išeminio insulto ar trumpalaikio išeminio išeminio priepuolio (TAI), kurio nesukelia kardinis embolizmas ar kitos apibrėžtos priežastys, nesusijusios su ateroskleroze.
    E.2.2Secondary objectives of the trial
    1. To investigate the safety of low dose colchicine (0.5mg/day) plus usual care (antiplatelet, lipid-lowering, antihypertensive treatment, and appropriate lifestyle advice) compared with usual care alone.
    2. To investigate the effect of colchicine on each component of the composite primary outcome measure.
    3. To investigate the effect of colchicine on fatal and non-fatal ischaemic stroke combined.
    4. To investigate the effect of colchicine on recurrent disabling and non-disabling ischaemic stroke.
    5. To investigate the effect of colchicine on late disability, compared with usual care.
    6. To assess whether the effect of treatment on the primary outcome is materially different among different categories of patient defined at baseline.
    7. To investigate the effect of colchicine on direct health care costs, adjusted for quality-adjusted life years.
    1. Ištirti mažos dozės „Colchicine“ (0,5 mg/dieną) plius įprastinės priežiūros, lyginant su tik įprastinę priežiūrą, saugumą.
    2. Ištirti «colchicine“ poveikį kiekvienam sudėtinio rezultato komponentui.
    3. Ištirti „cochicine“ poveikį jungtiniam mirtinam ir nemirtinam išeminiam insultui.
    4. Ištirti „cochicine“ poveikį dėl pasikartojančio invalidumą sukeliančio ir nesukeliančio išeminio insulto.
    5. Ištirti „colchicine“ poveikį dėl vėlyvo invalidumo, lyginant su įprastine priežiūra.
    6. Palyginti, ar pirminio rezultato gydymo poveikis materialiai skiriasi nuo skirtingų pacientų kategorijų, kaip apibrėžta pradinio įvertinimo metu.
    7. Ištirti „colchicine“ poveikį tiesioginėms sveikatos priežiūros išlaidoms, parengtoms pagal kokybę užtikrinantį paciento amžių
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible for inclusion, each subject must meet each of the following
    criteria at the screening assessment and baseline visit.

    1. Written informed consent consistent with ICH-GCP guidelines and
    local laws signed prior to all trial-related procedures.

    2. Age 40 years or greater.

    3. Patient has had either;-
    An ischaemic stroke without major disability (modified Rankin score 3 or
    less)(Clarification - retinal infarction due to retinal artery occlusion is
    allowed )
    or
    A high risk TIA*
    AND
    A brain CT or MRI has excluded primary intracranial haemorrhage
    AND
    The stroke/TIA has occurred more than 72 hours before randomisation
    AND no more than 28 days prior to randomisation
    * High-risk TIA is defined as transient focal neurological symptoms of
    presumed vascular cause with, in addition, one or more of the following
    criteria:
    (a) ABCD2 score 4 or more, with motor or speech symptoms (dysarthria
    or dysphasia)
    (b) DWI hyperintensity on acute MRI
    (c) Stenosis (lumen narrowing of 50% or greater on ultrasound, MRA,
    CTA, or invasive angiography) of the internal cartoid, vertebral, middle
    cerebral, anterior cerebral, or basilar artery in the arterial territory
    consistent with symptoms.

    4. Qualifying stroke/TIA probably caused by large artery stenosis, small
    artery occlusion (lacunar stroke), or cryptogenic embolism, with cardiac
    embolism or other defined stroke mechanism deemed unlikely, in the
    opinion of the treating physician.

    5. eGFR greater than or equal to 50 ml/min.

    6. In the opinion of the treating physician, patient is medically-stable,
    capable of participating in a randomised trial, and willing to attend follow-up.
    Atitikti įtraukimo kriterijus, kiekvienas subjektas privalo atitikti visus Atrankos įvertinimo kriterijus ir toliau juos atitikti, kad būtų užregistruoti šiam tyrimui (pradiniam vizitui).

    1. Raštu pateiktas sutikimas, atitinkantis ICH-GCP gaires ir vietinius įstatymus, pasirašytas prieš visas su tyrimais susijusias procedūras.

    2. Amžius 40 m. ar daugiau

    3. Pacientui diagnozuotas -
    • Išeminis insultas be žymios negalios (modifikuotas Rankin balas 3 ar mažiau)
    • arba
    • aukšta TIA * rizika

    IR
    Smegenų KT ar MR nenustatė pirminio intrakranijinio kraujavimo

    IR
    Insultas / TIA įvyko ilgiau nei prieš 72 valandas, prieš atsitiktinė atranką IR ne seniau, kaip 28 dienas iki atsitiktinės atrankos

    - *Aukštos rizikos TAI apibrėžiami, kaip trumpalaikiai židininiai neurologiniai manomos kraujagyslių priežasties simptomai papildomai su vienu ar keliais kriterijais:
    (a) ABCD2 balas 4 ar didesnis su motorikos ar kalbos simptomais (disartrija ir disfazija)
    (b) DWI hiperintensyvumas dėl ūminio MRI
    (c) Vidaus miego arterijos, slankstelių, vidurinių smegenų, priekinių smegenų ar baziliarinės arterijos aterijų plote stenozė, atitinkanti minėtus simptomus (liumeno susiaurėjimas 50% ar daugiau pagal ultragarso, MR, CTA ar invazinės angiografijos tyrimus)

    4. Kvalifikuotas insultas/TIA, kurį sukėlė didelė arterijų stenozė, nežymus arterijų užkimšimas (lakunarinis insultas) arba kriptogeninis embolizmas, kardialinis embolizmas ar kitas apibrėžtas insulto mechanizmas, laikomas mažai tikėtinu gydančio gydytojo nuomone.

    5. eGFR - didesnis nei ar lygus 50 ml/min.

    6. Remiantis gydančio gydytojo išvada pacientas mediciniškai stabilus, galintis dalyvauti atsitiktinėje atrankoje ir nori dalyvauti tolesniuose tyrimo etapuose.
    E.4Principal exclusion criteria
    1. Stroke/TIA, probably caused by identified atrial fibrillation
    (permanent or paroxysmal), in the opinion of the treating physician.

    2. Stroke/TIA probably caused by other identified cardiac source (intracardiac thrombus, endocarditis, metallic heart valve, low ejection
    fraction <30%),

    3. Stroke/TIA caused by dissection, endocarditis, paradoxical
    embolism, drug use, venous thrombosis, carotid or cardiac surgery,
    hypercoagulability states, migraine, or inherited cerebrovascular
    disorders.

    4. History of myopathy or myalgias with raised creatine kinase (CK) on
    statin therapy.

    5. Blood dyscrasia (haemoglobin<10g/dL,platelet count <150 x109/L,
    white cell count <4 x109/L)

    6. Impaired hepatic function (transaminases ALT and/or AST greater
    than twice upper limit of normal)

    7. Concurrent treatment with colchicine contraindicated drugs:-
    CYP3A4 inhibitors (clarithromycin, erythromycin, telithromycin, other
    macrolide antibiotics, ketoconazole, itraconazole,
    voriconazole,tolbutamide, ritonavir, atazanavir, indinavir, other HIV
    protease inhibitors, verapamil, diltiazem, quinidine, digoxin, disulfiram)
    or P-gp inhibitors (cyclosporine) at randomisation.

    8. Symptomatic peripheral neuropathy and pre-existing progressive
    neuromuscular disease

    9. Inflammatory bowel disease (Crohn's or ulcerative colitis) or chronic
    diarrhoea.

    10. Dementia, sufficient to impair independence in basic activities of
    daily living.

    11. Active malignancy, known hepatitis B or C, or HIV infection.

    12. Impaired swallow preventing oral administration of Colchicine

    13. History of poor medication compliance.

    14. Unlikely to comply with study procedures due to severe or
    fatalcomorbid illness or other factor (eg. inability to travel for follow up
    visits), in opinion of randomising physician.

    15. Women of childbearing potential (WCBP), or pregnant or are
    breastfeeding, are not eligible to participate in this study. (Clarification:
    A woman of childbearing potential is a woman who:
    - has not had surgery to remove the uterus and ovaries
    - has had menstrual periods at any time in the preceding 24
    consecutive months
    - Menstrual periods interrupted due to cancer chemotherapy
    treatment are considered WCBP as this may still allow conception.)
    Pregnancy is considered highly unlikely during the trial because
    women of childbearing potential are excluded. However, in the unlikely
    event that a woman in the trial becomes pregnant, pregnancy
    information will be collected.

    16. Patient concurrently participating in another clinical trial with an
    investigational drug or device, or use of investigational drug within 30 or
    5 half-lives before the Screening visit (whichever is longer).

    17. Known allergy or sensitivity to colchicine.

    18. Requirement for colchicine therapy for treatment of acute gout,
    gout prevention, or other rheumatological disorder

    19. Requirement for chronic daily immunosuppressants oral steroids, or
    non-steroidal anti-inflammatory drugs (NSAIDs)
    1. Insultas / TIA, tikriausiai sukeltas prieširdžio fibriliacijos (nuolatinės ar paroksizminės) gydančio gydytojo nuomone.

    2. Insultas / TIA, tikriausiai sukeltas kito apibrėžto kardialinio šaltinio (intrakardialinis trombas, endokarditas, metalinis širdies vožtuvas, žema išstūmimo frakcija <30%)
    3. Insultas / TIA, sukeltas, endokardito, paradoksalinio embolizmo, vaistų vartojimo, venų trombozės, karotido ar širdies chirurgijos, hiperkoaguliacijos būsenų, migrenos ar įgimtos cerebravaskuliniai sutrikimų.

    4. Miopatijos ar mialgijos istorija su padidėjusia kreatino kinaze (CK) pagal statinės terapijos priemones.

    5. Kraujo diskrazija (hemoglobinas <10 g / dL, trombocitų skaičius <150 x 109 / L, baltųjų ląstelių skaičius <4 x 109 / L)

    6. Sutrikusi kepenų funkcija (transaminazės yra didesnės nei dvigubos normos viršutinės ribos)

    7. Vartojant kartu su „colchicine“ kontraindikuotais vaistais: - CYP3A4 inhibitoriai (klaritromicinas, eritromicinas, telitromicinas, kiti makrolidiniai antibiotikai, ketokonazolas, itrakonazolas, vorikonazolas, ritonaviras, atazanaviras, indinaviras, kiti ŽIV proteazės inhibitoriai, verapamilas, diltiazemas, kvinidinas, digoksinas, disulfiramas) arba P -gp inhibitoriais (ciklosporinas) atsitinktinės atrankos metu.

    8. Simptominė periferinė neuropatija ir jau esama progresuojanti nervų ir raumenų liga.

    9. Uždegiminė žarnų liga (Krono ar opinis kolitas) arba lėtinis viduriavimas.

    10. Demencija, pakankama pakenkti savarankiškumui pagrindinėse kasdienio gyvenimo srityse.

    11. Aktyvus piktybinis navikas, žinomas hepatitas B ar C arba ŽIV infekcija.

    12. Sutrikęs nurijimas, neleidžiantis skirti „Colchicine.

    13. Netinkamos medikamentų atitikties istorija.

    14. Manoma, kad tyrimo procedūros bus netinkamos dėl rimtų ar mirtinų ligų ar kitų veiksnių (pvz.: negalėjimo atvykti tolesniems kontroliniams vizitams) atsitiktinės atrankos gydytojo nuomone.

    15. Nėštumas, maitinimas krūtine ar moteris iki menopauzės.

    16. Pacientas tuo pačiu metu dalyvauja kitame klinikiniame tyrime, kuris sietinas su tiriamuoju vaistu ar įrenginiu ar jo vartojimo 30 ar 5 pusperiodį prieš atrankos vizitą (priklausomai nuo ilgesnio laikotarpio).

    17. Žinoma alergija ar jautrumas „Colchicine“.

    18. „Cochicine“ gydymo terapija būtina gydant ūminę podagrą, siekiant užtikrinti prevenciją nuo podagros ar kitų reumatinių sutrikimų.

    19. Nuolatinis ir kasdieninis imunosupresantų oralinių steroidų ar nesteroidų antiuždegiminių vaistų (NSAID) vartojimo būtinybė.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy outcome measure will be time to the first occurrence of non-fatal recurrent ischaemic stroke, non-fatal myocardial infarction, non-fatal cardiac arrest, hhospitalisation for unstable angina or vascular death.

    Events confirmed through centralised adjudication to meet protocol-defined primary outcome criteria, will be included in the analyses of the number of occurrences of the composite primary outcome for the respective treatment group.

    The components of the primary composite efficacy outcome measure are defined below:

    1) Non-fatal ischaemic stroke: defined as one of the following:
    (a) A new focal neurological deficit, presumed due to cerebrovascular disease, persisting beyond 24 hours, without intracerebral haemorrhage or other mimic condition (eg. abcess, tumour, subdural haematoma) on brain CT or MRI.
    (b) If brain imaging is not performed, but the focal neurological deficit is acute in onset, persists beyond 24 hours, and is consistent with stroke in the opinion of the Site Investigator/Outcomes Committee, it will be classified as non-fatal ischaemic stroke
    (c) If acute new focal symptoms/signs last less than 24 hours but If brain CT or MRI demonstrates acute ischaemic change, (i.e. consistent with the ‘tissue definition’ of TIA).
    Note: In patients with symptom duration less than 24 hours, in whom brain CT/MRI are normal or not performed, they will be categorised as ‘TIA’ and not counted as stroke.
    (d) Retinal infarction, confirmed by an ophthalmologist.
    (e) Spinal cord infarction, with mimic conditions excluded by spinal MRI.

    2) Non-fatal myocardial infarction: defined according to the 3rd Universal Definition of MI criteria

    3) Non-fatal cardiac arrest: defined as recovery from sudden collapse, with ECG rhythm-strip verified cardiac asystole, ventricular tachycardia, or ventricular fibrillation

    4) Hospitalisation for Unstable Angina: TIMI definition

    4) Vascular death: Defined as death caused by recurrent ischaemic stroke within the previous 30 days or sudden death due to verified cardiac causes (cardiac arrest, myocardial infarction (as defined above or on autopsy), without other identified cause.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Clinic visits will be performed at 4 weeks, 6 months, and every 6 months thereafter until an outcome event occurs or end of trial (maximum duration approximately 60 months in patients entered in the Vanguard Stage, Year 1).

    In order to standardise the number of weeks between visits for all patients in the study: "weeks" rather than "calendar months" are being used. Therefore for this study the definition of a month is 4 weeks, a year is 52 weeks and a half a year is 26 weeks. All visits for each patient are scheduled out for the entire study based on the randomisation date of each patient.

    A brief telephone assessment will be performed at 90 days by the Site Investigator or Site study staff, to check for early outcome events, compliance, tolerability concerns, or adverse events.
    E.5.2Secondary end point(s)
    1) Safety
    The following safety outcomes will be compared between colchicine-treated and usual care groups:
    I. Adverse events (non-serious and serious)
    ii. Gastrointestinal (vomiting, nausea, diarrhoea)
    iii. Myalgia requiring discontinuation of study medication
    iv. Myopathy (defined as muscle pain or weakness associated with creatine kinase 2 or more times greater than the upper limit of normal (ULN))
    v. Hepatic impairment (transaminases (AST or ALT) ≥2 ULN)
    vi. Myelosuppression (defined per NIH Common Toxicity Criteria as at least Grade 2 suppression of circulating blood counts; ie. haemoglobin less than 10 and greater than 8 g/dL in the absence of major bleeding;absolute neutrophil count <1.5 - 1.0 x 109/L;platelet count <75.0 - 50.0 x 109/L)
    vii. Moderate or severe renal impairment, defined as glomerular filtration rate (GFR) less than 50 ml/min/1.73m2 on two measures at least 3 months apart
    viii. Peripheral neuropathy, defined as new or worsened symptoms of numbness, parasthesiae, burning or weakness in the extremities, with confirmation on nerve conduction studies
    ix. Rash, itch, or alopecia
    x. Major haemorrhage, per International Society on Thrombosis and Haemostasis classification. This includes fatal and non-fatal intracranial haemorrhage. (Although colchicine has not been associated with adverse effects on platelet function or coagulation, we will record major haemorrhage rates)
    xi. All cause-fatality

    2) Components of composite primary outcome measure
    The effect of colchicine on each of the components of the primary composite outcome measure will be analysed separately.

    3) Recurrent fatal or non-fatal ischaemic stroke
    Comparison of fatal plus non-fatal ischaemic stroke between colchicine and usual care arms will be performed.

    4) Recurrent disabling/non-disabling ischaemic stroke
    Comparison of rates of recurrent disabling ischaemic stroke (modified Rankin score 3-5) and recurrent non-disabling ischaemic stroke (modified Rankin score 0-2) between colchicine and usual care arms will be performed.

    5) Disability
    Comparison of disability in colchicine-treated and usual care groups will be assessed by modified Rankin score (shift analysis and proportion with no, mild, or moderate disability, defined as Rankin score of 0-2).

    6) Treatment effect interaction
    The effect of colchicine treatment on the primary outcome stratified by categories of key baseline variables (eg. age, gender, large artery stenosis) will be assessed.

    7) Health economic outcomes
    The effect of colchicine treatment on direct cumulative costs of health resource utilisation related to Quality Adjusted Life Years (QALYs) during the trial will be assessed.

    Exploratory outcome measures

    1) Cognition
    Cognition at baseline and end of study will be measured using the Montreal Cognitive Assessment, [MOCA] and compared between colchicine and usual care groups.

    2) Quality of life
    Health-related quality of life (self-reported) will be measured and compared using EuroQoL (EQ5D-5L).

    3) CRP
    Associations between colchicine treatment effect and baseline CRP will be analysed.

    4) Cumulative number of ischaemic events
    The relationship between colchicine therapy and the cumulative total number of component events in the primary outcome cluster detected over the duration of the trial will be investigated.




    E.5.2.1Timepoint(s) of evaluation of this end point
    Clinic visits will be performed at 4 weeks, 6 months, and every 6 months thereafter until an outcome event occurs or end of trial (maximum duration approximately 60 months in patients entered in the Vanguard Stage, Year 1).

    In order to standardise the number of weeks between visits for all patients in the study: "weeks" rather than "calendar months" are being used. Therefore for this study the definition of a month is 4 weeks, a year is 52 weeks and a half a year is 26 weeks. All visits for each patient are scheduled out for the entire study based on the randomisation date of each patient.

    A brief telephone assessment will be performed at 90 days by the Site Investigator or Site study staff, to check for early outcome events, compliance, tolerability concerns, or adverse events.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Prospective Randomised Open-Label Blinded-Endpoint Assessment
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Standard Usual Care
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA150
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Canada
    Czechia
    Denmark
    Estonia
    Germany
    Ireland
    Italy
    Lithuania
    North Macedonia
    Netherlands
    Poland
    Portugal
    Spain
    Switzerland
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1125
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2029
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1623
    F.4.2.2In the whole clinical trial 3154
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    All participants will be treated with best practice usual care as deemed appropriate by the treating physician.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Irish Stroke Clinical Trials Network
    G.4.3.4Network Country Ireland
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-08-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-08-06
    P. End of Trial
    P.End of Trial StatusOngoing
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