<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03231059</url>
  </required_header>
  <id_info>
    <org_study_id>039_2013_Substudy</org_study_id>
    <nct_id>NCT03231059</nct_id>
  </id_info>
  <brief_title>GLOBAL LEADERS Adjudication Sub-Study</brief_title>
  <acronym>GLASSY</acronym>
  <official_title>GLOBAL LEADERS Adjudication Sub-Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European Cardiovascular Research Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The GLOBAL LEADERS Adjudication Sub-StudY, GLASSY, is based on a re-assessment of all the&#xD;
      events reported in the dataset of the parent trial (COMPARATIVE EFFECTIVENESS OF 1 MONTH OF&#xD;
      TICAGRELOR PLUS ASPIRIN FOLLOWED BY TICAGRELOR MONOTHERAPY VERSUS A CURRENT-DAY INTENSIVE&#xD;
      DUAL ANTIPLATELET THERAPY IN ALL-COMERS PATIENTS UNDERGOING PERCUTANEOUS CORONARY&#xD;
      INTERVENTION WITH BIVALIRUDIN AND BIOMATRIX FAMILY DRUG-ELUTING STENT USE) by an independent&#xD;
      Clinical Event Committee (CEC), composed of three physicians not involved in the main trial.&#xD;
      The substudy include the first 19 top-enrolling sites of the GLOBAL LEADERS to reach the&#xD;
      estimated sample size of 7,186 patients for the two co-primary outcomes of death, any&#xD;
      non-fatal myocardial infarction, any non-fatal stroke or urgent target vessel&#xD;
      revascularization and bleeding events classified as 3 or 5 according to the Bleeding Academic&#xD;
      Research Consortium (BARC) criteria. To ensure a comprehensive assessment of clinical events,&#xD;
      a triggers logic is adopted to identify other potential events qualifying for study endpoints&#xD;
      but not reported as such by local investigators.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The GLOBAL LEADERS trial was designed to determine the benefits and risks of an&#xD;
      antithrombotic regimen using ticagrelor 90 mg BID combined with low-dose (75 mg OD)&#xD;
      acetylsalicylic acid (ASA) for one month followed by ticagrelor 90 mg BID alone for 23&#xD;
      months, compared to conventional dual antiplatelet therapy (DAPT) in all-comers patients with&#xD;
      coronary artery disease undergoing biolimus-eluting stent implantation on bivalirudin. It was&#xD;
      intended as a pragmatic clinical trial and, by design, endpoints included in primary and&#xD;
      secondary analyses are only investigator-reported (IR) and will not undergo independent&#xD;
      adjudication by a CEC. It is well known that in the absence of blinding of randomized&#xD;
      treatment (i.e. in an open-label design such as GLOBAL LEADERS) the use of IR outcome may&#xD;
      introduce detection and/or reporting bias. There are multiple lines of evidence indicating&#xD;
      that central and independent adjudication of events may affect the results of a randomized&#xD;
      trial by minimizing variability and heterogeneity inherently present when several different&#xD;
      clinicians and data managers apply definitions of endpoints which are complex and sometimes&#xD;
      not well known.Moreover, independent adjudication of ischaemic and bleeding endpoints may&#xD;
      provide important mechanistic information that may deepen understanding of the primary&#xD;
      endpoint result of the study by better characterizing component of such endpoints including,&#xD;
      but not limited to, precise cause of death, sub-type of myocardial infarction (MI), and&#xD;
      bleeding location. The objectives of this substudy are: to assess the impact of&#xD;
      CEC-adjudication process on the results of the study; to quantify the added value of CEC&#xD;
      adjudication process for endpoint reporting by evaluating the concordance between IR-reported&#xD;
      and CEC-adjudicated events; to gather mechanistic information to aid in the interpretation of&#xD;
      the effect of the experimental treatment in the parent trial and to identify specific&#xD;
      subgroups of patients that could particularly benefit from the experimental therapy in terms&#xD;
      of ischemic and bleeding events.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 1, 2017</start_date>
  <completion_date type="Actual">May 30, 2020</completion_date>
  <primary_completion_date type="Actual">December 30, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Composite of death, stroke, cardiac and bleeding events</measure>
    <time_frame>24 months</time_frame>
    <description>Death, any non-fatal MI, any non-fatal stroke (i.e. including both ischemic and haemorrhagic) or urgent target vessel revascularization (TVR) (co-primary efficacy endpoint) Bleeding 3 or 5 according to Bleeding Academic Research Consortium (BARC) definition (co-primary safety endpoint).&#xD;
Primary outcome will be defined as the occurrence of the sum of listed events</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Death</measure>
    <time_frame>24 months or at earlier time point</time_frame>
    <description>Any death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-fatal MI</measure>
    <time_frame>24 months or at earlier time point</time_frame>
    <description>Any non-fatal MI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-fatal stroke</measure>
    <time_frame>24 months or at earlier time point</time_frame>
    <description>Any non-fatal stroke (i.e. including both ischemic and haemorrhagic)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rates of urgent revascularization of the target vessel (Urgent TVR)</measure>
    <time_frame>24 months or at earlier time point</time_frame>
    <description>One or more episodes of rest pain, presumed to be ischemic in origin which results in either urgent percutaneous coronary intervention or urgent coronary artery by pass graft. To be considered urgent, the repeat revascularization will be initiated within 24 hours of the last episode of ischemia and not be identified as planned or staged.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Definite, probable or possible Stent thrombosis</measure>
    <time_frame>24 months or at earlier time point</time_frame>
    <description>Definite, probable or possible Stent thrombosis according to Academic Research Consortium (ARC) classification</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bleeding events</measure>
    <time_frame>24 months or at earlier time point</time_frame>
    <description>Bleeding events according to Bleeding Academic Research Consortium (BARC), Thrombolysis In Myocardial Infarction (TIMI) and Global Use of Strategies To Open coronary arteries (GUSTO) classifications</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences between the rates of outcomes reported by the investigators and the rates of outcomes as adjudicated by an independent clinical event committee</measure>
    <time_frame>24 months or at earlier time point</time_frame>
    <description>Concordance between IR- and CEC- endpoints</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">7365</enrollment>
  <condition>Coronary Artery Disease</condition>
  <condition>Platelet-aggregation Inhibitors</condition>
  <arm_group>
    <arm_group_label>Experimental treatment strategy</arm_group_label>
    <description>All patients in the treatment group received acetylsalicylic acid (ASA) and ticagrelor for 1 month followed by 23 months of ticagrelor monotherapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Reference treatment strategy</arm_group_label>
    <description>Acute Coronary Syndrome (ACS) patients incl. unstable angina (UA) patients: ASA and ticagrelor for 12 months followed by 12 months of ASA monotherapy.&#xD;
Stable Coronary Artery Disease (CAD) patients: ASA and clopidogrel for 12 months followed by 12 months of ASA monotherapy.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Patients included in the GLOBAL LEADERS Trial, e.g. &quot;All comers&quot; with coronary artery&#xD;
        disease requiring percutaneous coronary intervention (PCI)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        &quot;All comer&quot; patients&#xD;
&#xD;
          1. Age ≥18 years;&#xD;
&#xD;
          2. Presence of one or more coronary artery stenoses of 50% or more in a native coronary&#xD;
             artery or in a saphenous venous or arterial bypass conduit suitable for coronary stent&#xD;
             implantation. The vessel should have a reference vessel diameter of at least 2.25 mm&#xD;
             (no limitation on the number of treated lesions, vessels, or lesion length);&#xD;
&#xD;
          3. Able to provide informed consent and willing to participate in 2 year follow- up&#xD;
             period.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Known intolerance to aspirin, P2Y12 inhibitors, bivalirudin, stainless steel or&#xD;
             biolimus;&#xD;
&#xD;
          2. Known intake of a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin,&#xD;
             nefazodone, ritonavir, and atazanavir), as co-administration may lead to a substantial&#xD;
             increase in exposure to ticagrelor;&#xD;
&#xD;
          3. Known moderate to severe hepatic impairment (alanine-aminotransferase ≥ 3 x ULN);&#xD;
&#xD;
          4. Planned surgery, including CABG as a staged procedure (hybrid) within 12 months of the&#xD;
             index procedure, unless dual antiplatelet therapy is maintained throughout the&#xD;
             peri-surgical period;&#xD;
&#xD;
          5. Need for chronic oral anti-coagulation therapy;&#xD;
&#xD;
          6. Active major bleeding or major surgery within the last 30 days;&#xD;
&#xD;
          7. Known history of intracranial haemorrhagic stroke or intra-cranial aneurysm;&#xD;
&#xD;
          8. Known stroke (any type) within the last 30 days;&#xD;
&#xD;
          9. Known pregnancy at time of randomisation;&#xD;
&#xD;
         10. Female who is breastfeeding at time of randomisation;&#xD;
&#xD;
         11. Currently participating in another trial and not yet at its primary endpoint&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stephan Windecker, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Inselspital Bern University Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Marco Valgimigli, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Inselspital Bern University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Wilhelminenspital 1160</name>
      <address>
        <city>Vienna</city>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Bonheiden 3204</name>
      <address>
        <city>Bonheiden</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Charleroi 3202</name>
      <address>
        <city>Charleroi</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Genk 3205</name>
      <address>
        <city>Genk</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Hasselt 3203</name>
      <address>
        <city>Hasselt</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Sofia, 9901</name>
      <address>
        <city>Sofia</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Bad Nauheim 4902</name>
      <address>
        <city>Bad Nauheim</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Essen 4903</name>
      <address>
        <city>Essen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Arezzo 3902</name>
      <address>
        <city>Arezzo</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Ferrara 3905</name>
      <address>
        <city>Ferrara</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Pavia 3903</name>
      <address>
        <city>Pavia</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Terni 3909</name>
      <address>
        <city>Terni</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Amsterdam 3104</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Rotterdam 3101</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Chrzanow 4802</name>
      <address>
        <city>Chrzanów</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Dabrowa Gornicza 4801</name>
      <address>
        <city>Dąbrowa Górnicza</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Krakov 4807</name>
      <address>
        <city>Kraków</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Inselspital Bern University Hospital</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research centre Blackburn 4404</name>
      <address>
        <city>Blackburn</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Bulgaria</country>
    <country>Germany</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>Poland</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Vranckx P, Valgimigli M, Windecker S, Steg PG, Hamm C, Juni P, Garcia-Garcia HM, van Es GA, Serruys PW. Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial. EuroIntervention. 2016 Nov 20;12(10):1239-1245. doi: 10.4244/EIJY15M11_07.</citation>
    <PMID>26606735</PMID>
  </reference>
  <reference>
    <citation>Seltzer JH, Turner JR, Geiger MJ, Rosano G, Mahaffey KW, White WB, Sabol MB, Stockbridge N, Sager PT. Centralized adjudication of cardiovascular end points in cardiovascular and noncardiovascular pharmacologic trials: a report from the Cardiac Safety Research Consortium. Am Heart J. 2015 Feb;169(2):197-204. doi: 10.1016/j.ahj.2014.11.003. Epub 2014 Nov 10.</citation>
    <PMID>25641528</PMID>
  </reference>
  <reference>
    <citation>Lopes RD, Dickerson S, Hafley G, Burns S, Tourt-Uhlig S, White J, Newby LK, Komajda M, McMurray J, Bigelow R, Home PD, Mahaffey KW. Methodology of a reevaluation of cardiovascular outcomes in the RECORD trial: study design and conduct. Am Heart J. 2013 Aug;166(2):208-216.e28. doi: 10.1016/j.ahj.2013.05.005. Epub 2013 Jun 22.</citation>
    <PMID>23895802</PMID>
  </reference>
  <reference>
    <citation>Vranckx P, McFadden E, Cutlip DE, Mehran R, Swart M, Kint PP, Zijlstra F, Silber S, Windecker S, Serruys PW. Clinical endpoint adjudication in a contemporary all-comers coronary stent investigation: methodology and external validation. Contemp Clin Trials. 2013 Jan;34(1):53-9. doi: 10.1016/j.cct.2012.08.012. Epub 2012 Sep 10.</citation>
    <PMID>22975439</PMID>
  </reference>
  <reference>
    <citation>Vranckx P, McFadden E, Mehran R, Cutlip DE. Clinical event committees in coronary stent trials: insights and recommendations based on experience in an unselected study population. EuroIntervention. 2012 Jul 20;8(3):368-74. doi: 10.4244/EIJV8I3A56.</citation>
    <PMID>22829511</PMID>
  </reference>
  <reference>
    <citation>Mahaffey KW, Wampole JL, Stebbins A, Berdan LG, McAfee D, Rorick TL, French JK, Kleiman NS, O'Connor CM, Cohen EA, Granger CB, Armstrong PW; APEX-AMI Investigators. Strategic lessons from the clinical event classification process for the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Contemp Clin Trials. 2011 Mar;32(2):178-87. doi: 10.1016/j.cct.2010.12.013. Epub 2011 Jan 8.</citation>
    <PMID>21220052</PMID>
  </reference>
  <reference>
    <citation>Frederich R, Alexander JH, Fiedorek FT, Donovan M, Berglind N, Harris S, Chen R, Wolf R, Mahaffey KW. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010 May;122(3):16-27. doi: 10.3810/pgm.2010.05.2138.</citation>
    <PMID>20463410</PMID>
  </reference>
  <reference>
    <citation>Kirwan BA, Lubsen J, de Brouwer S, Danchin N, Battler A, Bayes de Luna A, Dunselman PH, Glasser S, Koudstaal PJ, Sutton G, van Dalen FJ, Poole-Wilson PA; ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) investigators. Diagnostic criteria and adjudication process both determine published event-rates: the ACTION trial experience. Contemp Clin Trials. 2007 Nov;28(6):720-9. doi: 10.1016/j.cct.2007.04.001. Epub 2007 Apr 19.</citation>
    <PMID>17509947</PMID>
  </reference>
  <reference>
    <citation>Petersen JL, Haque G, Hellkamp AS, Flaker GC, Mark Estes NA 3rd, Marchlinski FE, McAnulty JH, Greenspon AJ, Marinchak RA, Lee KL, Lamas GA, Mahaffey KW; MOST Clinical Events Committee. Comparing classifications of death in the Mode Selection Trial: agreement and disagreement among site investigators and a clinical events committee. Contemp Clin Trials. 2006 Jun;27(3):260-8. doi: 10.1016/j.cct.2006.02.002. Epub 2006 Mar 29.</citation>
    <PMID>16574497</PMID>
  </reference>
  <reference>
    <citation>Mahaffey KW, Roe MT, Dyke CK, Newby LK, Kleiman NS, Connolly P, Berdan LG, Sparapani R, Lee KL, Armstrong PW, Topol EJ, Califf RM, Harrington RA. Misreporting of myocardial infarction end points: results of adjudication by a central clinical events committee in the PARAGON-B trial. Second Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network Trial. Am Heart J. 2002 Feb;143(2):242-8. doi: 10.1067/mhj.2002.120145.</citation>
    <PMID>11835026</PMID>
  </reference>
  <reference>
    <citation>Mahaffey KW, Harrington RA, Akkerhuis M, Kleiman NS, Berdan LG, Crenshaw BS, Tardiff BE, Granger CB, DeJong I, Bhapkar M, Widimsky P, Corbalon R, Lee KL, Deckers JW, Simoons ML, Topol EJ, Califf RM; For the PURSUIT Investigators. Disagreements between central clinical events committee and site investigator assessments of myocardial infarction endpoints in an international clinical trial: review of the PURSUIT study. Curr Control Trials Cardiovasc Med. 2001 Jul 17;2(4):187-194. doi: 10.1186/cvm-2-4-187.</citation>
    <PMID>11806794</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 19, 2017</study_first_submitted>
  <study_first_submitted_qc>July 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2017</study_first_posted>
  <last_update_submitted>July 31, 2020</last_update_submitted>
  <last_update_submitted_qc>July 31, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Coronary artery disease</keyword>
  <keyword>Percutaneous coronary intervention</keyword>
  <keyword>Drug-eluting stent</keyword>
  <keyword>Antiplatelet drugs</keyword>
  <keyword>Clinical event committee</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Myocardial Ischemia</mesh_term>
    <mesh_term>Coronary Disease</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03231059
org study id: 039_2013_Substudy
nct id: NCT03231059
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The GLOBAL LEADERS Adjudication Sub-StudY, GLASSY, is based on a re-assessment of all the
      events reported in the dataset of the parent trial (COMPARATIVE EFFECTIVENESS OF 1 MONTH OF
      TICAGRELOR PLUS ASPIRIN FOLLOWED BY TICAGRELOR MONOTHERAPY VERSUS A CURRENT-DAY INTENSIVE
      DUAL ANTIPLATELET THERAPY IN ALL-COMERS PATIENTS UNDERGOING PERCUTANEOUS CORONARY
      INTERVENTION WITH BIVALIRUDIN AND BIOMATRIX FAMILY DRUG-ELUTING STENT USE) by an independent
      Clinical Event Committee (CEC), composed of three physicians not involved in the main trial.
      The substudy include the first 19 top-enrolling sites of the GLOBAL LEADERS to reach the
      estimated sample size of 7,186 patients for the two co-primary outcomes of death, any
      non-fatal myocardial infarction, any non-fatal stroke or urgent target vessel
      revascularization and bleeding events classified as 3 or 5 according to the Bleeding Academic
      Research Consortium (BARC) criteria. To ensure a comprehensive assessment of clinical events,
      a triggers logic is adopted to identify other potential events qualifying for study endpoints
      but not reported as such by local investigators.
The GLOBAL LEADERS trial was designed to determine the benefits and risks of an
      antithrombotic regimen using ticagrelor 90 mg BID combined with low-dose (75 mg OD)
      acetylsalicylic acid (ASA) for one month followed by ticagrelor 90 mg BID alone for 23
      months, compared to conventional dual antiplatelet therapy (DAPT) in all-comers patients with
      coronary artery disease undergoing biolimus-eluting stent implantation on bivalirudin. It was
      intended as a pragmatic clinical trial and, by design, endpoints included in primary and
      secondary analyses are only investigator-reported (IR) and will not undergo independent
      adjudication by a CEC. It is well known that in the absence of blinding of randomized
      treatment (i.e. in an open-label design such as GLOBAL LEADERS) the use of IR outcome may
      introduce detection and/or reporting bias. There are multiple lines of evidence indicating
      that central and independent adjudication of events may affect the results of a randomized
      trial by minimizing variability and heterogeneity inherently present when several different
      clinicians and data managers apply definitions of endpoints which are complex and sometimes
      not well known.Moreover, independent adjudication of ischaemic and bleeding endpoints may
      provide important mechanistic information that may deepen understanding of the primary
      endpoint result of the study by better characterizing component of such endpoints including,
      but not limited to, precise cause of death, sub-type of myocardial infarction (MI), and
      bleeding location. The objectives of this substudy are: to assess the impact of
      CEC-adjudication process on the results of the study; to quantify the added value of CEC
      adjudication process for endpoint reporting by evaluating the concordance between IR-reported
      and CEC-adjudicated events; to gather mechanistic information to aid in the interpretation of
      the effect of the experimental treatment in the parent trial and to identify specific
      subgroups of patients that could particularly benefit from the experimental therapy in terms
      of ischemic and bleeding events.
observational model: Cohort
time perspective: Retrospective
measure: Composite of death, stroke, cardiac and bleeding events
time frame: 24 months
description: Death, any non-fatal MI, any non-fatal stroke (i.e. including both ischemic and haemorrhagic) or urgent target vessel revascularization (TVR) (co-primary efficacy endpoint) Bleeding 3 or 5 according to Bleeding Academic Research Consortium (BARC) definition (co-primary safety endpoint).
Primary outcome will be defined as the occurrence of the sum of listed events
measure: Death
time frame: 24 months or at earlier time point
description: Any death
measure: Non-fatal MI
time frame: 24 months or at earlier time point
description: Any non-fatal MI
measure: Non-fatal stroke
time frame: 24 months or at earlier time point
description: Any non-fatal stroke (i.e. including both ischemic and haemorrhagic)
measure: Rates of urgent revascularization of the target vessel (Urgent TVR)
time frame: 24 months or at earlier time point
description: One or more episodes of rest pain, presumed to be ischemic in origin which results in either urgent percutaneous coronary intervention or urgent coronary artery by pass graft. To be considered urgent, the repeat revascularization will be initiated within 24 hours of the last episode of ischemia and not be identified as planned or staged.
measure: Definite, probable or possible Stent thrombosis
time frame: 24 months or at earlier time point
description: Definite, probable or possible Stent thrombosis according to Academic Research Consortium (ARC) classification
measure: Bleeding events
time frame: 24 months or at earlier time point
description: Bleeding events according to Bleeding Academic Research Consortium (BARC), Thrombolysis In Myocardial Infarction (TIMI) and Global Use of Strategies To Open coronary arteries (GUSTO) classifications
measure: Differences between the rates of outcomes reported by the investigators and the rates of outcomes as adjudicated by an independent clinical event committee
time frame: 24 months or at earlier time point
description: Concordance between IR- and CEC- endpoints
arm group label: Experimental treatment strategy
description: All patients in the treatment group received acetylsalicylic acid (ASA) and ticagrelor for 1 month followed by 23 months of ticagrelor monotherapy
arm group label: Reference treatment strategy
description: Acute Coronary Syndrome (ACS) patients incl. unstable angina (UA) patients: ASA and ticagrelor for 12 months followed by 12 months of ASA monotherapy.
Stable Coronary Artery Disease (CAD) patients: ASA and clopidogrel for 12 months followed by 12 months of ASA monotherapy.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Stephan Windecker, MD
role: Study Chair
affiliation: Inselspital Bern University Hospital
last name: Marco Valgimigli, MD
role: Principal Investigator
affiliation: Inselspital Bern University Hospital
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Austria
country: Belgium
country: Bulgaria
country: Germany
country: Italy
country: Netherlands
country: Poland
country: Switzerland
country: United Kingdom
citation: Vranckx P, Valgimigli M, Windecker S, Steg PG, Hamm C, Juni P, Garcia-Garcia HM, van Es GA, Serruys PW. Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial. EuroIntervention. 2016 Nov 20;12(10):1239-1245. doi: 10.4244/EIJY15M11_07.
PMID: 26606735
citation: Seltzer JH, Turner JR, Geiger MJ, Rosano G, Mahaffey KW, White WB, Sabol MB, Stockbridge N, Sager PT. Centralized adjudication of cardiovascular end points in cardiovascular and noncardiovascular pharmacologic trials: a report from the Cardiac Safety Research Consortium. Am Heart J. 2015 Feb;169(2):197-204. doi: 10.1016/j.ahj.2014.11.003. Epub 2014 Nov 10.
PMID: 25641528
citation: Lopes RD, Dickerson S, Hafley G, Burns S, Tourt-Uhlig S, White J, Newby LK, Komajda M, McMurray J, Bigelow R, Home PD, Mahaffey KW. Methodology of a reevaluation of cardiovascular outcomes in the RECORD trial: study design and conduct. Am Heart J. 2013 Aug;166(2):208-216.e28. doi: 10.1016/j.ahj.2013.05.005. Epub 2013 Jun 22.
PMID: 23895802
citation: Vranckx P, McFadden E, Cutlip DE, Mehran R, Swart M, Kint PP, Zijlstra F, Silber S, Windecker S, Serruys PW. Clinical endpoint adjudication in a contemporary all-comers coronary stent investigation: methodology and external validation. Contemp Clin Trials. 2013 Jan;34(1):53-9. doi: 10.1016/j.cct.2012.08.012. Epub 2012 Sep 10.
PMID: 22975439
citation: Vranckx P, McFadden E, Mehran R, Cutlip DE. Clinical event committees in coronary stent trials: insights and recommendations based on experience in an unselected study population. EuroIntervention. 2012 Jul 20;8(3):368-74. doi: 10.4244/EIJV8I3A56.
PMID: 22829511
citation: Mahaffey KW, Wampole JL, Stebbins A, Berdan LG, McAfee D, Rorick TL, French JK, Kleiman NS, O'Connor CM, Cohen EA, Granger CB, Armstrong PW; APEX-AMI Investigators. Strategic lessons from the clinical event classification process for the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Contemp Clin Trials. 2011 Mar;32(2):178-87. doi: 10.1016/j.cct.2010.12.013. Epub 2011 Jan 8.
PMID: 21220052
citation: Frederich R, Alexander JH, Fiedorek FT, Donovan M, Berglind N, Harris S, Chen R, Wolf R, Mahaffey KW. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010 May;122(3):16-27. doi: 10.3810/pgm.2010.05.2138.
PMID: 20463410
citation: Kirwan BA, Lubsen J, de Brouwer S, Danchin N, Battler A, Bayes de Luna A, Dunselman PH, Glasser S, Koudstaal PJ, Sutton G, van Dalen FJ, Poole-Wilson PA; ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) investigators. Diagnostic criteria and adjudication process both determine published event-rates: the ACTION trial experience. Contemp Clin Trials. 2007 Nov;28(6):720-9. doi: 10.1016/j.cct.2007.04.001. Epub 2007 Apr 19.
PMID: 17509947
citation: Petersen JL, Haque G, Hellkamp AS, Flaker GC, Mark Estes NA 3rd, Marchlinski FE, McAnulty JH, Greenspon AJ, Marinchak RA, Lee KL, Lamas GA, Mahaffey KW; MOST Clinical Events Committee. Comparing classifications of death in the Mode Selection Trial: agreement and disagreement among site investigators and a clinical events committee. Contemp Clin Trials. 2006 Jun;27(3):260-8. doi: 10.1016/j.cct.2006.02.002. Epub 2006 Mar 29.
PMID: 16574497
citation: Mahaffey KW, Roe MT, Dyke CK, Newby LK, Kleiman NS, Connolly P, Berdan LG, Sparapani R, Lee KL, Armstrong PW, Topol EJ, Califf RM, Harrington RA. Misreporting of myocardial infarction end points: results of adjudication by a central clinical events committee in the PARAGON-B trial. Second Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network Trial. Am Heart J. 2002 Feb;143(2):242-8. doi: 10.1067/mhj.2002.120145.
PMID: 11835026
citation: Mahaffey KW, Harrington RA, Akkerhuis M, Kleiman NS, Berdan LG, Crenshaw BS, Tardiff BE, Granger CB, DeJong I, Bhapkar M, Widimsky P, Corbalon R, Lee KL, Deckers JW, Simoons ML, Topol EJ, Califf RM; For the PURSUIT Investigators. Disagreements between central clinical events committee and site investigator assessments of myocardial infarction endpoints in an international clinical trial: review of the PURSUIT study. Curr Control Trials Cardiovasc Med. 2001 Jul 17;2(4):187-194. doi: 10.1186/cvm-2-4-187.
PMID: 11806794
responsible party type: Sponsor
mesh term: Coronary Artery Disease
mesh term: Myocardial Ischemia
mesh term: Coronary Disease
sharing ipd: No