GLOBAL LEADERS Adjudication Sub-Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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GLOBAL LEADERS Adjudication Sub-Study

Conditions
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Coronary Artery Disease, Platelet-aggregation Inhibitors

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All comer patients Age ≥18 years; Presence of one or more coronary artery stenoses of 50% or more in a native coronary artery or in a saphenous venous or arterial bypass conduit suitable for coronary stent implantation. The vessel should have a reference vessel diameter of at least 2.25 mm (no limitation on the number of treated lesions, vessels, or lesion length); Able to provide informed consent and willing to participate in 2 year follow- up period. Exclusion Criteria: Known intolerance to aspirin, P2Y12 inhibitors, bivalirudin, stainless steel or biolimus; Known intake of a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor; Known moderate to severe hepatic impairment (alanine-aminotransferase ≥ 3 x ULN); Planned surgery, including CABG as a staged procedure (hybrid) within 12 months of the index procedure, unless dual antiplatelet therapy is maintained throughout the peri-surgical period; Need for chronic oral anti-coagulation therapy; Active major bleeding or major surgery within the last 30 days; Known history of intracranial haemorrhagic stroke or intra-cranial aneurysm; Known stroke (any type) within the last 30 days; Known pregnancy at time of randomisation; Female who is breastfeeding at time of randomisation; Currently participating in another trial and not yet at its primary endpoint

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental treatment strategy<br>All patients in the treatment group received acetylsalicylic acid (ASA) and ticagrelor for 1 month followed by 23 months of ticagrelor monotherapy | |
| Reference treatment strategy<br>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. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of death, stroke, cardiac and bleeding events | 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 | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | Any death | 24 months or at earlier time point | 
| Non-fatal MI | Any non-fatal MI | 24 months or at earlier time point | 
| Non-fatal stroke | Any non-fatal stroke (i.e. including both ischemic and haemorrhagic) | 24 months or at earlier time point | 
| Rates of urgent revascularization of the target vessel (Urgent TVR) | 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. | 24 months or at earlier time point | 
| Definite, probable or possible Stent thrombosis | Definite, probable or possible Stent thrombosis according to Academic Research Consortium (ARC) classification | 24 months or at earlier time point | 
| Bleeding events | 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 | 24 months or at earlier time point | 
| Differences between the rates of outcomes reported by the investigators and the rates of outcomes as adjudicated by an independent clinical event committee | Concordance between IR- and CEC- endpoints | 24 months or at earlier time point | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary artery disease, Percutaneous coronary intervention, Drug-eluting stent, Antiplatelet drugs, Clinical event committee