GLOBAL LEADERS Adjudication Sub-Study

Coronary Artery Disease Clinical Trial

— GLASSY  

Official title:

GLOBAL LEADERS Adjudication Sub-Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03231059
• Other study ID #: 039_2013_Substudy
• Status: Completed
• Start date: June 1, 2017
• Est. completion date: May 30, 2020

Study information

• Verified date: July 2020
• Source: University Hospital Inselspital, Berne
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7365
• Est. completion date: May 30, 2020
• Est. primary completion date: December 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

"All comer" patients

1. Age =18 years;

2. 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);

3. Able to provide informed consent and willing to participate in 2 year follow- up period.

Exclusion Criteria:

1. Known intolerance to aspirin, P2Y12 inhibitors, bivalirudin, stainless steel or biolimus;

2. 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;

3. Known moderate to severe hepatic impairment (alanine-aminotransferase = 3 x ULN);

4. 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;

5. Need for chronic oral anti-coagulation therapy;

6. Active major bleeding or major surgery within the last 30 days;

7. Known history of intracranial haemorrhagic stroke or intra-cranial aneurysm;

8. Known stroke (any type) within the last 30 days;

9. Known pregnancy at time of randomisation;

10. Female who is breastfeeding at time of randomisation;

11. Currently participating in another trial and not yet at its primary endpoint

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia
• Platelet-aggregation Inhibitors

Locations

Country	Name	City	State
Austria	Wilhelminenspital 1160	Vienna
Belgium	Research centre Bonheiden 3204	Bonheiden
Belgium	Research centre Charleroi 3202	Charleroi
Belgium	Research centre Genk 3205	Genk
Belgium	Research centre Hasselt 3203	Hasselt
Bulgaria	Research centre Sofia, 9901	Sofia
Germany	Research centre Bad Nauheim 4902	Bad Nauheim
Germany	Research centre Essen 4903	Essen
Italy	Research centre Arezzo 3902	Arezzo
Italy	Research centre Ferrara 3905	Ferrara
Italy	Research centre Pavia 3903	Pavia
Italy	Research centre Terni 3909	Terni
Netherlands	Research centre Amsterdam 3104	Amsterdam
Netherlands	Research centre Rotterdam 3101	Rotterdam
Poland	Research centre Chrzanow 4802	Chrzanów
Poland	Research centre Dabrowa Gornicza 4801	Dabrowa Górnicza
Poland	Research centre Krakov 4807	Kraków
Switzerland	Inselspital Bern University Hospital	Bern
United Kingdom	Research centre Blackburn 4404	Blackburn

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne	European Cardiovascular Research Center

Countries where clinical trial is conducted

Austria,  Belgium,  Bulgaria,  Germany,  Italy,  Netherlands,  Poland,  Switzerland,  United Kingdom, 

References & Publications (11)

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. — View 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. Epub 2007 Apr 19. — View 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. — View 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. — View 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. — View 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. — View 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. Epub 2006 Mar 29. — View 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. — View 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. — View 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. — View Citation

Vranckx P, Valgimigli M, Windecker S, Steg PG, Hamm C, Jüni 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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Death	Any death	24 months or at earlier time point
Secondary	Non-fatal MI	Any non-fatal MI	24 months or at earlier time point
Secondary	Non-fatal stroke	Any non-fatal stroke (i.e. including both ischemic and haemorrhagic)	24 months or at earlier time point
Secondary	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
Secondary	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
Secondary	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
Secondary	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