Trial DesignRationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial
Section snippets
Background
Type 2 diabetes mellitus (T2DM) is a growing global epidemic affecting approximately 350 million people,1 the majority of whom will die from cardiovascular disease.2, 3 Epidemiological analyses of United Kingdom Prospective Diabetes Study data from newly diagnosed T2DM identified higher low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, hyperglycemia, hypertension, and smoking as potentially modifiable cardiovascular risk factors.4 However, even after adjustment
Overview
EXSCEL is a multinational, placebo-controlled, double-blind, parallel-group pragmatic trial randomizing patients with T2DM to receive once-weekly exenatide or matching placebo (unloaded microspheres), in addition to their usual care (Figure). It will assess the impact of once-weekly exenatide therapy in approximately 14,000 patients, with or without known cardiovascular disease, from heterogeneous practice environments in 35 countries from North and South America, Europe, Africa, Asia, and
Sample size and power calculations
The sample size was estimated initially to be 9,600, assuming an annual 3.8% primary composite cardiovascular end point event rate, 1% annual lost to follow-up rate, 5% annual study drug discontinuation rate, and with a 60:40 ratio of those with or without a history of cardiovascular disease. Given that the observed (blinded) overall primary end point event rate to date was lower than expected, the sample size was increased to 14,000 in 2013, and the proportion of patients with history of
Biomarker and genetic assessments
Two optional substudies are included in EXSCEL for the first 9,600 patients to be recruited. A genetic substudy aims to collect whole blood samples at baseline for future genetic research, and a biomarker substudy will collect urine and blood samples before study drug exposure and annually thereafter for proteomic and metabolomic research. Separate consent will be obtained for each of these substudies.
Health economic analysis
EXSCEL will collect physician-reported data on resource use and patient-reported quality of life to undertake cost-effectiveness analyses relevant to the countries taking part in the study. Resource use data on hospitalizations, visits, and medications will be combined with appropriate national unit costs to calculate a cost per patient per year. Quality of life data will be combined with survival data to calculate quality-adjusted time in the trial per patient.
Study organization
EXSCEL is run jointly by 2 academic research organizations, the Duke Clinical Research Institute (Durham, NC) and the University of Oxford Diabetes Trials Unit (Oxford, UK), in an academic collaboration with pharmaceutical companies. Amylin Pharmaceuticals Inc (San Diego, CA) was the original sponsor, later joined in an alliance with Eli Lilly and Company (Indianapolis, IN). Subsequently, sponsorship transitioned to Bristol-Myers Squibb (Princeton, NJ) and AstraZeneca (Gaithersburg, MD) with
Ethical considerations
The EXSCEL trial complies with the Declaration of Helsinki, its subsequent revisions, and Good Clinical Practice Guidelines. Institutional review board approval has been obtained for all sites, and subjects sign informed consent before any study procedures commence. EXSCEL is registered on www.clinicaltrials.gov (NCT01144338).
Discussion
The EXSCEL trial will determine whether once-weekly exenatide, on top of usual diabetes care, reduces cardiovascular events in patients with T2DM compared with usual diabetes care without a GLP-1 receptor agonist.
EXSCEL is the largest GLP-1 receptor agonist cardiovascular outcome trial to date, recruiting 14,000 participants, and differs from other ongoing studies in a number of respects. Designed from the outset to test for superiority for the primary composite cardiovascular outcome, it will
Conclusion
In summary, EXSCEL is an ongoing multinational, double-blind, placebo-controlled, randomized trial of once-weekly exenatide that will provide important data on its long-term cardiovascular safety and potential cardiovascular benefit. Given its pragmatic design, inclusion of patients with a broad range of cardiovascular risk, and no restrictions on concomitant glucose-lowering therapies (other than GLP-1 receptor agonists), the trial is expected to provide results that are generalizable and
Conflicts of interest
R.R.H. has received research support from Bayer, BMS, and Merck; attended advisory boards with Amgen, Bayer, Elcelyx, Merck, Novartis, and Novo Nordisk; and given lectures supported by Bayer.
M.A.B. has received research funding from Novartis and Bayer.
J.G. has received consulting fees, speaker fees, travel expenses, and/or research support from Amylin, AstraZeneca, Boeringher Ingelhiem, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novo Nordisk, Sanofi, and Takeda.
A.F.H. has received
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2021, AtherosclerosisCitation Excerpt :The design and primary results of the EXSCEL trial (NCT01144338) have been previously published. EXSCEL was a double-blind, pragmatic, placebo-controlled, international trial examining the effect of adding once-weekly exenatide to usual care versus usual care alone on MACE in patients with T2D (defined as an HbA1c of 6.5%–10%) with or without previous cardiovascular disease [7,8]. The trial randomized 14,752 patients from 35 countries and was designed so that 70% of enrolled patients had a previous cardiovascular event (defined as a history of major clinical manifestation of coronary artery disease, ischemic cerebrovascular disease, or atherosclerotic peripheral arterial disease).
Uchechukwu Sampson, MD, served as guest editor for this article.