Elsevier

American Heart Journal

Volume 174, April 2016, Pages 103-110
American Heart Journal

Trial Design
Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial

https://doi.org/10.1016/j.ahj.2015.12.009Get rights and content

Exenatide once-weekly is an extended release formulation of exenatide, a glucagon-like peptide–1 receptor agonist, which can improve glycemic control, body weight, blood pressure, and lipid levels in patients with type 2 diabetes mellitus (T2DM). The EXenatide Study of Cardiovascular Event Lowering (EXSCEL) will compare the impact of adding exenatide once-weekly to usual care with usual care alone on major cardiovascular outcomes.

EXSCEL is an academically led, phase III/IV, double-blind, pragmatic placebo-controlled, global trial conducted in 35 countries aiming to enrol 14,000 patients with T2DM and a broad range of cardiovascular risk over approximately 5 years. Participants will be randomized (1:1) to receive exenatide once-weekly 2 mg or matching placebo by subcutaneous injections. The trial will continue until 1,360 confirmed primary composite cardiovascular end points, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, have occurred.

The primary efficacy hypothesis is that exenatide once-weekly is superior to usual care with respect to the primary composite cardiovascular end point. EXSCEL is powered to detect a 15% relative risk reduction in the exenatide once-weekly group, with 85% power and a 2-sided 5% alpha. The primary safety hypothesis is that exenatide once-weekly is noninferior to usual care with respect to the primary cardiovascular composite end point. Noninferiority will be concluded if the upper limit of the CI is <1.30.

EXSCEL will assess whether exenatide once-weekly can reduce cardiovascular events in patients with T2DM with a broad range of cardiovascular risk. It will also provide long-term safety information on exenatide once-weekly in people with T2DM.

ClinicalTrials.gov Identifier: NCT01144338

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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    Uchechukwu Sampson, MD, served as guest editor for this article.

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