EXenatide Study of Cardiovascular Event Lowering Trial (EXSCEL): A Randomized, Placebo Controlled Clinical Trial to Evaluate Cardiovascular Outcomes After Treatment with Exenatide Once Weekly in Patients with Type 2 Diabetes Mellitus
EXSCEL will be a multinational, placebo-controlled, double-blind, randomized,
parallel-group pragmatic clinical trial. Eligible patients will have type 2 diabetes with an HbA1c[Greater than or equal to 6.5% and less than or equalto 10.0 % on up to three (i.e., 0-3) oral aHas or insulin either alone or in combination with up to 2 (i.e., 0-2) oral AHAs. Patients enrolled will be at a wide range of CV risk with approximately 60% having had a prior CV event. Approximately 9500 patients meeting all enrollment criteria will be recruited in to the trial over an approximately three year period, randomly allocated to treatment with either EQW 2 mg or matching placebo subcutaneous injections once weekly in a 1:1 ratio, and followed up for a minimum of four years. The trial will continue until adjudicated 1591 primary endpoint events have been accrued, or until the independent Data Safety Monitoring Board (DSMB)advises otherwise. The trial will assess the impact of EQW therapy upon CV outcomes in a large population from a heterogeneous group of countries and practice environments. approximately one-third of patients will be enrolled in the americas (north/South america and Canada), one-third in europe and one-third in the asia/australasia. Given that this population will be at elevated CV risk, it is anticipated that patients will see their usual care provider at least twice per year for routine care.
Trial follow up will consist of a blend of trial visits and phone calls during the double-blind placebo-controlled treatment period, which is expected to provide an average 5.5 patient years of follow up. There is no requirement to achieve glycemic equipoise between randomized groups but all patients during the double-blind treatment period will have their aHa regimens adjusted as deemed necessary by their usual care provider with the addition or substitution of other AHAs, including insulin but excluding GLP-1 receptor agonists, to achieve appropriate individualized glycemic goals in line with national guidelines. adjustments in aHa medications are permitted any time after randomization, but usual care providers will be asked to avoid this until HbA1c levels begin to reflect the initial effect of randomized study medication. Prior to randomization, it is anticipated that all patients will have received counseling regarding appropriate diet and level of physical activity as part of usual care for type 2 diabetes. Per usual care, HbA1c values should be measured locally.
Each patient must meet the following criteria to be enrolled in this trial. a. Patient has type 2 diabetes mellitus
b. Patient will be able to see a usual care provider at least twice a year
c. Patient has an HbA1c of >=6.5 % and <= 10.0% and is currently using one of the following
* Treatment with up to three (i.e., 0-3) oral AHAs (concomitant use of DPP-4 inhibitors is
* Insulin therapy, either alone or in combination with up to two (i.e., 0-2) oral AHAs (use
of basal and prandial insulins is permitted in any combination of individual or premixed
All patients should be on a stable diabetes management regimen, as assessed by the
investigator, at the time of enrollment.
HbA1c values must be from within the 3 months prior to randomization. If multiple values
are available, the most recent reported value should be used. A patient whose HbA1c is
>10.0% may, at the discretion of the investigator, have their oral AHA or insulin therapy
adjusted and be re-screened once for HbA1c randomization eligibility (>=6.5 % and <=10.0%). d. Patients with any level of CV risk and meeting all other inclusion criteria may be enrolled.
Recruitment will be constrained such that approximately 40% will not have had a prior CV
event and 60% will have had a prior CV event.
A prior CV event is defined as at least one of the following:
* History of a major clinical manifestation of coronary artery disease i.e. myocardial
infarction, surgical or percutaneous (balloon and/or stent) coronary revascularization
procedure, or coronary angiography showing at least one stenosis >=50% in a major
epicardial artery or branch vessel
* Ischemic cerebrovascular disease, including:
o History of ischemic stroke; strokes not known to be hemorrhagic will be allowed as
part of this criterion; transient ischemic attacks (TIAs) are not included o History of carotid arterial disease as documented by >=50 % stenosis documented by
carotid ultrasound, magnetic resonance imaging (MRI), or angiography, with or
without symptoms of neurologic deficit
* Atherosclerotic peripheral arterial disease, as documented by objective evidence such as
amputation due to vascular disease, current symptoms of intermittent claudication
confirmed by an ankle-brachial pressure index or toe brachial pressure index less than
0.9, or history of surgical or percutaneous revascularization procedure.
e. Female patients must not be breast feeding and agree to use an effective method of
contraception or must not otherwise be at risk of becoming pregnant.
f. Patient understands the trial procedures, alternative treatments available, the risks involved
with the trial, and voluntarily agrees to participate by providing written informed consent.
g. Patient agrees to provide permission to obtain all medical records necessary for complete
data ascertainment during the follow-up period, and agrees to communication between the
trial site and the usual care provider in order to facilitate routine care.
h. Patient is 18 years or older at enrollment.