Protocol

Academic Leadership

EXSCEL is managed by the Duke Clinical Research Institute and the University of Oxford Diabetes Trial Unit. The EXSCEL Executive Committee has responsibility for oversight of the trial with the majority of members being independent academics. The Operations Committee, which facilitates trial oversight at the local level, comprises academic investigators.

Sponsor

Amylin Pharmaceuticals, Inc

Study Phase

Phase 3b/4

Study Title

EXenatide Study of Cardiovascular Event Lowering

Study Drug

Exenatide is a receptor agonist for the human incretin Glucagon-Like Peptide-1 (GLP-1). Incretins enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. The GLP-1 system increases insulin secretion only in the presence of elevated plasma glucose levels, avoiding inappropriately high insulin levels during fasting. The drug also moderates peak serum glucagon levels during hyperglycemic periods following meals, but does not interfere with glucagon release in response to hypoglycemia. Secondary effects of drug administration reduces the rate of gastric emptying and decreases food intake, mitigating the potential severity of hyperglycemic events after meals.  Exenatide will be administered subcutaneously once a week in this trial.

Patient Population

Patients 18 years or older with T2DM with HbA1C of ≥7.0% and ≤10.0% on stable doses of up to three oral AHAs for at least 3 months.  Patients currently taking insulin will be excluded.  Patients with any level of CV risk can be enrolled.  Recruitment will be constrained such that 40% will not have had a prior CV event and 60% will have had a prior CV event defined as at least one of the following:  MI, surgical or percutaneous revascularization procedure, coronary angiography showing at least one stenosis ≥ 50% in a major epicardial artery or branch vessel, ischemic cerebrovascular disease including history of ischemic stroke, history of carotid arterial disease as documented by ≥50% stenosis, PAD as documented by intermittent claudication with ABI less than 0.9, amputation due to vascular disease, or history of surgical or percutaneous revascularization procedure.

Scope/Study Operations

This is a global pragmatic trial of approximately 9,500 patients conducted in over 400 sites in Asia, Australasia, Europe, Latin America, and North America.  The data collection and adverse event reporting will be streamlined.  We are looking for sites which can conduct pre-screening efforts and have proven ability to enroll patients and sustain enrollment and follow-up for cardiovascular outcome trial.

Study Design

This is an integrated study design with no interruption in usual care.  Exenatide/Placebo will be added to the ongoing AHA care regimen.  Patients will need to be on stable doses of up to 3 AHAs for at least 3 months i.e. no oral AHA adjustments within the past 3 months.

Primary Objective

To evaluate the effect of once weekly exenatide used in conjunction with the current usual care for glycemic control, on major macrovascular events when administered to patients with type 2 diabetes.

Patient Follow Up Visits

Screening and Randomization can be done at the same visit. Clinic visits will be scheduled at 1 week, 2 months, 6 months, 12 months, and then every six months until the end of study.  All patients will receive a 90 day post-study drug phone call.  Follow-up is expected to be an average of 5 ½ years.

Site Budget

Trial sites will be paid a fixed per patient fee which will cover study related expenditure including institution overheads and patient related reimbursement. Sites will be paid quarterly based on attended visits and 'clean' data which will be monitored by the Data Co-ordinating Centre. Further details will be provided should your site be eligible to participate in EXSCEL.

Site Identification

Priority will be given to sites with:

• Prior success in either large cardiovascular or diabetes trials or prior experience in phase 3b/4 diabetes trials
• Ability to perform screening of large numbers of potential patients
• Ability to manage the trial with minimal requirement for on-site monitoring visits.  The initial evaluation of sites will be conducted by telephone. Subsequent on site monitoring will occur twice in the first year and then annually. It is critical that the site PI and identified coordinator have adequate experience in independent trial management.

Study Timelines

First Patient randomised June 2010. The recruitment period is expected to be around 3 years and patients will have a minimum of 4 years follow up.

EXSCEL Study, Diabetes Trials Unit, OCDEM, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ
Tel: +44 (0)1865 857260     Fax: +44 (0)1865 857246     Email: exscel@dtu.ox.ac.uk

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