title: Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial.
abstract: 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.
authors.affiliation: Diabetes Trials Unit, University of Oxford, Oxford, United Kingdom. Electronic address: rury.holman@dtu.ox.ac.uk.
authors.forename: Rury R
authors.initials: RR
authors.lastname: Holman
authors.affiliation: Diabetes Trials Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Mary Angelyn
authors.initials: MA
authors.lastname: Bethel
authors.affiliation: Diabetes Trials Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Jyothis
authors.initials: J
authors.lastname: George
authors.affiliation: Diabetes Trials Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Harald
authors.initials: H
authors.lastname: Sourij
authors.affiliation: Diabetes Trials Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Doran
authors.affiliation: Diabetes Trials Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Keenan
authors.affiliation: AstraZeneca Research and Development, Gaithersburg, MD.
authors.forename: Nardev S
authors.initials: NS
authors.lastname: Khurmi
authors.affiliation: Duke Clinical Research Institute, Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mentz
authors.affiliation: Diabetes Trials Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Oulhaj
authors.affiliation: University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC.
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Juliana C
authors.initials: JC
authors.lastname: Chan
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ.
authors.forename: Nayyar
authors.initials: N
authors.lastname: Iqbal
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Kundu
authors.affiliation: ANMCO Research Centre, Florence, Italy.
authors.forename: Aldo P
authors.initials: AP
authors.lastname: Maggioni
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Marso
authors.affiliation: AstraZeneca Research and Development, Gaithersburg, MD.
authors.forename: Peter
authors.initials: P
authors.lastname: Öhman
authors.affiliation: Duke Clinical Research Institute, Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pencina
authors.affiliation: International Centre for Circulatory Health, NHLI, Imperial College London, London, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Poulter
authors.affiliation: Dance Biopharm, Inc, Brisbane, CA.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Porter
authors.affiliation: India Diabetes Research Foundation and Dr. A. Ramachandran's Diabetes Hospitals, Chennai, India.
authors.forename: Ambady
authors.initials: A
authors.lastname: Ramachandran
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
authors.affiliation: Duke Clinical Research Institute, Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Hernandez
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D002681:China / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D000077270:Exenatide; D005260:Female; D005500:Follow-Up Studies; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D015994:Incidence; D007279:Injections, Subcutaneous; D007558:Italy / Q000453:epidemiology; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D009864:Ontario / Q000453:epidemiology; D010455:Peptides / Q000008:administration & dosage*; D011379:Prognosis; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D006113:United Kingdom / Q000453:epidemiology; D014481:United States / Q000453:epidemiology; D014688:Venoms / Q000008:administration & dosage*
chemical_list: D001786:Blood Glucose; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; C517652:hemoglobin A1c protein, human