Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide) (ELIXA)

• Time to the first occurrence of cardiovascular (CV) death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure positively adjudicated by the CAC [ Time Frame: week 0 to week 203 ] [ Designated as safety issue: No ]
• Time to the first occurrence of cardiovascular (CV) death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure, coronary revascularization procedure positively adjudicated by the CAC [ Time Frame: week 0 to week 203 ] [ Designated as safety issue: No ]
• Percent change in the urinary albumin/creatinine ratio [ Time Frame: From baseline to 108 weeks ] [ Designated as safety issue: No ]

• Time to the first occurrence of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure adjudicated and validated by the CAC [ Time Frame: week 0 to week 176 ] [ Designated as safety issue: No ]
• Time to the first occurrence of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure, hospitalization for coronary revascularization procedure adjudicated and validated by the CAC [ Time Frame: week 0 to week 176 ] [ Designated as safety issue: No ]
• Percent change in the urinary albumin/creatinine ratio [ Time Frame: from baseline to 108 weeks ] [ Designated as safety issue: No ]
• Glycosylated haemoglobin HbA1c [ Time Frame: week 0 to week 176 ] [ Designated as safety issue: No ]
• Fasting plasma glucose (FPG) [ Time Frame: week 0 to week 176 ] [ Designated as safety issue: No ]
• body weight change [ Time Frame: week 0 to week 176 ] [ Designated as safety issue: No ]
• Cardiovascular risk markers: high-sensitivity C-reactive protein (hs-CRP), brain natriuretic peptide (BNP), N-terminal prohormone brain natriuretic peptide (NT-proBNPs) [ Time Frame: week 0 to week 176 ] [ Designated as safety issue: No ]

Primary Objective:

- To demonstrate that lixisenatide can reduce cardiovascular morbidity and mortality [composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina] compared to placebo in type 2 diabetic patients who recently experienced an acute coronary syndrome (ACS) event.

Secondary Objectives:

To demonstrate that when compared to placebo, lixisenatide can reduce:

• composite endpoint of cardiovascular death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or hospitalization for heart failure
• composite endpoint of cardiovascular death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization procedure
• urinary albumin excretion (based on the urinary albumin/creatinine ratio).

To assess the safety and tolerability of lixisenatide.

The estimated maximum study duration for the first randomized patient will be approximately 204 weeks (± 14 days), with a median follow-up over all patients of approximately 91 weeks, broken down as follows:

• placebo-run-in period: 7 days (+ 3 days)
• double-blind study treatment period: 203 weeks (± 14 days) (with about a 37 months of recruitment period)
• post-treatment follow-up period: 3 days (± 1 day)

All patients will be followed from randomization until the end of study, which should occur when the last randomized patient has been followed for approximately 10 months. The actual end date of the study will be "event driven"and the study will end when there are approximately 844 positively-adjudicated primary cardiovascular outcome events.

• Drug: lixisenatide (AVE0010)

  Pharmaceutical form:sterile aqueous solution

  Route of administration: subcutaneous

  Other Name: Lyxumia
• Drug: placebo

  Pharmaceutical form:sterile aqueous solution

  Route of administration: subcutaneous

• Experimental: Lixisenatide
  Titration period (week 0 to 2): 10 µg lixisenatide (0.10 mL injection) once a day in the morning within 1 hour prior to breakfast Maintenance period (week 2 to 176): 20 µg lixisenatide (0.20 mL injection) once a day in the morning within 1 hour prior to breakfast
  Intervention: Drug: lixisenatide (AVE0010)
• Placebo Comparator: placebo
  Run-in period (week -1 to 0): 10 µg volume-matched placebo ( 0.10 mL injection) once a day in the morning within 1 hour prior to breakfast Titration period (week 0 to 2): 10 µg volume-matched placebo (0.10 mL injection) once a day in the morning within 1 hour prior to breakfast Maintenance period (week 2 to 176): 20 µg volume-matched placebo (0.20 mL injection) once a day in the morning within 1 hour prior to breakfast
  Intervention: Drug: placebo

• Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, Lawson FC, Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL, Riddle MC, Solomon SD, Tardif JC; ELIXA Investigators. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015 Dec 3;373(23):2247-57. doi: 10.1056/NEJMoa1509225.
• Bentley-Lewis R, Aguilar D, Riddle MC, Claggett B, Diaz R, Dickstein K, Gerstein HC, Johnston P, Køber LV, Lawson F, Lewis EF, Maggioni AP, McMurray JJ, Ping L, Probstfield JL, Solomon SD, Tardif JC, Wu Y, Pfeffer MA; ELIXA Investigators. Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J. 2015 May;169(5):631-638.e7. doi: 10.1016/j.ahj.2015.02.002. Epub 2015 Feb 12.
• Wohlfart P, Linz W, Hübschle T, Linz D, Huber J, Hess S, Crowther D, Werner U, Ruetten H. Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies. J Transl Med. 2013 Mar 28;11:84. doi: 10.1186/1479-5876-11-84.

Inclusion criteria:

• Men and women who experienced a spontaneous acute coronary syndrome (ACS) event [i.e., ST-segment elevation myocardial infarction (STEMI)] or non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina (USA)] with a documented elevation above the normal reference range of a cardiac biomarker (Troponin or Creatinine Kinase (CK)-MB) and the clinical presentation consistent with an acute coronary syndrome which leads to admission to an acute care facility, within 180 days following the ACS event and prior to screening.
• Patients with a history of type 2 diabetes (for patients newly diagnosed, diagnosis will be based on the World Health Organization (WHO) criteria: i.e., either a fasting venous plasma glucose concentration ≥ 7.0 mmol/L [126 mg/dL] or 2-hour post glucose load venous plasma glucose ≥ 11.1 mmol/L [200 mg/dL], confirmed on 2 occasions) prior to the screening visit.

Exclusion criteria:

• Type 1 diabetes mellitus or history of ketoacidosis within 6 months prior to screening.
• HbA1c <5.5 % or >11% measured at screening visit.
• Required to use incretin-based agents (eg, Glucagon-like peptide -1(GLP-1) agonists or Dipeptidyl Peptidase-4 (DPP-4) inhibitors) other than the study drug during the doubleblind treatment period.
• Patients who have undergone CABG surgery following the qualifying ACS event.
• Patients who have undergone PCI within 15 days prior to screening.
• Patients with planned revascularization procedure (PCI or CABG) or coronary angiogram within 90 days after screening visit.
• History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease, personal or family history of medullary thyroid cancer (MTC), or genetic conditions that predisposes to MTC (eg, multiple endocrine neoplasia syndromes).
• Any clinically significant abnormality identified at the time of screening that in the judgment of the Investigator or any sub-Investigator would preclude safe completion of the study or constrain endpoints assessment such as major systemic diseases.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.