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

• Time to First Occurence of CV Event: CV Death, Non-Fatal MI, Non-Fatal Stroke, Hospitalization for Unstable Angina or Hospitalization For Heart Failure [ Time Frame: From randomization up to the end of study (median follow-up of 25 months) ]
  All CV events were positively adjudicated by the CAC, used in the analysis of the composite CV endpoint comprised of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina or hospitalization for heart failure. Number of observed participants with endpoint events were reported.
• Time to First Occurence of CV Event: CV Death, Non-Fatal MI, Non-Fatal Stroke, Hospitalization for Unstable Angina, Hospitalization For Heart Failure or Coronary Revascularization Procedure [ Time Frame: From randomization up to the end of study (median follow-up of 25 months) ]
  All CV events were positively adjudicated by CAC, used in the analysis of the composite CV endpoint comprised of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization procedure. Number of observed participants with endpoint events were reported.
• Percent Change From Baseline in the Urinary Albumin/Creatinine Ratio (UACR) at Week 108 [ Time Frame: Baseline to Week 108 (LOCF) ]
  Presence of albumin in urine is a marker of nephropathy, an important microvascular complication of diabetes. UACR was defined as the ratio: mg of albumin per gram of creatinine. UACR data were log transformed before the analysis. Calculation was based on geometric mean.

• 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 ]
• 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 ]
• Percent change in the urinary albumin/creatinine ratio [ Time Frame: from baseline to 108 weeks ]
• Glycosylated haemoglobin HbA1c [ Time Frame: week 0 to week 176 ]
• Fasting plasma glucose (FPG) [ Time Frame: week 0 to week 176 ]
• body weight change [ Time Frame: week 0 to week 176 ]
• 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 ]

Primary Objective:

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

Secondary Objectives:

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

• composite endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or hospitalization for heart failure.
• composite endpoint of CV 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 participant was approximately 204 weeks (± 14 days), with a median follow-up over all participants 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 participants were followed from randomization until the end of study, which should occur when the last randomized participant had been followed for approximately 10 months. The actual end date of the study was "event driven" and the study end when there were approximately 844 positively-adjudicated primary cardiovascular outcome events.

• Drug: Lixisenatide (AVE0010)
  Pharmaceutical form: Sterile aqueous solution; Route of administration: Subcutaneous within 1-hour before breakfast using self-injector pen device (Opticlik®). If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 15 or 10 mcg.
  Other Name: Lyxumia
• Drug: Placebo
  Pharmaceutical form: Sterile aqueous solution; Route of administration: Subcutaneous within 1-hour before breakfast.

• Placebo Comparator: Placebo
  Placebo matched to lixisenatide once daily (QD) up to end of treatment.
  Intervention: Drug: Placebo
• Experimental: Lixisenatide
  Lixisenatide 10 mcg QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to end of treatment.
  Intervention: Drug: Lixisenatide (AVE0010)

• 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.
• 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.
• 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 ACS event (i.e., ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation MI (NSTEMI) or unstable angina) 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 ACS which lead to admission to an acute care facility, within 180 days following the ACS event and prior to screening.
• Participants with a history of type 2 diabetes (for participants newly diagnosed, diagnosis was 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.
• Glycosylated hemoglobin (HbA1c) <5.5 % or >11% measured at screening visit.
• Required to use incretin-based agents (e.g., Glucagon-like peptide -1 (GLP-1) agonists or Dipeptidyl Peptidase-4 (DPP-4) inhibitors) other than the study drug during the double-blind treatment period.
• Participants who had undergone coronary artery bypass graft (CABG) surgery following the qualifying ACS event.
• Participants who had undergone percutaneous coronary intervention (PCI) within 15 days prior to screening.
• Participants 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 (e.g., 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 participant's potential participation in a clinical trial.