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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate Cardiovascular Outcomes During Treatment With Lixisenatide in Type 2 Diabetic Patients After an Acute Coronary Syndrome

Conditions
-----------------
Acute Coronary Syndrome

Intervention / Treatment
-----------------
* Drug: Lixisenatide (AVE0010)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 30 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo matched to lixisenatide once daily (QD) up to end of treatment. | Drug: Placebo<br>* Pharmaceutical form: Sterile aqueous solution; Route of administration: Subcutaneous within 1-hour before breakfast.<br>|
| Experimental: Lixisenatide<br>Lixisenatide 10 mcg QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to end of treatment. | Drug: Lixisenatide (AVE0010)<br>* 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.<br>* Other names: Lyxumia;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Occurence of Primary CV Event: CV Death, Non-Fatal MI, Non-Fatal Stroke or Hospitalization for Unstable Angina | Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the onset of primary CV endpoint over time. Number of observed participants with endpoint events were reported. A CV event adjudication committee (CAC) reviewed and adjudicated, in a blinded fashion, all potential events. | From randomization up to the end of study (median follow-up of 25 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Occurence of CV Event: CV Death, Non-Fatal MI, Non-Fatal Stroke, Hospitalization for Unstable Angina or Hospitalization For Heart Failure | 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. | From randomization up to the end of study (median follow-up of 25 months) | 
| 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 | 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. | From randomization up to the end of study (median follow-up of 25 months) | 
| Percent Change From Baseline in the Urinary Albumin/Creatinine Ratio (UACR) at Week 108 | 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. | Baseline to Week 108 (LOCF) |