Acute Coronary Syndrome
Conditions
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.
Interventions
DRUGLixisenatide (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.
DRUGPlacebo
Pharmaceutical form: Sterile aqueous solution; Route of administration: Subcutaneous within 1-hour before breakfast.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurence of Primary CV Event: CV Death, Non-Fatal MI, Non-Fatal Stroke or Hospitalization for Unstable Angina | From randomization up to the end of study (median follow-up of 25 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurence of CV Event: CV Death, Non-Fatal MI, Non-Fatal Stroke, Hospitalization for Unstable Angina or Hospitalization For Heart Failure | 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 | 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 | 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. |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Denmark, Ecuador, Egypt, Estonia, Finland, France, Georgia, Germany, Guatemala, India, Israel, Italy, Japan, Latvia, Lithuania, Mexico, Netherlands, Norway, Panama, Peru, Philippines, Poland, Portugal, Romania, Russia, Serbia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Tunisia, Turkey (Türkiye), Ukraine, United Arab Emirates, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 829 centers in 49 countries. A total of 7719 participants were screened between June 24, 2010 and July 24, 2013. 1651 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment details
7627 participants underwent 1 week placebo run-in period. 1559 were run-in failures due to exclusion criteria met. 6068 participants were randomized 1:1 to lixisenatide and placebo arms in double-blind treatment period. Duration of study was event driven until approximately 844 positively adjudicated primary cardiovascular (CV) outcome events.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matched to lixisenatide QD SC up to end of treatment (median exposure: 23 months). | 3,034 |
| Lixisenatide Lixisenatide 10 mcg QD SC for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to end of treatment (median exposure: 22 months). | 3,034 |
| Total | 6,068 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 14 | 11 |
| Overall Study | Other than specified | 0 | 1 |
| Overall Study | Site termination by sponsor | 13 | 5 |
| Overall Study | Withdrawal by Subject | 83 | 88 |
Baseline characteristics
| Characteristic | Placebo | Lixisenatide | Total |
|---|---|---|---|
| Age, Continuous | 60.6 years STANDARD_DEVIATION 9.6 | 59.9 years STANDARD_DEVIATION 9.7 | 60.3 years STANDARD_DEVIATION 9.7 |
| Body Mass Index (BMI) | 30.2 kg/m^2 STANDARD_DEVIATION 5.79 | 30.12 kg/m^2 STANDARD_DEVIATION 5.6 | 30.16 kg/m^2 STANDARD_DEVIATION 5.69 |
| Body Weight | 85.06 kg STANDARD_DEVIATION 19.64 | 84.64 kg STANDARD_DEVIATION 19.21 | 84.85 kg STANDARD_DEVIATION 19.43 |
| Duration of Diabetes | 9.38 years STANDARD_DEVIATION 8.32 | 9.2 years STANDARD_DEVIATION 8.19 | 9.29 years STANDARD_DEVIATION 8.25 |
| Ethnicity Hispanic | 903 participants | 865 participants | 1768 participants |
| Ethnicity Not Hispanic | 2131 participants | 2169 participants | 4300 participants |
| Gender Female | 938 Participants | 923 Participants | 1861 Participants |
| Gender Male | 2096 Participants | 2111 Participants | 4207 Participants |
| Glycosylated Hemoglobin (HbA1c) | 7.64 Percentage of HbA1c STANDARD_DEVIATION 1.28 | 7.72 Percentage of HbA1c STANDARD_DEVIATION 1.32 | 7.68 Percentage of HbA1c STANDARD_DEVIATION 1.3 |
| Qualifying Acute Coronary Syndrome (ACS) event Non ST-segment elevation MI | 1183 participants | 1165 participants | 2348 participants |
| Qualifying Acute Coronary Syndrome (ACS) event Not qualifying ACS event | 2 participants | 1 participants | 3 participants |
| Qualifying Acute Coronary Syndrome (ACS) event ST-segment elevation myocardial infarction (MI) | 1317 participants | 1349 participants | 2666 participants |
| Qualifying Acute Coronary Syndrome (ACS) event Unclassified | 4 participants | 5 participants | 9 participants |
| Qualifying Acute Coronary Syndrome (ACS) event Unstable angina | 528 participants | 514 participants | 1042 participants |
| Race Asian/Oriental | 367 participants | 404 participants | 771 participants |
| Race Black | 103 participants | 118 participants | 221 participants |
| Race Caucasian/White | 2318 participants | 2258 participants | 4576 participants |
| Race Other | 246 participants | 254 participants | 500 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,270 / 3,032 | 1,597 / 3,031 |
| serious Total, serious adverse events | 669 / 3,032 | 625 / 3,031 |
Outcome results
Primary
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.
Time frame: From randomization up to the end of study (median follow-up of 25 months)
Population: Intent-to-treat (ITT) population defined as all randomized participants analyzed according to the treatment group allocated at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurence of Primary CV Event: CV Death, Non-Fatal MI, Non-Fatal Stroke or Hospitalization for Unstable Angina | 399 participants |
| Lixisenatide | Time to First Occurence of Primary CV Event: CV Death, Non-Fatal MI, Non-Fatal Stroke or Hospitalization for Unstable Angina | 406 participants |
Comparison: Analysis was performed using Cox proportional hazards model with treatment groups, and region (North America, South and Central America, Western Europe, Eastern Europe, Africa/Near East, and Asia/Pacific) as covariates, and the associated two-sided 95% confidence interval (CI).95% CI: [0.886, 1.168]
Comparison: Analysis was performed using Cox proportional hazards model with treatment groups, and region (North America, South and Central America, Western Europe, Eastern Europe, Africa/Near East, and Asia/Pacific) as covariates, and the associated two-sided 95% CI. Superiority of lixisenatide versus placebo was to be claimed if the upper bound of the 2-sided 95% CI of the hazard ratio was \<1.0.p-value: 0.854295% CI: [0.886, 1.168]Log Rank
Secondary
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.
Time frame: Baseline to Week 108 (LOCF)
Population: ITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline UACR value. Missing data was imputed using last observation carried forward (LOCF) using the last available post-baseline UACR before Week 108 as the value at Week 108, regardless of treatment discontinuation or not.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in the Urinary Albumin/Creatinine Ratio (UACR) at Week 108 | 34.21 percent change | Standard Error 3.09 |
| Lixisenatide | Percent Change From Baseline in the Urinary Albumin/Creatinine Ratio (UACR) at Week 108 | 24.17 percent change | Standard Error 2.84 |
Secondary
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.
Time frame: From randomization up to the end of study (median follow-up of 25 months)
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | 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 | 659 participants |
| Lixisenatide | 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 | 661 participants |
Secondary
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.
Time frame: From randomization up to the end of study (median follow-up of 25 months)
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurence of CV Event: CV Death, Non-Fatal MI, Non-Fatal Stroke, Hospitalization for Unstable Angina or Hospitalization For Heart Failure | 469 participants |
| Lixisenatide | Time to First Occurence of CV Event: CV Death, Non-Fatal MI, Non-Fatal Stroke, Hospitalization for Unstable Angina or Hospitalization For Heart Failure | 456 participants |