AMI
Conditions
Brief summary
Primary objective: To demonstrate that in hyperglycemic subjects with anterior STEMI (ST Elevation Myocardial Infarction) undergoing Percutaneous Coronary Intervention (PCI), tight glycemic control using insulin glulisine and insulin glargine, i.e. Intensive Insulin Therapy (IIT), results in reducing infarct size at day 60 versus (vs) Standard Glycemic Care (SGC). Secondary objectives: To demonstrate that tight glycemic control using insulin glulisine and insulin glargine reduces markers of inflammation and improves Left Ventricular (LV) function and Cardio-Vascular (CV) outcomes from baseline values, in hyperglycemic subjects with STEMI undergoing Percutaneous Coronary Intervention (PCI).
Interventions
Subcutaneous insulin glargine was initiated 90 prior to the insulin glulisine infusion discontinuation (i.e. 48 hours after randomization) and titrated as per physician preference to maintain the plasma glucose between 90-130 mg/dL
DRUGInsulin Glulisine (Apidra)
Prior PCI, subjects received a single IV bolus of insulin glulisine. The dose was 0.025 U/kg based upon patient reported weight. Then IV insulin glulisine infusion was started within one hour of the IV insulin glulisine bolus and administered at a minimum rate of 2 U/h for 48 hours. The infusion was titrated in order to achieve and maintain the plasma glucose between 90 and 130 mg/dL.
DRUGStandard Therapy
Standard insulin therapy titrated to blood sugar control
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
35 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Men or women = or \> 35 years of age presenting to the hospital with hyperglycemia (plasma glucose \>140 mg/dL) and Primary Anterior wall ST-Elevation Myocardial Infarction (AW STEMI) * No history of illicit drug abuse in past year * A minimum of 30 minutes but \< or = 6 hours of continuous pain/symptoms immediately prior to presentation * Subjects who will undergo primary percutaneous coronary intervention (PCI) * At least 2 contiguous precordial leads demonstrating at least 2 mm of ST-segment elevation consistent with anterior wall MI * Signed informed consent and HIPAA documentation (US only) prior to participation in the study * Subjects ability and willingness to adhere to and be compliant with study protocol
Exclusion criteria
* A prior history of Myocardial Infarction (MI) * Subjects who have received any thrombolytic therapy during the current hospital admission * Severe Heart Failure or cardiogenic shock (Killip class 3 or 4) by history or present at the time of screening * Subjects with a plasma glucose \>400 mg/dL or diabetic ketoacidosis (DKA) * History of Type 1 diabetes * Active bleeding * Active malignancy, chronic or other medical conditions likely to result in death over the next one year * Recent hypotension requiring inotropic support in the past 30 days * Participation in another clinical research study in the past 30 days * Pregnant or lactating women (women of childbearing potential must have a negative pregnancy test at study entry and a medically approved contraception method) * Unwilling to give informed consent * Subjects directly involved in the conduct of the study * Known hypersensitivity to insulin glargine or glulisine * Contraindication to MRI: a)Intracranial aneurysm clips (Unless the investigator is certain that it is made of non-ferromagnetic material such as titanium)b)Intra-orbital metal fragments c)Any electrically, magnetically or mechanically activated implants (including cardiac pacemakers, biostimulators, neurostimulators, cochlear implants, and hearing aids) d)Warning about Gadolinium-based contrast agents (GBCAs) Exposure to GBCAs increases the risk for nephrogenic systemic fibrosis (NSF). Therefore the following subjects should be excluded from the trial based on a history and/or laboratory tests: * acute or chronic severe renal insufficiency (glomerular filtration rate \<30 mL/min/1.73m2), as calculated by the MDRD (Modification of diet in Renal Disease) equation, or * acute renal insufficiency of any severity * Subjects with blood pressure \> or = to 200/110 mmHg at time of randomization * Subjects with a high degree of non-transient AV (Atrio-Ventricular) block The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Infarct Size Absolute Change From Baseline at Day 60 | From baseline at Day 60 | Infarct size is measured by cardiac Magnetic Resonance Imaging (MRI) as the percentage of Left Ventricular (LV) mass. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Left Ventricular (LV) Function Evaluated by Cardiac Magnetic Resonance Imaging (MRI) | At Day 3 | Due to study early termination and the limited number of randomized subjects, descriptive statistics for the Day 3 Ejection Fraction were selected for presentation instead of for Day 60 as initially planned. |
| Occurrence of the Major Adverse Cardiovascular Events (MACE) | At Day 60 | MACE: Cardiac death, New onset or worsening congestive heart failure (\>24 h post-admission) event evaluating using New York Heart Association (NYHA) Class II or greater Non-fatal Myocardial Infarction, Severe arrhythmia, Stroke/TIA (Transient Ischemic Attack), Cardiogenic shock, Catheterization/revascularization, Unstable angina leading to hospitalisation |
| Biomarkers of Inflammation Measurement: CRP (C-Reactive Protein) | At Day 60 | — |
Countries
Argentina, Brazil, Canada, Mexico, United States
Participant flow
Recruitment details
Multicenter study: 60 out of the 90 centers planned were initiated. Only 17 centers randomized patients (i.e. 7 sites in the United States, 5 sites in Argentina, 3 sites in Brazil and 2 sites in Mexico).
Pre-assignment details
Although 34 patients signed the informed consent form for study inclusion, one patient did not sign the Health Insurance Portability and Accountability Act (HIPAA) form, electing to keep his/her medical information private, and was therefore not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Intensive Insulin Therapy (IIT) In IIT arm, subjects received intravenous (IV) insulin glulisine and subcutaneous (sc) insulin glargine to maintain a Blood Glucose (BG) concentration between 90-130 mg/dL | 18 |
| Standard Glycemic Care (SGC) In SGC arm Subjects assigned to standard of care received subcutaneous regular insulin per sliding scale. | 15 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death or MACE | 0 | 1 |
| Overall Study | Not meeting the selection criteria | 2 | 0 |
| Overall Study | Not treated | 2 | 2 |
Baseline characteristics
| Characteristic | Standard Glycemic Care (SGC) | Total | Intensive Insulin Therapy (IIT) |
|---|---|---|---|
| Age Continuous | 62.80 years STANDARD_DEVIATION 11.12 | 61.88 years STANDARD_DEVIATION 10.89 | 61.11 years STANDARD_DEVIATION 10.95 |
| Body Mass Index (BMI) | 28.49 Kg/m^2 STANDARD_DEVIATION 3.92 | 27.65 Kg/m^2 STANDARD_DEVIATION 3.64 | 26.95 Kg/m^2 STANDARD_DEVIATION 3.34 |
| Diabetes diagnosis at study entry No | 8 participants | 20 participants | 12 participants |
| Diabetes diagnosis at study entry Yes | 7 participants | 13 participants | 6 participants |
| Duration of Diabetes at study entry | 7.50 Years STANDARD_DEVIATION 6.8 | 8.50 Years STANDARD_DEVIATION 7.79 | 9.50 Years STANDARD_DEVIATION 9.2 |
| Mean time to Percutaneous Coronary Intervention (PCI) | 101.54 minutes STANDARD_DEVIATION 51.47 | 106.07 minutes STANDARD_DEVIATION 88.21 | 110.00 minutes STANDARD_DEVIATION 112.69 |
| Myocardial Infarction (MI) duration greater than 3 hours No | 9 participants | 22 participants | 13 participants |
| Myocardial Infarction (MI) duration greater than 3 hours Yes | 6 participants | 11 participants | 5 participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 6 Participants |
| Sex: Female, Male Male | 13 Participants | 25 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 16 | 6 / 13 |
| serious Total, serious adverse events | 6 / 16 | 3 / 13 |
Outcome results
Primary
Infarct Size Absolute Change From Baseline at Day 60
Infarct size is measured by cardiac Magnetic Resonance Imaging (MRI) as the percentage of Left Ventricular (LV) mass.
Time frame: From baseline at Day 60
Population: Analysis was performed on the Modified Intention To Treat (MITT) population which includes all randomized subjects who took at least one dose of the study medication, undergone PCI procedure at hospital admission, and had a valid post-PCI infarct size.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intensive Insulin Therapy (IIT) | Infarct Size Absolute Change From Baseline at Day 60 | -7.84 percentage of LV mass change | Standard Deviation 9.19 |
| Standard Glycemic Care (SGC) | Infarct Size Absolute Change From Baseline at Day 60 | -15.72 percentage of LV mass change | Standard Deviation 22.41 |
Secondary
Biomarkers of Inflammation Measurement: CRP (C-Reactive Protein)
Time frame: At Day 60
Population: Analysis was performed on the Modified Intention To Treat (MITT) population which includes all randomized subjects who took at least one dose of the study medication, undergone PCI procedure at hospital admission, and had a valid post-PCI infarct size.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intensive Insulin Therapy (IIT) | Biomarkers of Inflammation Measurement: CRP (C-Reactive Protein) | 2.52 mg/L | Standard Deviation 2.1 |
| Standard Glycemic Care (SGC) | Biomarkers of Inflammation Measurement: CRP (C-Reactive Protein) | 2.96 mg/L | Standard Deviation 4.07 |
Secondary
Left Ventricular (LV) Function Evaluated by Cardiac Magnetic Resonance Imaging (MRI)
Due to study early termination and the limited number of randomized subjects, descriptive statistics for the Day 3 Ejection Fraction were selected for presentation instead of for Day 60 as initially planned.
Time frame: At Day 3
Population: Analysis was performed on the Modified Intention To Treat (MITT) population which includes all randomized subjects who took at least one dose of the study medication, undergone PCI procedure at hospital admission, and had a valid post-PCI infarct size.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intensive Insulin Therapy (IIT) | Left Ventricular (LV) Function Evaluated by Cardiac Magnetic Resonance Imaging (MRI) | 43.08 percentage of Ejection Fraction | Standard Deviation 11.34 |
| Standard Glycemic Care (SGC) | Left Ventricular (LV) Function Evaluated by Cardiac Magnetic Resonance Imaging (MRI) | 43.43 percentage of Ejection Fraction | Standard Deviation 6.87 |
Secondary
Occurrence of the Major Adverse Cardiovascular Events (MACE)
MACE: Cardiac death, New onset or worsening congestive heart failure (\>24 h post-admission) event evaluating using New York Heart Association (NYHA) Class II or greater Non-fatal Myocardial Infarction, Severe arrhythmia, Stroke/TIA (Transient Ischemic Attack), Cardiogenic shock, Catheterization/revascularization, Unstable angina leading to hospitalisation
Time frame: At Day 60
Population: Analysis was performed on the safety population which includes all subjects who received any study treatment. All subjects in this population were analyzed according to the actual treatment they received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intensive Insulin Therapy (IIT) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | Severe arrhythmia | 7 events |
| Intensive Insulin Therapy (IIT) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | Shock | 0 events |
| Intensive Insulin Therapy (IIT) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | Revascularization | 1 events |
| Intensive Insulin Therapy (IIT) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | New onset or worsening of congestive heart failure | 1 events |
| Intensive Insulin Therapy (IIT) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | Myocardial Infarction (MI) | 1 events |
| Intensive Insulin Therapy (IIT) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | Death | 1 events |
| Standard Glycemic Care (SGC) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | Myocardial Infarction (MI) | 0 events |
| Standard Glycemic Care (SGC) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | Severe arrhythmia | 2 events |
| Standard Glycemic Care (SGC) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | New onset or worsening of congestive heart failure | 0 events |
| Standard Glycemic Care (SGC) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | Shock | 1 events |
| Standard Glycemic Care (SGC) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | Death | 1 events |
| Standard Glycemic Care (SGC) | Occurrence of the Major Adverse Cardiovascular Events (MACE) | Revascularization | 0 events |