Effect of Additional Treatment With EXenatide in Patients With an Acute Myocardial Infarction (the EXAMI Trial)

Sponsor

Amsterdam UMC, location VUmc (Other)

Overall Status

Unknown status

CT.gov ID

NCT01254123

Collaborator

(none)

Enrollment

Location

Arms

Study Details

Study Description

Brief Summary

Myocardial infarction (MI) causes loss of myocytes and may lead to loss of ventricular function, morbidity and mortality. The most effective therapy is early reperfusion of the ischemic myocardium by percutaneous coronary intervention (PCI). Reperfusion limits myocardial ischaemic necrosis, but also induces inflammation, oxidative stress and calcium overload: a process referred to as reperfusion injury leading to necrosis and apotosis. Glucagon Like Peptide-1 (GLP-1) is an incretin hormone that has shown to activate anti-apoptotic enzymes, reducing reperfusion injury. GLP-1 agonists have been demonstrated to be cardioprotective in several animal studies and in a single small non-randomized clinical study. In this pilot study we will assess the safety and efficacy of GLP-1 receptor agonist Exenatide infusion compared to placebo in patients with an acute myocardial infarction undergoing primary PCI.

A total of 40 patients will be included in this single centre prospective randomised placebo controlled two-arm pilot study. Patients who are to undergo a primary PCI for a first acute ST elevation myocardial infarction are randomly assigned to placebo or Exenatide 5ug bolus in 30 minutes, followed by a continuous Exenatide infusion of 20ug/ 24 hours for 72 hours. Blood samples are obtained for assessment of enzymatic infarct size and Exenatide levels. Side effects of Exenatide are stringently monitored. Cardiac function will be measured using Cardiac Magnetic Resonance Imaging (CMRI) and 3D echocardiography at 1 week and 4 months post MI. Infarct size will be assessed by means of the final infarct size at 4 months post MI as a percentage of the area at risk at 1 week post MI. Furthermore we will compare the RNA profile of both groups.

Condition or Disease	Intervention/Treatment	Phase
Patients With a First Acute Myocardial Infarction to be Treated With Primary Percutaneous Coronary Intervention (PCI).	Drug: Exenatide infusion Drug: Placebo infusion.	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single

Primary Purpose:

Treatment

Official Title:

Effect of Additional Treatment With EXenatide in Patients With an Acute Myocardial Infarction (the EXAMI Trial)

Study Start Date :

Nov 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Exenatide	Drug: Exenatide infusion On arrival to our cardiac care unit (CCU) and after informed consent patients will be randomized to Exenatide infusion or Placebo infusion. Patients in the Exenatide group will immediately be treated be with Exenatide iv, 5ug bolus in 30 minutes, followed by a continuous Exenatide infusion of 20ug/ 24 hours. Exenatide preparation: Byetta injection pens containing 1,2 ml (concentration 0,25 mg/ml; 60 doses of 5 μg) will be obtained. 3 doses (15 μg) will be diluted in 49 ml saline and 1 ml Human Serum Albumen (Cealb 200g/L, 10ml) to get a total of 50 ml containing 15 μg exenatide (or 300 ng exenatide / ml). A 50cc syringe will be placed in a pump system that is connected with a cannula in the patient's vein. The infusionrate will be 33,3 ml/hr for the first 30 minutes, followed by an infusion rate of 2,8 ml/hr for 72 hours. New 50cc syringes will be made every 8 hours.
Placebo Comparator: Placebo	Drug: Placebo infusion. On arrival to our cardiac care unit (CCU) and after informed consent patients will be randomized to Exenatide infusion or Placebo infusion. Patients in the placebo group will immediately be treated with placebo infusion. Placebo preparation: 49ml saline and 1ml Human Serum Albumen (Cealb 200g/L, 10ml) to get a total of 50 ml will be placed in a 50cc syringe and placed in a pump system that is connected with a cannula in the patient's vein. The infusionrate will be 33,3 ml/hr for the first 30 minutes, followed by an infusion rate of 2,8 ml/hr for 72 hours. New 50cc syringes will be made every 8 hours.

Arm

Intervention/Treatment

Active Comparator: Exenatide

Drug: Exenatide infusion

On arrival to our cardiac care unit (CCU) and after informed consent patients will be randomized to Exenatide infusion or Placebo infusion. Patients in the Exenatide group will immediately be treated be with Exenatide iv, 5ug bolus in 30 minutes, followed by a continuous Exenatide infusion of 20ug/ 24 hours. Exenatide preparation: Byetta injection pens containing 1,2 ml (concentration 0,25 mg/ml; 60 doses of 5 μg) will be obtained. 3 doses (15 μg) will be diluted in 49 ml saline and 1 ml Human Serum Albumen (Cealb 200g/L, 10ml) to get a total of 50 ml containing 15 μg exenatide (or 300 ng exenatide / ml). A 50cc syringe will be placed in a pump system that is connected with a cannula in the patient's vein. The infusionrate will be 33,3 ml/hr for the first 30 minutes, followed by an infusion rate of 2,8 ml/hr for 72 hours. New 50cc syringes will be made every 8 hours.

Placebo Comparator: Placebo

Drug: Placebo infusion.

On arrival to our cardiac care unit (CCU) and after informed consent patients will be randomized to Exenatide infusion or Placebo infusion. Patients in the placebo group will immediately be treated with placebo infusion. Placebo preparation: 49ml saline and 1ml Human Serum Albumen (Cealb 200g/L, 10ml) to get a total of 50 ml will be placed in a 50cc syringe and placed in a pump system that is connected with a cannula in the patient's vein. The infusionrate will be 33,3 ml/hr for the first 30 minutes, followed by an infusion rate of 2,8 ml/hr for 72 hours. New 50cc syringes will be made every 8 hours.

Outcome Measures

Primary Outcome Measures

Safety of GLP-1 receptor agonist Exenatide infusion compared to placebo in patients with an acute myocardial infarction undergoing primary PCI []

Secondary Outcome Measures

Infarct size, assessed by means of the final infarct size at 4 months post myocardial infarction (CMRI) as a percentage of the area at risk at 1 week post myocardial infarction (T2 weighed CMRI). []
Regional myocardial function based on a MRI segmental analysis at 1 weeek and at 4 months post myocardial infarction. []
Global left ventricular ejection fraction (EF), Left Ventricular End Systolic Volume (LVESV), Left Ventricular End Diastolic Volume (LVEDV) at 1 week and at 4 months post myocardial infarction measured by Cardiac MRI. []
Regional myocardial function assessed by 2D and 3D echocardiography at 1 week and at 4 months post myocardial infarction. []
Global left ventricular EF, LVESV, LVEDV at 1 week and at 4 months post myocardial infarction measured by 2D and 3D echocardiography. []
Angiographic parameters as Trombolysis In Myocardial Infarction (TIMI) frame count and TIMI blush grade after PCI. []
The occurrence within 4 months of a Major Adverse Cardiac Event (MACE) defined as cardiac death, myocardial infarction, coronary bypass grafting, or a repeat PCI . []
Side effects of exenatide []
Serum-glucose levels during the first 72 hours. []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

18 and < 80 years of age
First myocardial infarction
ST elevation of more than one mm in at least 2 separate leads on the electrocardiogram (ECG)
Delay between onset of sustained chestpain and PCI < 6 hours.

Exclusion Criteria:

Cardiac rhythm is other than normal sinus rhythm.
Patient in Killip class 3 or 4 of heart failure
Cardiogenic shock defined as sustained systolic blood pressure ≤ 80mmHg despite fluid hydration.
Post cardiac resuscitation
Need for intra aortic balloon counterpulsation therapy
The patient is unable to hold his/her breath for up to 20 seconds due to age or concomitant illness
No former PCI performed
No recanalisation achieved of the occluded coronary artery
Culprit not in segment 1,2,3,6,7,11,12,13 of the coronary artery
No definite culprit
More than one occluded vessel, or a more than 70% stenosis by visual assessment in a non-culprit vessel.
TIMI 3 flow in culprit lesion at presentation
Decreased renal function eGFR < 30ml/min
Any contraindication for MRI ie: implanted electronic devices such as pacemakers, internal defibrillators, neurostimulators, implanted drug infusion devices, cochlear implants, cerebrovascular clips, claustrophobia. previous vascular surgery: aneurysm clip, carotid artery vascular clamp, aortic clips, venous umbrella spinal/intra-ventricular shunts
Metal fragments in eye, head, ear, skin or shoulder.
Swann-Ganz catheter.
Known pre-existing left ventricular dysfunction measured by any technique (ejection fraction < 45% prior to current admission for myocardial infarction)
Prior myocardial infarction
Prior coronary artery bypass grafting
Moderate to severe cardiac valve disease
Stroke or transient ischemic attack within the previous 24 hours
Serious known concomitant disease with a life expectancy of less than one year
Follow up impossible
Previous participation in a trial within the previous 30 days
Known type I Diabetes Mellitus
Known type II Diabetes Mellitus
Pregnancy and/or lactation