COMBinAtion Therapy in Myocardial Infarction: The COMBAT-MI Trial

Study Overview
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Brief Summary
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Remote ischemic conditioning (RIC) and intravenous exenatide administered immediately before primary angioplasty have been found to limit infarct size in patients with STEMI (ST segment elevation myocardial infarction), but the reduction is limited. This study investigates whether a combination therapy including both therapies is more effective.

Detailed Description
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COMBAT-MI is an investigator-driven, randomized, double-blind and placebo-controlled clinical trial aimed at evaluating the effect of Remote Ischemic Conditioning and exenatide, alone and in combination, on Myocardial Infarct size in 428 STEMI patients (107 per group) (ST segment elevation myocardial infarction). Patients with TIMI (Thrombolysis in Myocardial Infarction) flow grade > 1 will be excluded. The study has a 2 x 2 factorial design (Remote Ischemic Conditioning , Exenatide, both or neither). The primary end-point will be Myocardial Infarct size measured by Cardiac Magnetic Resonance Imaging (CMRI) performed 3 - 7 days after primary Percutaneous Coronary Intervention (pPCI) (expressed as % of left ventricular (LV) mass). Sample size has been calculated in 274 patients with TIMI 0-1 available for analysis of the primary end-point, and inclusion will end when this number is reached, which will require, according to the current rate of TIMI 0-1 in our STEMI population, to randomize 428 patients. Secondary end-points will include myocardial salvage index, based on angiographic and CMRI derived estimations of the area at risk, and frequency of Major Adverse Cardiovascular Events (MACE) and of major adverse events during admission.

Official Title
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COMBinAtion Therapy in Myocardial Infarction: The COMBAT-MI Trial

Conditions
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ST Elevation Acute Myocardial Infarction

Intervention / Treatment
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* Drug: Exenatide
* Other: Remote Ischemic Conditioning (RIC)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women ≥18 years of age STEMI characterized by 2 mm ST segment elevation in 2 or more V1 through V4 leads or presumed new left bundle branch block with minimum of 1 mm concordant ST elevation or 1 mV(millivolt) ST segment elevation in the limb leads (II, III and aVF leads, I, aVL leads) and V4-V6. Patients presenting within 6 hours of chest pain. Exclusion Criteria: Known hypersensitivity to exenatide or any of the excipients Known contraindication to CMR imaging such as significant claustrophobia, severe allergy to gadolinium chelate contrast, severe renal insufficiency (defined as estimated glomerular filtration rate [eGFR] (epidermal growth factor receptor) <30 mL/min/1.73 m2), presence of CMRI contraindicated implanted devices (e.g., pacemaker, implanted cardiac defibrillator, cardiac resynchronization therapy device, cochlear implant), embedded metal objects (e.g., shrapnel), or any other contraindication for CMRI. Assumed life expectancy < 1 year e.g. due to non-cardiac disease. TIMI flow grade > 1 at the time of diagnostic coronary angiography. These patients will be excluded from the analysis of infarct size but will be included in the safety analysis. Pregnant women Patients with loss of consciousness or confused, not able to read the information and to sign the writting consent Patients with oro-tracheal intubation Patients with cardiogenic shock persisting 48h after reperfusion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Remote Ischemic Conditioning<br>Remote Ischemic Conditioning + placebo | Other: Remote Ischemic Conditioning (RIC)<br>* Remote ischemic conditioning with a cuff in the arm<br>Drug: Placebo<br>* Intrevenous administration of Placebo<br>|
| Active Comparator: Combined treatment<br>Remote Ischemic Conditioning + exenatide | Drug: Exenatide<br>* Intravenous administration of Exenatide<br>Other: Remote Ischemic Conditioning (RIC)<br>* Remote ischemic conditioning with a cuff in the arm<br>|
| Placebo Comparator: Placebo<br>Sham Remote Ischemic Conditioning + placebo | Other: Remote Ischemic Conditioning (RIC)<br>* Remote ischemic conditioning with a cuff in the arm<br>Drug: Placebo<br>* Intrevenous administration of Placebo<br>|
| Active Comparator: Exenatide<br>Sham Remote Ischemic Conditioning + exenatide | Drug: Exenatide<br>* Intravenous administration of Exenatide<br>Other: Remote Ischemic Conditioning (RIC)<br>* Remote ischemic conditioning with a cuff in the arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial Infarct Size | MI, measured by late gadolinium enhancement in CMRI 3-7 days after pPCI, and expressed as percent of left ventricular mass. | 3-7 days after pPCI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial salvage index | Myocardial salvage index defined as the difference between infarct size and area at risk, defined by the T2 CMRI and expressed as a percent of total LV (Left Ventricular) mass, divided by the area at risk. | 3-7 days after pPCI | 
| Transmurality index | Transmurality index, defined as the ratio of the mass of myocardium showing late gadolinium enhancement to the mass of the myocardial segment containing it. | 3-7 days after pPCI | 
| Ventricular volumes | LV (Left Ventricular) end-diastolic volume and LVEF (Left Ventricular Ejection Fraction), as determined by CMRI. | 3-7 days after pPCI | 
| Microvascular obstruction | Volume of myocardium with microvascular obstruction determined by late gadolinium enhancement expressed as percent of infarct size. | 3-7 days after pPCI | 
| Markers of successful reperfusion | Markers of successful myocardial reperfusion: ST segment resolution 90 minutes post-pPCI , TIMI flow and frame-count post-pPCI , and TIMI blush grade . | First 90 min after reperfusion | 
| Major adverse cardiac events (MACE) | MACE rate during hospitalization, defined as death, non-fatal myocardial rupture, or appearance or worsening of heart failure during the hospitalization period and after 1 year of follow-up | Hospital discharge and expected average of 1 week, one year follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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STEMI, Reperfusion Injury, Myocardial Infarction, Myocardial Ischemia, Remote Ischemic Conditioning, Exenatide, Glucagon-Like Peptide-1 (GLP-1), Acute Coronary Syndrome, Cardioprotection