Evaluation of Myocardial Effects of MTP-131 for Reducing Reperfusion Injury in Patients With Acute Coronary Events

Study Overview
=================
Brief Summary
-----------------
The EMBRACE-STEMI trial was a Phase 2a prospective, multicenter, multinational randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and efficacy of IV administered elamipretide (also known as MTP-131, or Bendavia) on a background of standard-of-care therapy for reduction of reperfusion injury in patients with first time acute, anterior wall ST-segment elevation myocardial infarction (STEMI).

Detailed Description
-----------------
The EMBRACE-STEMI trial was a Phase 2a prospective, multicenter, multinational randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and efficacy of IV administered elamipretide on a background of standard-of-care therapy for reduction of reperfusion injury in patients with first time acute, anterior wall STEMI. Patients were randomized to receive either an infusion of elamipretide at 0.05 mg/kg/hr or an identically appearing placebo administered as an IV infusion at 60 mL/hr. The infusion began at least 15 minutes but no more than 1 hour prior to the anticipated reperfusion event and continued through approximately 1 hour following re-establishment of blood flow through the culprit vessel. The reduction of reperfusion injury, or infarct size, was estimated using the area under the curve (AUC) of the serum creatine kinase (CK) isoenzyme, as well as using magnetic resonance imaging (MRI) performed on the Day 4±1 and on Day 30±7 (both MRI assessments measured infarct size and the ratio of infarct size to myocardial mass). The analyses of cardiac MRI data were performed for both the primary endpoint population and also in all patients who had adequate Day 4/Day 30 cardiac MRI studies. After completion of the percutaneous coronary intervention (PCI) and stenting, patients received standard medical treatment.

Official Title
-----------------
A Phase 2a Trial to Evaluate the Safety, Tolerability and Efficacy of Intravenous MTP-131 on Reperfusion Injury in Patients Undergoing Primary Percutaneous Coronary Intervention and Stenting for ST-segment Elevation Myocardial Infarction Infarction

Conditions
-----------------
Reperfusion Injury, STEMI

Intervention / Treatment
-----------------
* Drug: Bendavia (MTP-131)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 and <85 years The patient presents with first-time acute, anterior wall STEMI scheduled to undergo primary PCI and stenting. The patient has symptoms of cardiac ischemia of ≥10 minutes. The patient must demonstrate an anterior wall STEMI with >0.1 millivolt (mV) ST-segment elevation in at least two contiguous precordial leads (i.e., V1-V4) or presumed new left bundle branch block. The time from onset of symptoms of cardiac ischemia to the anticipated time of initial PCI balloon inflation does not exceed four (4) hours and it is anticipated that the door-to-balloon time will be <2 hours. For female patients of child-bearing potential, an adequate form of contraception must be adhered to prior to entry into the study and for a further 3 months after the follow-up visit. Female patients of childbearing potential must have a negative serum pregnancy test prior to entry into the study. Female patients not of childbearing potential (i.e. female patients who are postmenopausal since last regular menses, or have been surgically sterilized at least 1 year prior to screening visit) are eligible to enter the study. For male patients with female partners of child-bearing potential, an adequate form of contraception must be adhered to prior to entry into the study and for a further 3 months after the post-study medical. Written informed consent obtained that strictly adheres to the written guidelines from the local Institutional Review Board (IRB)/ Ethical Committee (EC). Exclusion Criteria Cardiogenic shock or maximal systolic blood pressure (BP) <80 mm Hg after fluid and/or vasopressor resuscitation on at least two consecutive readings. Ongoing vasopressor support. Uncontrolled hypertension defined as a systolic BP >180 mm Hg or a diastolic BP >110 mm Hg on at least two consecutive readings. Cardiac arrest or arrhythmia requiring prolonged (>5 minutes) chest compressions/ cardiopulmonary resuscitation (CPR). Prior coronary artery bypass graft surgery (CABG). Prior myocardial infarction (MI). Implantable cardioverter-defibrillator (ICD) or permanent pacemaker (PPM) unless known to be MRI safe. The presence of an MRI-compatible pacemaker or other MRI-compatible hardware will not be a contraindication to participation in this trial. Known left ventricular ejection fraction <30% prior to the qualifying infarct. History of clinically significant hepatic disturbance or chronic renal impairment at the time of admission. Cerebrovascular accident (CVA) or transient ischemic attack (TIA) within the last 30 days. Any known disorder that is associated with immunologic dysfunction (e.g., cancer, lymphoma, a positive serologic test for the human immunodeficiency virus, or hepatitis) more recently than 6 months before presentation or the administration of immunosuppressive drugs within 10 days of the STEMI at doses expected to be associated with immunosuppression including high dose steroids (>2.5 mg/d hydrocortisone or equal potency of synthetic steroids), tumor necrosis factor-alpha (TNF-α) blockers or methotrexate/azathioprine. Any condition that, in the Investigator's opinion, would prevent adherence to the requirements of the protocol including language barrier or current alcohol or drug abuse. Contraindications (including claustrophobia) to cardiac MRI at study entry. Participation in an investigational drug or device study within the 30 days prior to enrollment into the EMBRACE-STEMI Trial or anticipated within the next 4 days. Female patients who are pregnant or breastfeeding during the study or intend to within 30 days of receiving study drug.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 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 |
| --- | --- |
| Active Comparator: Bendavia™<br>Bendavia™ administered intravenously at 0.05 mg/kg/hr at least 15, but no more than 60 minutes, prior to the anticipated time of the PCI, and continued for 1 hour after re-establishment of blood flow through the culprit vessel. | Drug: Bendavia (MTP-131)<br>* 0.05 mg/kg/hr<br>* Other names: Elamipretide;|
| Placebo Comparator: Placebo<br>Placebo administered intravenously at 60 mL/hr at least 15, but no more than 60 minutes, prior to the anticipated time of the PCI, and continued for 1 hour after re-establishment of blood flow through the culprit vessel. | Drug: Placebo<br>* Identically appearing placebo<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) of Serum Creatine Kinase Isoenzyme Type Muscle-brain (CK-MB) | Infarct size as measured by the AUC of serum CK-MB at 24 and 72 hours post-PCI | The initial 24 and 72 hours post-percutaneous coronary intervention (PCI) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC of Troponin 1 Enzyme | Infarct size as calculated by the AUC of Troponin I Enzyme over the initial 24 and 72 hours post-PCI | Initial 24 and 72 hours post-PCI | 
| Ratio of Volume of Infarcted Myocardium to Left Ventricular Mass | Cardiac infarct size calculated as the ratio of volume of infarcted myocardium to left ventricular mass at Day 30 as measured by MRI. | Day 30 + 7 | 
| Thrombosis in Myocardial Infarction (TIMI) Perfusion Grade Flow at Completion of PCI | TIMI perfusion grade flow at completion of PCI will be categorized as 0,1, or 1.5, 2 or 2.5, 3, and treated as ordinal data, where higher score means better perfusion and lower score means worse perfusion and worse outcome. | Initiation to Completion of PCI, no longer than 4 hours | 
| Corrected TIMI Frame Count | Corrected TIMI Frame Count at Completion of PCI as captured by angiogram and analyzed as a continuous variable. | Completion of PCI, no longer than 4 hours | 
| ST-Segmented Elevation From Pre-PCI to 24 Hours Post-PCI and Presence of ST-Segmented Resolution | ST-Segmented Elevation from pre-PCI to 24 hours post-PCI and Presence of ST-Segmented Resolution by ECG | pre-PCI to 24 hours post-PCI | 
| Change in Serum Creatinine From Baseline | Change in serum creatinine, from baseline (prior to study drug administration) to Day 30 +7 post-PCI | Day 30 +7 | 
| Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline | Change in eGFR from baseline (prior to study drug administration) to Day 30 +7 post-PCI | Day 30 +/- 7 | 
| Cystatin C Change From Baseline | Change in Cystatin C from baseline (prior to study drug administration) to Day 30 +7 post-PCI | Day 30 + 7 | 
| Blood Urea Nitrogen (BUN) Change From Baseline | Blood Urea Nitrogen (BUN) Change from baseline (prior to study drug administration) to Day 30 + 7 post-PCI | Baseline to Day 30 | 
| Number and Percent of Grade 1 Episode of Contrast-Induced Nephropathy Post-PCI | Number of Participants with Grade 1 Episode of Contrast-Induced Nephropathy within 48 hours of initial PCI or MRI, based on lab data. | Baseline to 48 hours post PCI or MRI | 
| Immediate Myocardial Complications: Ventricular Tachycardia or Fibrillation | Number and percent of participants with Immediate Myocardial Complications: Ventricular Tachycardia or Fibrillation Requiring Medical Intervention | Baseline up to 1 hour post-PCI | 
| Immediate Myocardial Complications: Mechanical Complications | Number and Percent of Participants with Immediate Myocardial Complications: Mechanical Complications: (Free wall Rupture, Ventricular Septal Defect, Ischemic Mitral Regurgitation) | Baseline up to 1 hour post-PCI | 
| Emergency Use of Medications During PCI Procedure | Emergency Use of Nitroprusside, Calcium Channel Blocker, Adenosine Administration During the PCI Procedure | Initiation to Completion of PCI, no longer than 4 hours | 
| ProB-type Natriuretic Peptide (NT-proBNP) Change From Baseline to Day 30 | NT-proBNP: Change from baseline to Day 30 +7 (Laboratory marker for chronic heart failure (CHF) and systemic inflammation.) | Baseline to Day 30 | 
| High Sensitivity C-Reactive Protein (hsCRP): Change From Baseline to Day 30 | High Sensitivity C-Reactive Protein (hsCRP): Change from baseline to Day 30 +7 (Laboratory Marker for CHF and Systemic Inflammation) | Baseline to Day 30 | 
| Left Ventricular (LV) Ejection Fraction (%) | Difference in Left Ventricular (LV) Ejection Fraction (%) from Day 4 To Day 30 | Day 4 to Day 30 | 
| Difference Between Left Ventricular End Diastolic Volume, Corrected | Difference between Left Ventricular End Diastolic Volume Corrected for Body Surface Area between Day 4 and Day 30 | Day 4 and Day 30 | 
| Difference Between Left Ventricular End Systolic Volume, Corrected | Difference between Left Ventricular End Systolic Volume Corrected for Body Surface Area from Day 4 and Day 30 | Day 4 and Day 30 | 
| Chronic Heart Failure | Number and Percentage of Patients with Clinical Events: Chronic Heart Failure beginning within 24 hours after PCI but within the duration of the index hospitalization (Subjects with CHF started within 24 hours after the last balloon deflation while the patient was still in the hospital {including patients who had missing discharge date}). | Within 24 hours after PCI | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Myocardial Reperfusion, Primary PCI, Stenting for ST-segment Elevation Myocardial Infarction