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

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

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).

Study Overview

• Status: Completed
• Conditions: Reperfusion Injury; STEMI
• Intervention / Treatment: Drug: Bendavia (MTP-131); Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 12203
    • Universitätsmedizin Berlin, Charité Campus Benjamin Franklin
  • Bielefeld, Germany, 33604
    • Staedtische Kliniken Bielefeld
  • Bitburg, Germany, 54634
    • Marienhaus Klinikum Eifel
  • Freiburg, Germany, 79095
    • Universitaetsklinikum Freiburg
  • Herford, Germany, 32049
    • Klinikum Herford
  • Stuttgart, Germany, 70376
    • Robert-Bosch-Krankenhaus Kardiologie
  • Wuppertal, Germany, 42117
    • Helios Klinikum Wuppertal, Herzzentrum Elberfeld
• Hungary
  • Budapest, Hungary, 1096
    • Gottsegen György Országos Kardiológiai Intézet
  • Budapest, Hungary, 1122
    • Semmelweis Egyetem Kardiológiai Központ, Városmajor u. 68
  • Budapest, Hungary, 1134
    • Honvédkórház-Állami Egészségügyi Központ
  • Pecs, Hungary, H-7624
    • PTE Klinikai Központ Szívgyógyászati Klinika
  • Szekesfehervar, Hungary, H-8000
    • Szent György Kórház, II. Belgyógyászati Osztály
  • Zalaegerszeg, Hungary, H-8900
    • Zala Megyei Kórház, Kardiológiai Osztály, Zrínyi Miklós út 1.
• Poland
  • Bialystok, Poland, 15-276
    • Medical University of Bialystok
  • Katowice, Poland, 40-635
    • SPSK Nr 7 Klaskiego Uniwersytetu Medycznego w Katowicach, Gornoslaskie Centrum Medyczne im. Prof. Leszka Gieca, III Oddzial Kardiologii, Zklad Kardiologii Inwazjnejul, Ziolowa 45-47
  • Katowice, Poland, 40-635
    • SPSK Nr 7 Slaskiego Uniwersytetu Medycznego w Katowicach, Gornoslaskie Centrum Medyczne im. Prof. Leszaka Gieca, I Oddzial Kardiologii, ul. Ziolowa 45-47
  • Kielce, Poland, 25-736
    • Wojewodzki Szpital Zespolony w Kielcach, Swietokrzyskie Centrum Kardiologii
  • Kraków, Poland, 31-202
    • Krakowski Szpital Specjalistyczny im. Jana Pwla II, Centrum Interwencyjnego Leczenia Chorob Serca i Naczyn z Pododdzialem Kariologii Interwencyjnej
  • Lodz, Poland, 91-347
    • Wojewodzki Specjalistyczny Szpital im WI. Bieganskiego, II Katedra i Klinika Kardiologii Uniwersytetu Medycznego w Lodzi, Pracownia Kardiologii Inwazyinej, ul. Kniaziewicza 1/5
  • Opole, Poland, 45-418
    • SP ZOZ Wojewodzkie Centrum Medyczne, Zaklad Diagnostyki Obrazowej, AI. W. Witosa 26
  • Oswiecim, Poland, 32-600
    • Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii
  • Warsaw, Poland, 01-809
    • Szpital Bielanski im. ks. Jerzego Popieluszki
  • Warsaw, Poland, 02-097
    • Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie, Pracownia Kardiologii Inwazyjnej
  • Warsaw, Poland, 04-628
    • Instytut Kardiologii im. Prymasa Tysiaclecia Stefana Kardynala Wyszynskiego
  • Wroclaw, Poland, 50-420
    • Dolnoslaski Szpital Specjalistyczny im. T. Marciniaka, Centrum Medycyny Ratunkowe
  • Wroclaw, Poland, 51-124
    • Wojewodzki Szpital Specjalistyczny we Wroclawiu, Oddzial Kardiologiczny, ul. H. Kamieskiego 73a
  • Zamosc, Poland, 22-400
    • Samodzielny Publiczny Szpital Wojewodzki im. Papieza Jana Pawla II w Zamosciu, Oddzial Kardiologii z Pododdzialem Intensywnej Terapil Kardiologicznej, ul. Aleje Jana Pawta II 10
• United States
  • Florida
    • Port Orange, Florida, United States, 32127
      • Advanced Medical Research Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68131
      • Creighton Cardiac Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Bendavia™; 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); 0.05 mg/kg/hr; Other Names: MTP-131; Elamipretide
Placebo Comparator: Placebo; 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; Identically appearing placebo

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

Collaborators and Investigators

• Sponsor: Stealth BioTherapeutics Inc.
• Collaborators: ICON Clinical Research
• Investigators: Principal Investigator: Anjan Chakrabarti, MD, Beth Israel Deaconess Medical Center, Interventional Cardiology, 185 Pilgrim Rd, Baker 4, Boston, MA 02215; Study Chair: C. M. Gibson, MD, Beth Israel Deaconess Medical Center, Interventional Cardiology, 185 Pilgrim Rd, Baer 4, Boston, MA 02215

Publications and helpful links

General Publications

• Daaboul Y, Korjian S, Weaver WD, Kloner RA, Giugliano RP, Carr J, Neal BJ, Chi G, Cochet M, Goodell L, Michalak N, Rusowicz-Orazem L, Alkathery T, Allaham H, Routray S, Szlosek D, Jain P, Gibson CM. Relation of Left Ventricular Mass and Infarct Size in Anterior Wall ST-Segment Elevation Acute Myocardial Infarction (from the EMBRACE STEMI Clinical Trial). Am J Cardiol. 2016 Sep 1;118(5):625-31. doi: 10.1016/j.amjcard.2016.06.025. Epub 2016 Jun 15.
• Chakrabarti AK, Feeney K, Abueg C, Brown DA, Czyz E, Tendera M, Janosi A, Giugliano RP, Kloner RA, Weaver WD, Bode C, Godlewski J, Merkely B, Gibson CM. Rationale and design of the EMBRACE STEMI study: a phase 2a, randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability and efficacy of intravenous Bendavia on reperfusion injury in patients treated with standard therapy including primary percutaneous coronary intervention and stenting for ST-segment elevation myocardial infarction. Am Heart J. 2013 Apr;165(4):509-514.e7. doi: 10.1016/j.ahj.2012.12.008. Epub 2013 Feb 15.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: March 28, 2012
• First Submitted That Met QC Criteria: April 4, 2012
• First Posted (Estimate): April 6, 2012

Study Record Updates

• Last Update Posted (Actual): June 11, 2020
• Last Update Submitted That Met QC Criteria: May 31, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Primary PCI; Myocardial Reperfusion; Stenting for ST-segment Elevation Myocardial Infarction
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Myocardial Infarction; Infarction; ST Elevation Myocardial Infarction; Wounds and Injuries; Reperfusion Injury
• Other Study ID Numbers: SPIRI-201