Evaluation of Myocardial Effects of MTP-131 for Reducing Reperfusion Injury in Patients With Acute Coronary Events
- Conditions
- STEMIReperfusion Injury
- Interventions
- Drug: Bendavia (MTP-131)Drug: Placebo
- Registration Number
- NCT01572909
- Lead Sponsor
- Stealth BioTherapeutics Inc.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 300
- 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.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Bendavia™ Bendavia (MTP-131) 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. Placebo 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.
- Primary Outcome Measures
Name Time Method Area Under the Curve (AUC) of Serum Creatine Kinase Isoenzyme Type Muscle-brain (CK-MB) The initial 24 and 72 hours post-percutaneous coronary intervention (PCI) Infarct size as measured by the AUC of serum CK-MB at 24 and 72 hours post-PCI
- Secondary Outcome Measures
Name Time Method AUC of Troponin 1 Enzyme Initial 24 and 72 hours post-PCI Infarct size as calculated by the AUC of Troponin I Enzyme over the initial 24 and 72 hours post-PCI
Thrombosis in Myocardial Infarction (TIMI) Perfusion Grade Flow at Completion of PCI Initiation to Completion of PCI, no longer than 4 hours 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.
Change in Serum Creatinine From Baseline Day 30 +7 Change in serum creatinine, from baseline (prior to study drug administration) to Day 30 +7 post-PCI
Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline Day 30 +/- 7 Change in eGFR from baseline (prior to study drug administration) to Day 30 +7 post-PCI
Blood Urea Nitrogen (BUN) Change From Baseline Baseline to Day 30 Blood Urea Nitrogen (BUN) Change from baseline (prior to study drug administration) to Day 30 + 7 post-PCI
Immediate Myocardial Complications: Mechanical Complications Baseline up to 1 hour post-PCI Number and Percent of Participants with Immediate Myocardial Complications: Mechanical Complications: (Free wall Rupture, Ventricular Septal Defect, Ischemic Mitral Regurgitation)
Ratio of Volume of Infarcted Myocardium to Left Ventricular Mass Day 30 + 7 Cardiac infarct size calculated as the ratio of volume of infarcted myocardium to left ventricular mass at Day 30 as measured by MRI.
Corrected TIMI Frame Count Completion of PCI, no longer than 4 hours Corrected TIMI Frame Count at Completion of PCI as captured by angiogram and analyzed as a continuous variable.
ST-Segmented Elevation From Pre-PCI to 24 Hours Post-PCI and Presence of ST-Segmented Resolution pre-PCI to 24 hours post-PCI ST-Segmented Elevation from pre-PCI to 24 hours post-PCI and Presence of ST-Segmented Resolution by ECG
Cystatin C Change From Baseline Day 30 + 7 Change in Cystatin C from baseline (prior to study drug administration) to Day 30 +7 post-PCI
Immediate Myocardial Complications: Ventricular Tachycardia or Fibrillation Baseline up to 1 hour post-PCI Number and percent of participants with Immediate Myocardial Complications: Ventricular Tachycardia or Fibrillation Requiring Medical Intervention
Emergency Use of Medications During PCI Procedure Initiation to Completion of PCI, no longer than 4 hours Emergency Use of Nitroprusside, Calcium Channel Blocker, Adenosine Administration During the PCI Procedure
Number and Percent of Grade 1 Episode of Contrast-Induced Nephropathy Post-PCI Baseline to 48 hours post PCI or MRI Number of Participants with Grade 1 Episode of Contrast-Induced Nephropathy within 48 hours of initial PCI or MRI, based on lab data.
High Sensitivity C-Reactive Protein (hsCRP): Change From Baseline to Day 30 Baseline to Day 30 High Sensitivity C-Reactive Protein (hsCRP): Change from baseline to Day 30 +7 (Laboratory Marker for CHF and Systemic Inflammation)
ProB-type Natriuretic Peptide (NT-proBNP) Change From Baseline to Day 30 Baseline to Day 30 NT-proBNP: Change from baseline to Day 30 +7 (Laboratory marker for chronic heart failure (CHF) and systemic inflammation.)
Left Ventricular (LV) Ejection Fraction (%) Day 4 to Day 30 Difference in Left Ventricular (LV) Ejection Fraction (%) from Day 4 To Day 30
Difference Between Left Ventricular End Diastolic Volume, Corrected Day 4 and Day 30 Difference between Left Ventricular End Diastolic Volume Corrected for Body Surface Area between Day 4 and Day 30
Difference Between Left Ventricular End Systolic Volume, Corrected Day 4 and Day 30 Difference between Left Ventricular End Systolic Volume Corrected for Body Surface Area from Day 4 and Day 30
Chronic Heart Failure Within 24 hours after PCI 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}).
Trial Locations
- Locations (30)
Universitaetsklinikum Freiburg
🇩🇪Freiburg, Germany
Honvédkórház-Állami Egészségügyi Központ
🇭🇺Budapest, Hungary
Semmelweis Egyetem Kardiológiai Központ, Városmajor u. 68
🇭🇺Budapest, Hungary
Robert-Bosch-Krankenhaus Kardiologie
🇩🇪Stuttgart, Germany
Advanced Medical Research Center
🇺🇸Port Orange, Florida, United States
Marienhaus Klinikum Eifel
🇩🇪Bitburg, Germany
Helios Klinikum Wuppertal, Herzzentrum Elberfeld
🇩🇪Wuppertal, Germany
Zala Megyei Kórház, Kardiológiai Osztály, Zrínyi Miklós út 1.
🇭🇺Zalaegerszeg, Hungary
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
Krakowski Szpital Specjalistyczny im. Jana Pwla II, Centrum Interwencyjnego Leczenia Chorob Serca i Naczyn z Pododdzialem Kariologii Interwencyjnej
🇵🇱Kraków, Poland
Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii
🇵🇱Oswiecim, Poland
Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie, Pracownia Kardiologii Inwazyjnej
🇵🇱Warsaw, Poland
Dolnoslaski Szpital Specjalistyczny im. T. Marciniaka, Centrum Medycyny Ratunkowe
🇵🇱Wroclaw, Poland
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
Creighton Cardiac Center
🇺🇸Omaha, Nebraska, United States
Universitätsmedizin Berlin, Charité Campus Benjamin Franklin
🇩🇪Berlin, Germany
Staedtische Kliniken Bielefeld
🇩🇪Bielefeld, Germany
Klinikum Herford
🇩🇪Herford, Germany
Gottsegen Gyorgy Orszagos Kardiologiai Intezet
🇭🇺Budapest, Hungary
Szent György Kórház, II. Belgyógyászati Osztály
🇭🇺Szekesfehervar, Hungary
PTE Klinikai Központ Szívgyógyászati Klinika
🇭🇺Pecs, Hungary
Medical University of Bialystok
🇵🇱Bialystok, Poland
SPSK Nr 7 Slaskiego Uniwersytetu Medycznego w Katowicach, Gornoslaskie Centrum Medyczne im. Prof. Leszaka Gieca, I Oddzial Kardiologii, ul. Ziolowa 45-47
🇵🇱Katowice, Poland
Wojewodzki Szpital Zespolony w Kielcach, Swietokrzyskie Centrum Kardiologii
🇵🇱Kielce, Poland
SP ZOZ Wojewodzkie Centrum Medyczne, Zaklad Diagnostyki Obrazowej, AI. W. Witosa 26
🇵🇱Opole, Poland
Wojewodzki Specjalistyczny Szpital im WI. Bieganskiego, II Katedra i Klinika Kardiologii Uniwersytetu Medycznego w Lodzi, Pracownia Kardiologii Inwazyinej, ul. Kniaziewicza 1/5
🇵🇱Lodz, Poland
Szpital Bielanski im. ks. Jerzego Popieluszki
🇵🇱Warsaw, Poland
Instytut Kardiologii im. Prymasa Tysiaclecia Stefana Kardynala Wyszynskiego
🇵🇱Warsaw, Poland
Samodzielny Publiczny Szpital Wojewodzki im. Papieza Jana Pawla II w Zamosciu, Oddzial Kardiologii z Pododdzialem Intensywnej Terapil Kardiologicznej, ul. Aleje Jana Pawta II 10
🇵🇱Zamosc, Poland
Wojewodzki Szpital Specjalistyczny we Wroclawiu, Oddzial Kardiologiczny, ul. H. Kamieskiego 73a
🇵🇱Wroclaw, Poland