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

STEMI Clinical Trial

— EMBRACE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01572909
• Other study ID #: SPIRI-201
• Status: Completed
• Phase: Phase 2
• Start date: April 2012
• Est. completion date: February 2015

Study information

• Verified date: May 2020
• Source: Stealth BioTherapeutics Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Completed
• Enrollment: 300
• Est. completion date: February 2015
• Est. primary completion date: November 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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-a) 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.

Related Conditions & MeSH terms

• Reperfusion Injury
• ST Elevation Myocardial Infarction
• STEMI
• Wounds and Injuries

Intervention

Drug:
• Bendavia (MTP-131)
0.05 mg/kg/hr
• Placebo
Identically appearing placebo

Locations

Country	Name	City	State
Germany	Universitätsmedizin Berlin, Charité Campus Benjamin Franklin	Berlin
Germany	Staedtische Kliniken Bielefeld	Bielefeld
Germany	Marienhaus Klinikum Eifel	Bitburg
Germany	Universitaetsklinikum Freiburg	Freiburg
Germany	Klinikum Herford	Herford
Germany	Robert-Bosch-Krankenhaus Kardiologie	Stuttgart
Germany	Helios Klinikum Wuppertal, Herzzentrum Elberfeld	Wuppertal
Hungary	Gottsegen Gyorgy Orszagos Kardiologiai Intezet	Budapest
Hungary	Honvédkórház-Állami Egészségügyi Központ	Budapest
Hungary	Semmelweis Egyetem Kardiológiai Központ, Városmajor u. 68	Budapest
Hungary	PTE Klinikai Központ Szívgyógyászati Klinika	Pecs
Hungary	Szent György Kórház, II. Belgyógyászati Osztály	Szekesfehervar
Hungary	Zala Megyei Kórház, Kardiológiai Osztály, Zrínyi Miklós út 1.	Zalaegerszeg
Poland	Medical University of Bialystok	Bialystok
Poland	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	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	Krakowski Szpital Specjalistyczny im. Jana Pwla II, Centrum Interwencyjnego Leczenia Chorob Serca i Naczyn z Pododdzialem Kariologii Interwencyjnej	Kraków
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	SP ZOZ Wojewodzkie Centrum Medyczne, Zaklad Diagnostyki Obrazowej, AI. W. Witosa 26	Opole
Poland	Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii	Oswiecim
Poland	Instytut Kardiologii im. Prymasa Tysiaclecia Stefana Kardynala Wyszynskiego	Warsaw
Poland	Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie, Pracownia Kardiologii Inwazyjnej	Warsaw
Poland	Szpital Bielanski im. ks. Jerzego Popieluszki	Warsaw
Poland	Dolnoslaski Szpital Specjalistyczny im. T. Marciniaka, Centrum Medycyny Ratunkowe	Wroclaw
Poland	Wojewodzki Szpital Specjalistyczny we Wroclawiu, Oddzial Kardiologiczny, ul. H. Kamieskiego 73a	Wroclaw
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
United States	Henry Ford Hospital	Detroit	Michigan
United States	Creighton Cardiac Center	Omaha	Nebraska
United States	Advanced Medical Research Center	Port Orange	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Stealth BioTherapeutics Inc.	ICON Clinical Research

Countries where clinical trial is conducted

United States,  Germany,  Hungary,  Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Left Ventricular (LV) Ejection Fraction (%)	Difference in Left Ventricular (LV) Ejection Fraction (%) from Day 4 To Day 30	Day 4 to Day 30
Secondary	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
Secondary	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
Secondary	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