Clinical trial NCT01572909: Evaluation of Myocardial Effects of MTP-131 for Reducing Reperfusion Injury in Patients With Acute Coronary Events
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Reperfusion Injury
STEMI
Keywords: Myocardial Reperfusion
Primary PCI
Stenting for ST-segment Elevation Myocardial Infarction
Lead sponsor: Stealth BioTherapeutics Inc.
Sponsor class: INDUSTRY
Collaborators: name: ICON Clinical Research
First posted: 2012-04-06
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Area Under the Curve (AUC) of Serum Creatine Kinase Isoenzyme Type Muscle-brain (CK-MB)
timeFrame: The initial 24 and 72 hours post-percutaneous coronary intervention (PCI)
Secondary outcomes:
measure: AUC of Troponin 1 Enzyme
timeFrame: Initial 24 and 72 hours post-PCI
measure: Ratio of Volume of Infarcted Myocardium to Left Ventricular Mass
timeFrame: Day 30 + 7
measure: Thrombosis in Myocardial Infarction (TIMI) Perfusion Grade Flow at Completion of PCI
timeFrame: Initiation to Completion of PCI, no longer than 4 hours
measure: Corrected TIMI Frame Count
timeFrame: Completion of PCI, no longer than 4 hours
measure: ST-Segmented Elevation From Pre-PCI to 24 Hours Post-PCI and Presence of ST-Segmented Resolution
timeFrame: pre-PCI to 24 hours post-PCI
measure: Change in Serum Creatinine From Baseline
timeFrame: Day 30 +7
measure: Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline
timeFrame: Day 30 +/- 7
measure: Cystatin C Change From Baseline
timeFrame: Day 30 + 7
measure: Blood Urea Nitrogen (BUN) Change From Baseline
timeFrame: Baseline to Day 30
measure: Number and Percent of Grade 1 Episode of Contrast-Induced Nephropathy Post-PCI
timeFrame: Baseline to 48 hours post PCI or MRI
measure: Immediate Myocardial Complications: Ventricular Tachycardia or Fibrillation
timeFrame: Baseline up to 1 hour post-PCI
measure: Immediate Myocardial Complications: Mechanical Complications
timeFrame: Baseline up to 1 hour post-PCI
measure: Emergency Use of Medications During PCI Procedure
timeFrame: Initiation to Completion of PCI, no longer than 4 hours
measure: ProB-type Natriuretic Peptide (NT-proBNP) Change From Baseline to Day 30
timeFrame: Baseline to Day 30
measure: High Sensitivity C-Reactive Protein (hsCRP): Change From Baseline to Day 30
timeFrame: Baseline to Day 30
measure: Left Ventricular (LV) Ejection Fraction (%)
timeFrame: Day 4 to Day 30
measure: Difference Between Left Ventricular End Diastolic Volume, Corrected
timeFrame: Day 4 and Day 30
measure: Difference Between Left Ventricular End Systolic Volume, Corrected
timeFrame: Day 4 and Day 30
measure: Chronic Heart Failure
timeFrame: Within 24 hours after PCI
Other outcomes:
Locations:
city: Port Orange
country: United States
facility: Advanced Medical Research Center
state: Florida
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Omaha
country: United States
facility: Creighton Cardiac Center
state: Nebraska
city: Berlin
country: Germany
facility: Universitätsmedizin Berlin, Charité Campus Benjamin Franklin
city: Bielefeld
country: Germany
facility: Staedtische Kliniken Bielefeld
city: Bitburg
country: Germany
facility: Marienhaus Klinikum Eifel
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Herford
country: Germany
facility: Klinikum Herford
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus Kardiologie
city: Wuppertal
country: Germany
facility: Helios Klinikum Wuppertal, Herzzentrum Elberfeld
city: Budapest
country: Hungary
facility: Gottsegen Gyorgy Orszagos Kardiologiai Intezet
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Kardiológiai Központ, Városmajor u. 68
city: Budapest
country: Hungary
facility: Honvédkórház-Állami Egészségügyi Központ
city: Pecs
country: Hungary
facility: PTE Klinikai Központ Szívgyógyászati Klinika
city: Szekesfehervar
country: Hungary
facility: Szent György Kórház, II. Belgyógyászati Osztály
city: Zalaegerszeg
country: Hungary
facility: Zala Megyei Kórház, Kardiológiai Osztály, Zrínyi Miklós út 1.
city: Bialystok
country: Poland
facility: Medical University of Bialystok
city: Katowice
country: Poland
facility: SPSK Nr 7 Klaskiego Uniwersytetu Medycznego w Katowicach, Gornoslaskie Centrum Medyczne im. Prof. Leszka Gieca, III Oddzial Kardiologii, Zklad Kardiologii Inwazjnejul, Ziolowa 45-47
city: Katowice
country: Poland
facility: SPSK Nr 7 Slaskiego Uniwersytetu Medycznego w Katowicach, Gornoslaskie Centrum Medyczne im. Prof. Leszaka Gieca, I Oddzial Kardiologii, ul. Ziolowa 45-47
city: Kielce
country: Poland
facility: Wojewodzki Szpital Zespolony w Kielcach, Swietokrzyskie Centrum Kardiologii
city: Kraków
country: Poland
facility: Krakowski Szpital Specjalistyczny im. Jana Pwla II, Centrum Interwencyjnego Leczenia Chorob Serca i Naczyn z Pododdzialem Kariologii Interwencyjnej
city: Lodz
country: Poland
facility: Wojewodzki Specjalistyczny Szpital im WI. Bieganskiego, II Katedra i Klinika Kardiologii Uniwersytetu Medycznego w Lodzi, Pracownia Kardiologii Inwazyinej, ul. Kniaziewicza 1/5
city: Opole
country: Poland
facility: SP ZOZ Wojewodzkie Centrum Medyczne, Zaklad Diagnostyki Obrazowej, AI. W. Witosa 26
city: Oswiecim
country: Poland
facility: Centrum Kardiologii Inwazyjnej, Elektroterapii i Angiologii
city: Warsaw
country: Poland
facility: Szpital Bielanski im. ks. Jerzego Popieluszki
city: Warsaw
country: Poland
facility: Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie, Pracownia Kardiologii Inwazyjnej
city: Warsaw
country: Poland
facility: Instytut Kardiologii im. Prymasa Tysiaclecia Stefana Kardynala Wyszynskiego
city: Wroclaw
country: Poland
facility: Dolnoslaski Szpital Specjalistyczny im. T. Marciniaka, Centrum Medycyny Ratunkowe
city: Wroclaw
country: Poland
facility: Wojewodzki Szpital Specjalistyczny we Wroclawiu, Oddzial Kardiologiczny, ul. H. Kamieskiego 73a
city: Zamosc
country: Poland
facility: Samodzielny Publiczny Szpital Wojewodzki im. Papieza Jana Pawla II w Zamosciu, Oddzial Kardiologii z Pododdzialem Intensywnej Terapil Kardiologicznej, ul. Aleje Jana Pawta II 10
Study officials:
affiliation: Beth Israel Deaconess Medical Center, Interventional Cardiology, 185 Pilgrim Rd, Baker 4, Boston, MA 02215
name: Anjan Chakrabarti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Beth Israel Deaconess Medical Center, Interventional Cardiology, 185 Pilgrim Rd, Baer 4, Boston, MA 02215
name: C. M. Gibson, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.