PROTECTION AMI PROTECTION AMI ion of ion of -Protein Kinase C for Reduction of -Protein Kinase C for Reduction of Size in Acute Myocardial Infarction Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. A. Michael Lincoff, M.D. Director, C5Research Director, C5Research (Cleveland Clinic Coordinating (Cleveland Clinic Coordinating Center for Clinical Research) Center for Clinical Research) Vice Chairman for Clinical Vice Chairman for Clinical Research, Research, Lerner Research Institute Lerner Research Institute Vice Chairman of Cardiovascular Vice Chairman of Cardiovascular Medicine Medicine Professor of Medicine Professor of Medicine Heart and Heart and Vascular Vascular Institute Institute Late Breaking Clinical Trials – ACC 2011 Late Breaking Clinical Trials – ACC 2011
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PROTECTION AMI Inhibition of -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research.
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PROTECTION AMIPROTECTION AMIInhibition of Inhibition of -Protein Kinase C for Reduction of Infarct-Protein Kinase C for Reduction of Infarct
Size in Acute Myocardial InfarctionSize in Acute Myocardial Infarction
A. Michael Lincoff, M.D.A. Michael Lincoff, M.D.
Director, C5ResearchDirector, C5Research(Cleveland Clinic Coordinating Center for (Cleveland Clinic Coordinating Center for
Clinical Research)Clinical Research)
Vice Chairman for Clinical Research,Vice Chairman for Clinical Research,Lerner Research InstituteLerner Research Institute
Vice Chairman of Cardiovascular MedicineVice Chairman of Cardiovascular Medicine
Professor of MedicineProfessor of Medicine
Heart and Vascular Heart and Vascular InstituteInstitute
Speaker Disclosure – A. Michael Lincoff, MDSpeaker Disclosure – A. Michael Lincoff, MDRelationships with Industry Research Sponsors Relationships with Industry Research Sponsors
PKC in Ischemia-Reperfusion InjuryPKC in Ischemia-Reperfusion Injury
activated in a variety of human, rodent and pig cells activated in a variety of human, rodent and pig cells exposed to ischemic conditions exposed to ischemic conditions in vitro in vitro andand in vivo in vivo
during reperfusion, activated during reperfusion, activated PKC translocates to the PKC translocates to the mitochondria and mediates necrosis and apoptosismitochondria and mediates necrosis and apoptosis
PKC KO mice have reduced free radical production PKC KO mice have reduced free radical production from endothelial cells and decreased damage following from endothelial cells and decreased damage following cardiac ischemia, and reduced infarct size after stroke.cardiac ischemia, and reduced infarct size after stroke.
PKC Activation in Response to IR InjuryPKC Activation in Response to IR Injury
DelcasertibDelcasertib
Peptide Inhibitor of PKC Localization - Selective InhibitorPeptide Inhibitor of PKC Localization - Selective Inhibitor
• disrupts binding of activated disrupts binding of activated PKC with its RACK (Receptor for PKC with its RACK (Receptor for Activated C-Kinase)Activated C-Kinase)
• reaches steady state within 5 - 30 minutes after the start of infusion, reaches steady state within 5 - 30 minutes after the start of infusion, terminal Tterminal T1/21/2 of 2 to 5 minutes of 2 to 5 minutes
• well-tolerated across range of doseswell-tolerated across range of doses
Animal Models:Animal Models:
• reduced infarct size, myocyte and endothelial reduced infarct size, myocyte and endothelial cellular damagecellular damage
• enhanced recovery of myocardial metabolic enhanced recovery of myocardial metabolic activity and regional LV functionactivity and regional LV function
• improved infarct zone microvascular flowimproved infarct zone microvascular flow
Ikeno F et al. Cardiovasc Res 2007;73:699-709Ikeno F et al. Cardiovasc Res 2007;73:699-709
DELTA MI TrialDELTA MI Trial
Intracoronary Delcasertib in 1o PCI for Anterior STEMIDose Escalation Phase 1/2 Trial – 154 Evaluable Patients
Intracoronary Delcasertib in 1o PCI for Anterior STEMIDose Escalation Phase 1/2 Trial – 154 Evaluable Patients
Roe MT et al. Circulation 2008 117: 857-859 Roe MT et al. Circulation 2008 117: 857-859
Inhibition of δ-PROTEin kinase C for the reducTION of infarct size in Acute Myocardial Infarction (PROTECTION AMI)
Inhibition of δ-PROTEin kinase C for the reducTION of infarct size in Acute Myocardial Infarction (PROTECTION AMI)
Study Hypothesis:Study Hypothesis:
intravenous administration of delcasertib will reduce infarct intravenous administration of delcasertib will reduce infarct size in subjects with anterior ST elevation myocardial infarction size in subjects with anterior ST elevation myocardial infarction (STEMI) undergoing primary PCI. (STEMI) undergoing primary PCI.
Trial DesignTrial DesignInclusion and Exclusion CriteriaInclusion and Exclusion Criteria
Acute STEMI with planned primary Acute STEMI with planned primary PCIPCI
Cardiac ischemia for at least 30 Cardiac ischemia for at least 30 minutes, arriving at PCI facility minutes, arriving at PCI facility within 6 hrs of symptom onsetwithin 6 hrs of symptom onset
Persistent ST elevation of:Persistent ST elevation of:
• ≥ ≥ 2 mm in at least two contiguous 2 mm in at least two contiguous precordial leads (V1-V4) (anterior precordial leads (V1-V4) (anterior STEMI cohort) STEMI cohort)
• ≥ ≥ 2 mm in two inferior leads (II, III, 2 mm in two inferior leads (II, III, aVF) with ST depression in two aVF) with ST depression in two other contiguous leads - total ≥ 8 other contiguous leads - total ≥ 8 mm (inferior STEMI cohort) mm (inferior STEMI cohort)
x Prior CABGPrior CABG
x LBBB or paced rhythmLBBB or paced rhythm
x Persistent SBP <90 mm Hg Persistent SBP <90 mm Hg unresponsive to IV fluidsunresponsive to IV fluids
x Vasopressors or inotropesVasopressors or inotropes
x ESRD on dialysisESRD on dialysis
x Severe hepatic dysfunctionSevere hepatic dysfunction
x Fibrinolysis within prior 72 hFibrinolysis within prior 72 h
x Pregnancy or breastfeedingPregnancy or breastfeeding
x Suspicion of non-thrombotic Suspicion of non-thrombotic cause of ST elevationcause of ST elevation
Trial DesignTrial DesignEndpointsEndpoints
PrimaryPrimary
• CK-MB area under the curve (AUC)CK-MB area under the curve (AUC)
SecondarySecondary
• ECG – continuous 24 hr AUC and ST recoveryECG – continuous 24 hr AUC and ST recovery
• CK-MB Peak; Troponin I and CK AUC and Peak CK-MB Peak; Troponin I and CK AUC and Peak
• Clinical Events – death, heart failure (HF), or serious ventricular Clinical Events – death, heart failure (HF), or serious ventricular arrhythmia through 1 yeararrhythmia through 1 year
• Serum NT-pro-B-type natriuretic peptide level at 3 monthsSerum NT-pro-B-type natriuretic peptide level at 3 months
• LV Ejection Fraction (LVEF) by MUGA at 3 months – anterior LV Ejection Fraction (LVEF) by MUGA at 3 months – anterior STEMI cohort onlySTEMI cohort only
Trial DesignTrial Design
Inferior CohortInferior Cohort~150 Pts (75 per group)~150 Pts (75 per group)
Inferior CohortInferior Cohort~150 Pts (75 per group)~150 Pts (75 per group)
Study drug (~2.5 hr infusion) and continuous 12-lead ECG immediately after randomizationStudy drug (~2.5 hr infusion) and continuous 12-lead ECG immediately after randomization
Cardiac catheterization and PCI per standard of careCardiac catheterization and PCI per standard of care
Serial cardiac enzymes x 72 hSerial cardiac enzymes x 72 h12-lead ECG monitoring x 24 h12-lead ECG monitoring x 24 hSerial cardiac enzymes x 72 hSerial cardiac enzymes x 72 h12-lead ECG monitoring x 24 h12-lead ECG monitoring x 24 h
Clinical Endpoints, NT-Pro BNP Clinical Endpoints, NT-Pro BNP and MUGA* at 3 monthsand MUGA* at 3 months
Clinical Endpoints, NT-Pro BNP Clinical Endpoints, NT-Pro BNP and MUGA* at 3 monthsand MUGA* at 3 months
StatisticsStatistics
Sample Size CalculationsSample Size Calculations
Primary analysis and sample size based upon anterior MI cohortPrimary analysis and sample size based upon anterior MI cohort• Inferior MI cohort exploratory – sample not statistically basedInferior MI cohort exploratory – sample not statistically based
Randomization stratified by region and Killip Class I vs II/IIIRandomization stratified by region and Killip Class I vs II/III
AssumptionsAssumptions
CK-MB AUC in placebo group – mean 7156, SD 4666 ng-hr/mLCK-MB AUC in placebo group – mean 7156, SD 4666 ng-hr/mL
20% reduction in mean with delcasertib20% reduction in mean with delcasertib
= 0.05 (2-sided); = 0.05 (2-sided); = 0.80 = 0.80
Target 227 patients per Rx group – total 908 in anterior cohortTarget 227 patients per Rx group – total 908 in anterior cohort
Academic LeadershipAcademic Leadership
Steering Committee / National CoordinatorsSteering Committee / National Coordinators
Data Safety Monitoring CommitteeData Safety Monitoring Committee
Michel Bertrand, MD - ChairMichel Bertrand, MD - Chair
Christopher Cannon, MDChristopher Cannon, MD
David Holmes, MDDavid Holmes, MD
Kerry Lee, PhDKerry Lee, PhD
Michel Bertrand, MD - ChairMichel Bertrand, MD - Chair
Christopher Cannon, MDChristopher Cannon, MD
David Holmes, MDDavid Holmes, MD
Kerry Lee, PhDKerry Lee, PhD
EnrollmentEnrollmentCountryCountry National CoordinatorNational Coordinator PatientsPatientsPolandPoland Prof. Andrezej Rynkiewcz Prof. Andrezej Rynkiewcz 226226IsraelIsrael Prof. Victor Guetta Prof. Victor Guetta 222222Czech RepublicCzech Republic Dr. Micheal ZelizkoDr. Micheal Zelizko 133133AustraliaAustralia Prof. Phil AylwardProf. Phil Aylward 8585United StatesUnited States Dr. Neal KleimanDr. Neal Kleiman 7777NetherlandsNetherlands Dr. Harry Suryapranata Dr. Harry Suryapranata 5353HungaryHungary Prof. Tamàs Forster Prof. Tamàs Forster 5252SpainSpain Dr. Antonio Fernández-Ortiz Dr. Antonio Fernández-Ortiz 5050SwedenSweden Prof. David ErlingeProf. David Erlinge 4949DenmarkDenmark Dr. Svend Eggert JensenDr. Svend Eggert Jensen 4545New ZealandNew Zealand Dr. Harvey White Dr. Harvey White 4545BelgiumBelgium Dr. Danny SchoorsDr. Danny Schoors 3939GermanyGermany Dr. Peter Radke Dr. Peter Radke 2828CanadaCanada Drs. Shamir Mehta/Shaun Goodman Drs. Shamir Mehta/Shaun Goodman 2323NorwayNorway Dr. Dan AtarDr. Dan Atar 2222FinlandFinland Dr. Michael LaineDr. Michael Laine 1919PortugalPortugal Dr. Jorge Manuel dos Santos Ferreira Dr. Jorge Manuel dos Santos Ferreira 1212ItalyItaly Dr. Guido Belli Dr. Guido Belli 11
1176 1176 PatientsPatients
RandomizeRandomizedd
1176 1176 PatientsPatients
RandomizeRandomizedd
EnrollmentEnrollment
Dec 4, 2008 Dec 4, 2008 June 21, 2010June 21, 2010
18 Countries18 Countries
114 Hospitals114 Hospitals
EnrollmentEnrollment
Top 10 Enrolling SitesTop 10 Enrolling Sites
CountryCountry Principal InvestigatorPrincipal Investigator # Randomized# Randomized
PolandPoland Dr. Jaroslaw TrebaczDr. Jaroslaw Trebacz 6363
PolandPoland Dr. Andrzej RynkiewiczDr. Andrzej Rynkiewicz 5454
Czech RepublicCzech Republic Dr. David HorakDr. David Horak 4848
IsraelIsrael Dr. Arthur PollakDr. Arthur Pollak 3737
PolandPoland Dr. Jaroslaw WojcikDr. Jaroslaw Wojcik 3636
IsraelIsrael Dr. Jonathan BalkinDr. Jonathan Balkin 3434
DenmarkDenmark Dr. Svend Eggert JensenDr. Svend Eggert Jensen 2828
IsraelIsrael Prof. Morris MosseriProf. Morris Mosseri 2626
IsraelIsrael Prof. Yoseph RozenmanProf. Yoseph Rozenman 2525
IsraelIsrael Prof. Hanoch HodProf. Hanoch Hod 2525
AustraliaAustralia Prof. Joseph SelvanayagamProf. Joseph Selvanayagam 2525
ST Recovery AUCST Recovery AUC NT-Pro BNPNT-Pro BNP
Delcasertib in STEMIDelcasertib in STEMI
PROTECTION AMI - ConclusionsPROTECTION AMI - Conclusions
Delcasertib, administered IV prior to and during primary PCI for Delcasertib, administered IV prior to and during primary PCI for acute anterior STEMI, did not reduce myocardial infarct size or acute anterior STEMI, did not reduce myocardial infarct size or improve clinical outcome.improve clinical outcome.
No differences in biomarkers of:No differences in biomarkers of: enzymatic infarct sizeenzymatic infarct size ECG markers of reperfusionECG markers of reperfusion LV function by 3 monthsLV function by 3 months NT-Pro BNPNT-Pro BNP
Other potential applications to IR injury yet to be investigatedOther potential applications to IR injury yet to be investigated
Heart and Vascular InstituteHeart and Vascular Institute