Late Breaking Clinical Trials – ACC 2011
PROTECTION AMI
Inhibition of d-Protein Kinase C for Reduction of Infarct
Size in Acute Myocardial Infarction
A. Michael Lincoff, M.D.
Director, C5Research
(Cleveland Clinic Coordinating Center for
Clinical Research)
Vice Chairman for Clinical Research,
Lerner Research Institute
Vice Chairman of Cardiovascular Medicine
Professor of Medicine
Heart and Vascular
Institute
Speaker Disclosure – A. Michael Lincoff, MD
Relationships with Industry Research Sponsors
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Anthera
AstraZeneca
Atherosys
Bristol-Myers Squibb (BMS)
Centocor
Cordis
Guidant
Heartscape
J&J
KAI Pharma
Lilly
Mannkind
Medicines Company
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Medtronic
Novartis
Novo Nordisk
Pfizer
Resverlogix
Roche / Genentech
Sankyo
Sanofi-Aventis
Schering-Plough
Scios
Takeda
VasoGenix
Consultant
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Schering-Plough
Bioline
BMS
Merck
Baxter
Aztra Zeneca
Roche
dPKC in Ischemia-Reperfusion Injury
dPKC Activation in Response to IR Injury
 activated in a variety of human, rodent and pig cells
exposed to ischemic conditions in vitro and in vivo
 during reperfusion, activated dPKC translocates to the
mitochondria and mediates necrosis and apoptosis
 dPKC KO mice have reduced free radical production
from endothelial cells and decreased damage following
cardiac ischemia, and reduced infarct size after stroke.
Delcasertib
Peptide Inhibitor of PKC Localization - Selective Inhibitor
• disrupts binding of activated dPKC with its RACK (Receptor for
Activated C-Kinase)
• reaches steady state within 5 - 30 minutes after the start of infusion,
terminal T1/2 of 2 to 5 minutes
• well-tolerated across range of doses
Animal Models:
• reduced infarct size, myocyte and endothelial
cellular damage
• enhanced recovery of myocardial metabolic
activity and regional LV function
• improved infarct zone microvascular flow
Ikeno F et al. Cardiovasc Res 2007;73:699-709
DELTA MI Trial
Intracoronary Delcasertib in 1o PCI for Anterior STEMI
Dose Escalation Phase 1/2 Trial – 154 Evaluable Patients
CK-MB AUC
ST AUC (uV/min)
12000
10822
10000
8000
6000
8914
8540
6956
6459
5549
5185
5651
4000
2000
0
0.05 mg
0.5 mg
1.25 mg
0.05 mg
0.5 mg
CK-MB AUC (ng/ml/min)
ST Recovery AUC
9000
6934
6000
4858
5226
6662
5740
4001
3000
0
5.0 mg
1.25 mg
8230
7352
0.05 mg
5.0 mg
0.5 mg
1.25 mg
Concurrent Placebo
Roe MT et al. Circulation 2008 117: 857-859
5.0 mg
Delcasertib in STEMI
Inhibition of δ-PROTEin kinase C for the reducTION of infarct
size in Acute Myocardial Infarction (PROTECTION AMI)
Study Hypothesis:
intravenous administration of delcasertib will reduce infarct
size in subjects with anterior ST elevation myocardial infarction
(STEMI) undergoing primary PCI.
 international, multi-center Phase 2b trial
 randomized, placebo-controlled, double-blind,
parallel group
 acute STEMI subjects undergoing primary PCI
Trial Design
Inclusion and Exclusion Criteria
 Acute STEMI with planned primary
PCI
 Cardiac ischemia for at least 30
minutes, arriving at PCI facility
within 6 hrs of symptom onset
 Persistent ST elevation of:
• ≥ 2 mm in at least two contiguous
precordial leads (V1-V4) (anterior
STEMI cohort)
• ≥ 2 mm in two inferior leads (II, III,
aVF) with ST depression in two
other contiguous leads - total ≥ 8
mm (inferior STEMI cohort)
x Prior CABG
x LBBB or paced rhythm
x Persistent SBP <90 mm Hg
unresponsive to IV fluids
x Vasopressors or inotropes
x ESRD on dialysis
x Severe hepatic dysfunction
x Fibrinolysis within prior 72 h
x Pregnancy or breastfeeding
x Suspicion of non-thrombotic
cause of ST elevation
Trial Design
Endpoints
Primary
•
CK-MB area under the curve (AUC)
Secondary
•
ECG – continuous 24 hr AUC and ST recovery
•
CK-MB Peak; Troponin I and CK AUC and Peak
•
Clinical Events – death, heart failure (HF), or serious ventricular
arrhythmia through 1 year
•
Serum NT-pro-B-type natriuretic peptide level at 3 months
•
LV Ejection Fraction (LVEF) by MUGA at 3 months – anterior
STEMI cohort only
Trial Design
STEMI to Undergo Planned Primary PCI
Anterior Cohort
~908 Patients (227 per group)
Randomize
Placebo
Inferior Cohort
~150 Pts (75 per group)
Randomize
1:1:1:1
Delcasertib Delcasertib Delcasertib
50 mg/hr
150 mg/hr
450 mg/hr
Placebo
1:1
Delcasertib
450 mg/hr
Study drug (~2.5 hr infusion) and continuous 12-lead ECG immediately after randomization
Cardiac catheterization and PCI per standard of care
Serial cardiac enzymes x 72 h
12-lead ECG monitoring x 24 h
Clinical Endpoints, NT-Pro BNP
and MUGA* at 3 months
Statistics
Sample Size Calculations

Primary analysis and sample size based upon anterior MI cohort
• Inferior MI cohort exploratory – sample not statistically based

Randomization stratified by region and Killip Class I vs II/III
Assumptions

CK-MB AUC in placebo group – mean 7156, SD 4666 ng-hr/mL

20% reduction in mean with delcasertib

a = 0.05 (2-sided); b = 0.80

Target 227 patients per Rx group – total 908 in anterior cohort
Academic Leadership
Steering Committee / National Coordinators
A. Michael Lincoff (PI)
Mitchell Krucoff (Co-PI)
Operations
Matthew Roe, USA
Committee
John Galla, USA
Phil Aylward, Australia
Andrezej Rynkiewcz, Poland
Victor Guetta, Israel
Micheal Zelizko, Czech Republic
Neal Kleiman, USA
Tamàs Forster, Hungary
Antonio Fernández-Ortiz, Spain
Harry Suryapranata, Netherlands
David Erlinge, Sweden
Svend Eggert Jensen, Denmark
Harvey White, New Zealand
Danny Schoors, Belgium
Peter Radke, Germany
Shamir Mehta, Canada
Shaun Goodman, Canada
Dan Atar, Norway
Michael Laine, Finland
Jorge Manuel dos Santos
Ferreira, Portugal
Guido Belli, Italy
Trial Organization
Cleveland Clinic Coordinating
Center for Clinical Research
Ellen McErlean, RN – Project Mnger
Trial Sponsors
Gregory Bell, MD - KAI
Fred Fiedorek, MD - BMS
Data Safety Monitoring Committee
CRO
Medpace, Inc
Cincinnati, OH
Michel Bertrand, MD - Chair
Christopher Cannon, MD
David Holmes, MD
Kerry Lee, PhD
Enrollment
Enrollment
Dec 4, 2008 June 21, 2010
18 Countries
114 Hospitals
1176
Patients
Randomize
d
Country
National Coordinator
Patients
Poland
Prof. Andrezej Rynkiewcz
226
Israel
Prof. Victor Guetta
222
Czech Republic
Dr. Micheal Zelizko
133
Australia
Prof. Phil Aylward
85
United States
Dr. Neal Kleiman
77
Netherlands
Dr. Harry Suryapranata
53
Hungary
Prof. Tamàs Forster
52
Spain
Dr. Antonio Fernández-Ortiz
50
Sweden
Prof. David Erlinge
49
Denmark
Dr. Svend Eggert Jensen
45
New Zealand
Dr. Harvey White
45
Belgium
Dr. Danny Schoors
39
Germany
Dr. Peter Radke
28
Canada
Drs. Shamir Mehta/Shaun Goodman
23
Norway
Dr. Dan Atar
22
Finland
Dr. Michael Laine
19
Portugal
Dr. Jorge Manuel dos Santos Ferreira 12
Italy
Dr. Guido Belli
1
Enrollment
Top 10 Enrolling Sites
Country
Poland
Poland
Czech Republic
Israel
Poland
Israel
Denmark
Israel
Israel
Israel
Australia
Principal Investigator
Dr. Jaroslaw Trebacz
Dr. Andrzej Rynkiewicz
Dr. David Horak
Dr. Arthur Pollak
Dr. Jaroslaw Wojcik
Dr. Jonathan Balkin
Dr. Svend Eggert Jensen
Prof. Morris Mosseri
Prof. Yoseph Rozenman
Prof. Hanoch Hod
Prof. Joseph Selvanayagam
# Randomized
63
54
48
37
36
34
28
26
25
25
25
Patient Flow
Anterior STEMI Cohort
Inferior STEMI Cohort
1010 patients
randomized
166 patients
randomized
997 patients
treated with
study drug
11 patients
not treated
2 patients
PCI only
Treated Population
159 patients
treated with
study drug
5 patients
not treated
2 patients
PCI only
Treated Population
86 patients
no PCI
4 patients
no PCI
911 patients
treated with
study drug and PCI
155 patients
treated with
study drug and PCI
Efficacy Population
Efficacy Population
Demographics and Treatment
Placebo
N = 249
Delcasertib Delcasertib Delcasertib
50 mg/hr
150 mg/hr
450 mg/hr
N = 254
N = 248
N = 246
61
[52, 70]
60
[53, 69]
61
[53, 70]
59
[52, 70]
79.5
78.3
81.0
79.3
27
[24, 30]
27
[24, 30]
27
[25, 30]
27
[25, 30]
Diabetes (%)
17.8
19.4
16.6
16.7
Prior MI (%)
11.7
11.1
10.9
11.0
Killip 2 or 3 (%)
8.8
8.7
8.5
8.9
Age (yrs - median, IQR)
Male (%)
BMI (kg/m2 - median, IQR)
Anterior MI Cohort, Treated Population
Treatment Times
Placebo
Time in minutes
Median and [IQR]
N = 249
Delcasertib Delcasertib Delcasertib
50 mg/hr
150 mg/hr
450 mg/hr
N = 254
N = 248
N = 246
Symptoms to hospital
presentation
120
[77, 188]
120
[63, 175]
115
[73, 185]
120
[77, 181]
Symptoms to study drug
initiation
173
[122, 255]
175
[130, 244]
171
[122, 245]
171
[122, 230]
Symptoms to PCI
193
[148, 272]
191
[143, 255]
190
[140, 275]
186
[143, 251]
17
[10, 25]
16
[9, 27]
17
[10, 29]
14
[9, 24]
Study drug initiation to
PCI
Anterior MI Cohort, Treated Population
1o Endpoint – Anterior MI
CK-MB Enzymes – Efficacy Population
8000
CK-MB AUC (ng-hr/ml)
Mean and SEM
p = 0.337
6000
500
CK-MB Peak (ng/ml)
Mean and SEM
p = 0.715
400
6471
5917
6204
369
5650
352
300
337
360
4000
200
2000
100
0
N=228
N=229
N=227
N=227
Placebo
Delcas
50
Delcas
150
Delcas
450
0
N=228
N=229
Placebo Delcas
50
N=227
N=227
Delcas
150
Delcas
450
ECG – Anterior MI
Continuous 24 hr ECG – Efficacy Population
10000
ECG ST Recovery AUC (microV-min)
Mean and SEM
p = 0.420
8000
8377
7707
7779
120
Time to Stable ST Recovery (min)
Mean and SEM
p = 0.523
100
8188
91
80
81
6000
75
70
60
4000
40
2000
0
20
Placebo
Delcas
50
Delcas
150
Delcas
450
0
Placebo
Delcas
50
Delcas
150
Delcas
450
Clinical Events – 3 Months
Placebo
Endpoint
(% of patients)
N = 249
Delcasertib Delcasertib Delcasertib
50 mg/hr
150 mg/hr
450 mg/hr
N = 254
N = 248
N = 246
Death, shock, CHF, or
arrhythmia
8.8
8.7
8.9
7.3
Death, shock, CHF
8.4
8.3
8.5
6.5
Death
3.2
3.9
4.0
2.4
Cardiogenic shock
3.6
2.4
3.2
0.8
CHF
4.4
3.9
2.8
4.5
Ventricular arrhythmia
1.2
0.8
0.4
1.6
Anterior MI Cohort, Treated Population
MUGA and NT-Pro BNP
3 Month Outcome
100
LV Ejection Fraction (%)
Mean and SD
80
8.6%
% of Pts with EF <30%
5.1%
7.3%
9.0%
60
140
N terminal Pro-BNP (pg/mL)
Mean and SEM
120
100
95.4
96.6
99.5
97.2
N=193
N=190
N=187
N=180
Placebo
Delcas
50
Delcas
150
Delcas
450
80
50.7
51.0
49.4
49.6
40
60
40
20
20
N=197
0
Placebo
N=189
Delcas
50
N=186
Delcas
150
N=186
Delcas
450
0
Anterior MI Cohort, Efficacy Population
Outcome by Pre-PCI TIMI Flow
% of Patients
Placebo
Delc 50
Delc 150
Delc 450
Pre-PCI TIMI 0 or 1
51.9
60.0
58.9
65.7
Pre-PCI TIMI 2 or 3
38.1
40.0
41.1
34.3
TIMI 0/1
10000
TIMI 2/3
CK-MB AUC (ng-hr/ml)
10000
CK-MB AUC (ng-hr/ml)
p = 0.145
p = 0.186
8000
8000
8013
7232
6000
6872
6879
6000
3606
3375
3591
Placebo
Delcas
50
Delcas
150
2000
2000
0
4743
4000
4000
Placebo
Delcas
50
Delcas
150
Delcas
450
0
Anterior MI Cohort
Delcas
450
Inferior MI Cohort
CK-MB AUC
6000
5000
CK-MB AUC (ng-hr/mL)
p = 0.845
5071
4944
ST Recovery AUC
ECG STR AUC (microV-min)
8000
p = 0.962
6000
6823
6858
NT-Pro BNP
100
NT-Pro BNP (pg/mL)
p = 0.248
80
4000
70.1
60
3000
4000
40
2000
2000
20
1000
0
Placebo
Delcas
450
0
42.7
Placebo
Delcas
450
0
Placebo
Delcas
450
Delcasertib in STEMI
PROTECTION AMI - Conclusions
Delcasertib, administered IV prior to and during primary PCI for
acute anterior STEMI, did not reduce myocardial infarct size or
improve clinical outcome.
No differences in biomarkers of:
 enzymatic infarct size
 ECG markers of reperfusion
 LV function by 3 months
 NT-Pro BNP
Other potential applications to IR injury yet to be investigated
Heart and Vascular Institute