Transcript Document 7613542

F.I.R.E. study
A Multicenter, Double-blind, Randomized,
Placebo-Controlled Study to Measure the Effect
of FX06 (a fibrin-derived peptide Bβ15-42) on
Ischemia-REperfusion Injury in Patients
Undergoing Primary Percutaneous Coronary
Intervention
Dan Atar MD
Professor and Head of Cardiology
Aker University Hospital,
University of Oslo, Norway
Conflicts-of-Interest
DA received honoraria from Fibrex Medical Research &
Development GmbH
Fibrex Medical Research & Development GmbH provided full
financial support for this study
Background
Early reperfusion by PCI or thrombolysis is the treatment of
choice for STEMI
Sudden re-initiation of blood flow achieved with PCI can lead to
further endothelial and myocardial damage, termed reperfusion
injury
Complex underlying cellular and molecular mechanism
Numerous pharmacologic strategies have been evaluated for
mitigating reperfusion injury, but few have been successful in
randomized controlled trials
F.I.R.E. – a Phase II trial of FX06 in STEMI
FX06: A Novel Compound
• Small peptide derived from the human fibrin sequence
• Human fibrinopeptide Bß15-42, MW 3039 D
• Prepared by solid phase peptide synthesis
Mode of action
• FX06: peptide that potently inhibits the binding of fibrin E1 fragment to
vascular endothelial (VE) cadherin
• Preserves endothelial barrier function, prevents capillary leak
• Inhibits transmigration of inflammatory cells through endothelium
• Exhibits anti-inflammatory effect
F.I.R.E. - Rationale
• To investigate the cardioprotective efficacy of FX06 as an adjunct to
reperfusion therapy in patients with acute ST elevation myocardial
infarction (STEMI)
• To assess safety and tolerability
Study design
FIRE Patients
Inclusion Criteria
Exclusion Criteria
• First MI
• Chest pain or other angina symptoms
in the 24 hours before the first
• Primary PCI indicated per standard of
recognized symptoms of the AMI
care
• Single index lesion with complete
occlusion (TIMI flow 0/I) of one target
vessel
• Administration of any thrombolytic
agent since onset of AMI symptoms
• Presence of cardiogenic shock:
hemodynamically unstable and/or
need for positive inotropic agents
• Onset of symptoms to balloon time
< 6 hrs
• ST elevation of at least 2 mm in at
least 3 leads on 12-lead ECG
•
•
•
•
•
Contraindication to MRI
Known renal dysfunction
Previous CABG
History of CHF
BMI > 35
F.I.R.E. across Europe
Design
• Exploratory „Proof-of-Concept“ trial
• Double-blind, placebo-controlled
multicenter study
Therapeutic target
• Cardioprotective efficacy
in AMI
• Safety and tolerability
Dose
• 400 mg FX06 i.v. vs. Placebo
Patients
• 234 STEMI patients randomized
Study flowchart
400 mg FX06 i.v.
(n = 114)
R
Primary PCI
STEMI at - 6 to 0 hrs
Follow-up 4 months
Visit 1
Visit 2
Visit 3
Placebo
(n = 120)
2 day in house follow up
R
= randomisation
Outcome Measures
FIRE Primary Outcome Measure
• Infarct size measured by C-MRI at 5 days
FIRE Secondary Outcome Measures
• Final infarct size/myocardial scar at 4 months
• LV function at 5 days and 4 months
• Troponin I
• Time to ST segment elevation resolution
• Combined major adverse cardiac event (MACE): cardiovascular death,
myocardial infarction or symptom-driven revascularization plus new
symptomatic heart failure (NYHA or Killip Class II or greater) plus rehospitalization for any cardiac cause
Acute Myocardial Infarction Imaged with LGE CMR
MVO zone
LV lumen
necrotic core zone
total LGE zone
normal myocardium
F.I.R.E. Baseline Characteristics
Baseline characteristics
Gender
Age
BMI
Diabetes
mellitus
FX06
Placebo
p-value
Female N
31
24
0.2189
(%)
(27.2%)
(20.0%)
Male N
83
96
(%)
(72.8%)
(80.0%)
Mean
60.03
59.79
(SD)
(11.38)
(11.37)
Mean
27.46
27.36
(SD)
(4.22)
(3.75)
N
14
12
%
(12.3%)
(10.0%)
0.7668
0.7769
Concomitant Medication
FX06
Placebo
N
%
N
%
Beta blocking agents
114
100%
118
98.3%
Renin-angiotensin acting
agents
103
90.4%
113
94.2%
GP IIb/IIIa Inhibitors
61
53.5%
66
55%
– Abciximab
– Eptifbatide
– Tirofiban Hydrochloride
32
28.1%
32
26.7%
14
12.3%
14
11.7%
15
13.2%
21
17.5%
Anti-platelet agents
114
100%
119
99.2%
– ASA
– Clopidogrel
– Ticlopidine
106
93%
112
93.3%
114
100%
119
99.2%
1
0.9%
3
2.5%
Procedural baseline data
FX06
Placebo
N
%
N
%
Location of
infarct
Anterior
50
45.5%
55
47%
Non-anterior
59
53.6%
61
52.1%
TIMI flow
before PCI
0
90
81.8%
103
88%
I
19
17.3%
14
12%
Collaterals
Collaterals
26
23.6%
20
17.1%
No collaterals
82
74.5%
95
81.2%
Pain-to-balloon < 3 hours
53
48.2%
55
47%
> 3 hours
55
50%
60
51.3%
P-value
0.8938
0.2635
0.2482
0.8937
Results:
Infarct size
and
Clinical Events
5 days post PCI: No difference in total late
enhancement zone
Necrotic core significantly reduced (ITT Population)
Median with 25- and 75-percentile
4.2 (0.30;9.93)
27.34
(11.74;44.89)
21.68
(8.33;47.09)
1.77
(0; 9.09)
* statistically significant
# Wilcoxon rank sum test
• Incidence of microvascular obstruction (MVO): 27.6% versus 37.5%
(not statistically significant)
4 mths post PCI: No difference in
• Total late enhancement zone
• Scar mass (ITT population)
Median with 25- and 75-percentile
2.84
(0.35; 7.26)
15.37
(5.70;36.43)
19.32
(7.51;31.37)
1.79
(0;8.78)
# Wilcoxon rank sum test
LV ejection fraction
FX06
Placebo
LVEF at 5 days:
46.7 %
46.6 %
LVEF at 4 months:
49.1%
48.9 %
LVEF 4 months post-PCI well preserved in all pats: successful recanalisation.
No significant reduction in biochemical markers of cardiac
necrosis
24 h
48 h
90 min
Clinical outcome parameters
FX06
N
Placebo
N
Cardiac death
2
5
Serious adverse cardiac related events day 30
15
25
Serious adverse cardiac related events overall
21
29
Composite of cardiac death and new
onset heart failure/pulmonary edema
5
10
Results – Safety
Safety (all randomized patients, n=234)
All cause mortality
FX06
(N=114)
Placebo
(N=120)
N
%
N
%
3
2.6%
5
4.2%
No difference in SAEs and AEs compared to placebo
No safety signals on
• arrhythmogenic potential
• thrombogenic potential
• hypotension
Cardiovascular SAEs (all randomized patients, n=234)
Cardiac death
Heart failure (non fatal)/Pulmonary oedema
VT / VF/ life-threatening Arrhythmia
Aute Coronary Syndromes
Acute stent thrombosis
Atrioventricular block IIIrd degree
Revascularization
Intraventricular thrombus
Hypotension
Non cardiac major vascular events
FX06
Placebo
2
5
3
5
5
7
3
4
2
2
2
2
2
2
1
1
3
3
1
1
(acute peripheral
ischemia)
TOTAL
21
(stroke)
29
Kaplan Meier plots
Overall survival
p=0.51
log rank
p=0.44
log rank
Time to cardiac death or onset of
heart failure
Conclusion:
FX06 results in the following effects vs. placebo…..
Imaging endpoints and biomarkers:
Clinical endpoints:
• Primary endpoint: Change in LGE zone not
statistically significant
• Necrotic core infarct zone at 5 days
significantly reduced (-58%, p<0.025)
• Incidence of microvascular obstruction
(27.6% versus 37.5%) not significantly
different
• Incidence of cardiac death: 2 vs. 5
• Major cardiovascular adverse
events: 21 vs. 29
• Combined incidence of cardiac
death and new onset CHF: 5 vs. 10
• Scar mass 4 mths post PCI not significantly
different
• LV-EF not significantly changed at 4 mths
• No significant change in CK-MB at 90 min
(-16%) and Troponin I at 24 (-10%) and 48
hrs (-17%) post PCI
• This study may suggest a cardioprotective role of FX06 as an adjunct treatment to PCI
• Effect of FX06 on necrotic infarct zone most likely achieved by amelioration of reperfusion
injury
• These findings from explorative study may encourage scrutinization in a larger trial
The FIRE team
• FIRE Steering Committee:
Dan Atar (Oslo, NO), Kurt Huber (Vienna, AU), Jürg Schwitter ( Zurich, CH), Bernard
Geudelin (Vienna, AU)
• CMR CORE LABORATORY
Peter Buser, University Hospital Basel, Switzerland
• ECG CORE LABORATORY
Peter Clemmensen, Rigshospitalet University of Copenhagen, Denmark
• Data Safety Monitoring Board (DSMB):
Frans Van de Werf, University Hospital Gasthuisberg, Leuven (Belgium), chairman of
DSMB, Lars Wallentin, University Hospital, Uppsala (Sweden), and Günter
Breithardt, Universitätsklinikum Münster (Germany)
• Investigators:
Netherlands – Rensing B, Slagboom T, Van der Ent M; Czech Republic - Stasek J;
Poland – Kasprzak JD, Tracz W ;Germany – Butter C, Süselbeck T, Wessely R,
Kurz T, Lepper W, Darius H, Kastrati A, Morguet A, Buerke M, Thiele H, Muth G,
Bode C ; Sweden – Grip L, Swahn E ; Denmark – Hansen PR ; Belgium – Beauloye
C, Schoors D ; Austria – Huber K, Glogar D ; Lithuania – Laucevicius A
• Statistician
Marcos Marin-Galiano, IFE-Europe, Essen, GE (CRO)
Sponsor: Fibrex Medical Research & Development GmbH
Rainer Henning, Katherine Brandl, Nora Breit
Publication
Results of the FIRE-trial:
Accepted for publication upon minor revision