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F.I.R.E. study A Multicenter, Double ‑ blind, Randomized, Placebo ‑ Controlled Study to Measure the Effect of FX06 (a fibrin ‑ derived peptide Bβ15 ‑

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Presentation on theme: "F.I.R.E. study A Multicenter, Double ‑ blind, Randomized, Placebo ‑ Controlled Study to Measure the Effect of FX06 (a fibrin ‑ derived peptide Bβ15 ‑"— Presentation transcript:


2 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

3 Conflicts-of-Interest DA received honoraria from Fibrex Medical Research & Development GmbH Fibrex Medical Research & Development GmbH provided full financial support for this study

4 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

5 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

6 Study design

7 FIRE Patients Inclusion Criteria First MI Primary PCI indicated per standard of care Single index lesion with complete occlusion (TIMI flow 0/I) of one target vessel Onset of symptoms to balloon time < 6 hrs ST elevation of at least 2 mm in at least 3 leads on 12-lead ECG Exclusion Criteria Chest pain or other angina symptoms in the 24 hours before the first recognized symptoms of the AMI Administration of any thrombolytic agent since onset of AMI symptoms Presence of cardiogenic shock: hemodynamically unstable and/or need for positive inotropic agents Contraindication to MRI Known renal dysfunction Previous CABG History of CHF BMI > 35

8 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

9 Follow-up 4 months 400 mg FX06 i.v. (n = 114) Placebo (n = 120) Treatment Visit 3 STEMI at - 6 to 0 hrs = randomisation R Study flowchart R 0 min FX06 10 min FX06 1.5h CKMB 24h Troponin Primary PCI 48h Troponin 5-7d CMR 2m MACE 4m MACE/CMR Visit 1 2 day in house follow up Visit 2

10 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 re- hospitalization for any cardiac cause

11 MVO zone necrotic core zone total LGE zone normal myocardium LV lumen Acute Myocardial Infarction Imaged with LGE CMR

12 F.I.R.E. Baseline Characteristics

13 Baseline characteristics FX06Placebop-value GenderFemale N 31240.2189 (%) (27.2%)(20.0%) Male N 8396 (%) (72.8%)(80.0%) AgeMean 60.0359.790.7668 (SD) (11.38)(11.37) BMIMean 27.4627.360.7769 (SD) (4.22)(3.75) Diabetes mellitus N 1412 % (12.3%)(10.0%)

14 Concomitant Medication FX06Placebo N%N% Beta blocking agents 114100%11898.3% Renin-angiotensin acting agents 10390.4%11394.2% GP IIb/IIIa Inhibitors 6153.5%6655% – Abciximab – Eptifbatide – Tirofiban Hydrochloride 32 14 15 28.1% 12.3% 13.2% 32 14 21 26.7% 11.7% 17.5% Anti-platelet agents 114100%11999.2% – ASA – Clopidogrel – Ticlopidine 106 114 1 93% 100% 0.9% 112 119 3 93.3% 99.2% 2.5%

15 Procedural baseline data FX06PlaceboP-value N%N% Location of infarct Anterior Non-anterior 50 59 45.5% 53.6% 55 61 47% 52.1% 0.8938 TIMI flow before PCI 0I0I 90 19 81.8% 17.3% 103 14 88% 12% 0.2635 Collaterals No collaterals 26 82 23.6% 74.5% 20 95 17.1% 81.2% 0.2482 Pain-to-balloon< 3 hours > 3 hours 53 55 48.2% 50% 55 60 47% 51.3% 0.8937

16 Results: Infarct size and Clinical Events

17 Median with 25- and 75-percentile 5 days post PCI: No difference in total late enhancement zone Necrotic core significantly reduced (ITT Population) * statistically significant # Wilcoxon rank sum test 1.77 (0; 9.09) 4.2 (0.30;9.93) 21.68 (8.33;47.09) 27.34 (11.74;44.89) Incidence of microvascular obstruction (MVO): 27.6% versus 37.5% (not statistically significant)

18 Median with 25- and 75-percentile 4 mths post PCI: No difference in Total late enhancement zone Scar mass (ITT population) # Wilcoxon rank sum test 15.37 (5.70;36.43) 2.84 (0.35; 7.26) 1.79 (0;8.78) 19.32 (7.51;31.37) LVEF 4 months post-PCI well preserved in all pats: successful recanalisation. LV ejection fractionFX06Placebo LVEF at 5 days: 46.7 %46.6 % LVEF at 4 months: 49.1%48.9 %

19 24 h 48 h 90 min No significant reduction in biochemical markers of cardiac necrosis

20 Clinical outcome parameters FX06 N Placebo N Cardiac death 25 Serious adverse cardiac related events - day 30 1525 Serious adverse cardiac related events - overall 2129 Composite of cardiac death and new onset heart failure/pulmonary edema 510

21 Results – Safety

22 Safety (all randomized patients, n=234) No difference in SAEs and AEs compared to placebo No safety signals on arrhythmogenic potential thrombogenic potential hypotension FX06 (N=114) Placebo (N=120) N%N% All cause mortality 32.6%54.2%

23 FX06Placebo Cardiac death 25 Heart failure (non fatal)/Pulmonary oedema 35 VT / VF/ life-threatening Arrhythmia 57 Aute Coronary Syndromes 34 Acute stent thrombosis 22 Atrioventricular block IIIrd degree 22 Revascularization 22 Intraventricular thrombus 11 Hypotension 33 Non cardiac major vascular events 1 1 TOTAL21 29 (acute peripheral ischemia) (stroke) Cardiovascular SAEs (all randomized patients, n=234)

24 p=0.51 log rank p=0.44 log rank Time to cardiac death or onset of heart failure Kaplan Meier plots Overall survival

25 Conclusion: FX06 results in the following effects vs. placebo….. Imaging endpoints and biomarkers: 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 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 Clinical endpoints: 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 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

26 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

27 Publication Results of the FIRE-trial: Accepted for publication upon minor revision

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