Presentation on theme: "MitoCare – HEALTH-F2-2010-261034 MITOCARE STUDY Multicenter, randomized, double-blind, placebo controlled study to assess safety and efficacy of TRO40303."— Presentation transcript:
MitoCare – HEALTH-F2-2010-261034 MITOCARE STUDY Multicenter, randomized, double-blind, placebo controlled study to assess safety and efficacy of TRO40303 for reduction of reperfusion injury in STEMI patients undergoing primary PCI Dan Atar, MD, Professor of Cardiology Dept. of Cardiology B, Oslo University Hospital Ulleval, and Faculty of Medicine, University of Oslo, Norway.
Disclosures: ENTIRE TRIAL SPONSORED BY EU-FP7 GRANT Dan Atar, MD, Professor of Cardiology Dept. of Cardiology B, Oslo University Hospital Ulleval, and Faculty of Medicine, University of Oslo, Norway.
MitoCare – HEALTH-F2-2010-261034 MITOCARE STUDY Multicenter, randomized, double-blind, placebo controlled study to assess safety and efficacy of TRO40303 for reduction of reperfusion injury in STEMI patients undergoing primary PCI Rationale: TRO40303 has been shown to reduce infarct size by 50% in rat and mouse models, and to improve LVEF at 24h and 1 month in these models. It has also shown protective effects on human isolated cells. Mechanism: The mitochondrial permeability transition pore is believed to be a promising target for preventing reperfusion injury.TRO40303 has shown to inhibit the opening of this transition pore. Scope and Enrolment Period of the Study: October 2011-September 2013 10 interventional sites in Denmark, France, Norway, Sweden.
MitoCare – HEALTH-F2-2010-261034 Study Design V1 / D30 Follow-up Echocardiography Safety Assessment V0 Inclusion and PCI TRO40303 Dose 6 mg /kg, N = 90 Placebo, N = 90 D3-D5 (72h) D2 (48h) D1 (24h) Cardiac Magnetic Resonance Echocardiography Troponin I, CK: at T0 (baseline), 6h, 12h, 18h, 24h, 36h, 48h and 72h after stenting Hospitalization Drug/placebo given as IV bolus by large peripheral vein, during PCI, just before balloon inflation. at 720h after stenting
MitoCare – HEALTH-F2-2010-261034 Key Inclusion / Exclusion Criteria Age >18 years old First time STEMI Presenting within 6h of onset of chest pain Clinical decision to treat with PCI Occlusion / TIMI flow 0-1 in culprit artery before PCI --------------------------------------------------------------------------- Cardiac arrest, ventricular fibrillation, cardiogenic shock, stent thrombosis, previous AMI, angina within 48h before infarction, previous CABG Atrial fibrillation Pacemaker
MitoCare – HEALTH-F2-2010-261034 Study Flow-Chart ITT Population N=163 Safety Population N=165 168 patients entered in the eCRF 1 patient did not meet the inclusion criteria 167 patients randomized 81 assigned to Placebo86 assigned to TRO40303 1 patient did not meet the inclusion criteria 85 received TRO4030380 received Placebo 80 underwent PCI83 underwent PCI 1 patient had a CABG instead of PCI 1 patient had a dissection of coronary artery 1 Adverse Event 5 Lost to follow up 3 Consent withdrawn 1 Death 2 Adverse Event 6 Lost to follow up 0 Consent withdrawn 3 Deaths 80 included in the Safety analysis 80 included in the Intent to treat analysis 72 included in the Per Protocol analysis 85 included in the Safety analysis 83 included in the Intent to treat analysis 70 included in the Per Protocol analysis
Baseline Characteristics Placebo, n = 80 TRO40303, n = 83 Age60.0 (37-84)63.8 (40-86) Men/Women63/1773/10 BMI, kg/m 2 26.7 (20-39) (n=74)27.5 (20-45) (n=77) Hypertension25 (31.3%)24 (28.9%) Dyslipidemia17 (21.3%)9 (10.8%) Diabetes Mellitus7 (8.8%)5 (6.0%) (Median (min-max), N patients or % per group) Baseline characteristics were well-balanced between the two groups except for age which was higher in the TRO40303 group Procedural Characteristics Pain-to-balloon time: 180 min (mean) Door-to-balloon time: 38 min (mean) Anterior/Posterior Infarction: 33/47 31/51
Procedural Characteristics MitoCare – HEALTH-F2-2010-261034 (Median (min-max), N patients or % per group) Procedural characteristics were well-balanced between the two groups except for unsuccessful reperfusion
Study Results: Co-primary Endpoint MitoCare – HEALTH-F2-2010-261034 Mean +/- SEM. Analysis of AUC by ANCOVA. N = 163
MitoCare – HEALTH-F2-2010-261034 MRI Endpoints PlaceboTRO40303N/gpP (*) Main MRI endpoint: Myocardial salvage index (MSI) 0.58 (0.2-0.9)0.52 (0.2-0.8)43/500.1000 Infarct Size/Left Ventricle0.15 (0.0-0.4)0.17 (0.1-0.4)43/500.1034 Infarct Size (gr)20.01 (1.8-82.9)21.88 (3.1-62.1)43/500.1650 Microvascular Obstruction0.02 (0.0-0.1)0.02 (0.0-0.2)43/500.8512 LV End Diastolic Volume (ml)178.22 (73.7-274.6)177.02 (73.7-288.7)54/570.9966 LV End Systolic Volume (ml)93.1 (37.4-186.8)96.25 (31.9-185.1)54/570.6485 LV Ejection Fraction0.48 (0.2-0.6)0.46 (0.3-0.6)54/570.1526 Mixed model of ANCOVA
Additional Secondary Endpoint: Echocardiography at D30 Data presented as mean +/- SEM Number patients analysed = 105 for LVEDV; 104 for LVESD; 139 for LVEF Placebo TRO40303 ANCOVA (Time to PCI and culprit artery in the model, center as random effect) P value LV end Diastolic Volume (ml)0.8789 LV end Systolic Volume (ml)0.8048 LV end Ejection Fraction (%)0.2784 MitoCare – HEALTH-F2-2010-261034
Safety Number of eventsPlaceboTRO40303 Total number of events1126 Cardiogenic shock24 Death13 Heart Failure13 Myocardial Infarction01 Revascularization29 Ventricular Arrhythmia56 PlaceboTRO40303 Number of patients with at least one event 8 (10%)21 (24.7%) Fischer exact Test: P=0.013 No difference in AE’s in both study arms CEC adjudicated SAE’s:
MITOCARE - Conclusions MitoCare – HEALTH-F2-2010-261034 The MITOCARE trial did not show any protective effect of TRO40303 compared to placebo in preventing reperfusion injury in STEMI patients treated with primary PCI A high standard of care accounted for the relatively small infarct size after primary PCI, leaving little room for improvement There were more adjudicated events in the TRO40303-group than in the placebo-group This could partly be explained by the difference in unsuccessful reperfusion between the groups (12.1% in the TRO40303-group versus 6.3% in the placebo-group) These results combined with the many failures in the field raise a provocative issue: whether reperfusion injury occurs at all in man, and, if it does, whether this type of injury really accounts for a significant part of the remaining infarct