Presentation on theme: "MITOCARE STUDY Multicenter, randomized, double-blind, placebo controlled study to assess safety and efficacy of TRO40303 for reduction of reperfusion."— Presentation transcript:
1 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 PCIDan Atar, MD, Professor of Cardiology Dept. of Cardiology B, Oslo University Hospital Ulleval, and Faculty of Medicine, University of Oslo, Norway.MitoCare – HEALTH-F
2 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.
3 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 interventional sites in Denmark, France, Norway, Sweden.MitoCare – HEALTH-F
4 Cardiac Magnetic Resonance Echocardiography Study DesignV1 / D30Follow-upEchocardiographySafety AssessmentV0Inclusion and PCITRO Dose 6 mg /kg, N = 90Placebo, N = 90D3-D5(72h)D2(48h)D1(24h)Cardiac Magnetic Resonance EchocardiographyTroponin I, CK:at T0 (baseline) , 6h, 12h, 18h, 24h, 36h, 48h and 72h after stentingHospitalizationDrug/placebo given as IV bolus by large peripheral vein, during PCI, just before balloon inflation.at 720h after stentingMitoCare – HEALTH-F
5 Key Inclusion / Exclusion Criteria Age >18 years oldFirst time STEMIPresenting within 6h of onset of chest painClinical decision to treat with PCIOcclusion / TIMI flow 0-1 in culprit artery before PCICardiac arrest, ventricular fibrillation, cardiogenic shock,stent thrombosis, previous AMI, angina within 48h before infarction, previous CABGAtrial fibrillationPacemakerMitoCare – HEALTH-F
6 Study Flow-Chart Safety Population N=165 ITT Population N=163 168 patients entered in the eCRF1 patient did not meet the inclusion criteria167 patients randomized81 assigned to Placebo86 assigned to TRO4030385 received TRO4030380 received Placebo80 underwent PCI83 underwent PCI1 patient had a CABG instead of PCI1 patient had a dissection of coronary artery1 Adverse Event5 Lost to follow up3 Consent withdrawn1 Death2 Adverse Event6 Lost to follow up0 Consent withdrawn3 Deaths80 included in the Safety analysis80 included in the Intent to treat analysis72 included in the Per Protocol analysis85 included in the Safety analysis83 included in the Intent to treat analysis70 included in the Per Protocol analysisSafety Population N=165ITT Population N=163MitoCare – HEALTH-F
7 Baseline Characteristics (Median (min-max), N patients or % per group)Placebo,n = 80TRO40303,n = 83Age60.0 (37-84)63.8 (40-86)Men/Women63/1773/10BMI, kg/m226.7 (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%)Anterior/Posterior Infarction: / /51Baseline characteristics were well-balanced between the two groups except for age which was higher in the TRO40303 groupProcedural CharacteristicsPain-to-balloon time: 180 min (mean)Door-to-balloon time: 38 min (mean)
8 Procedural Characteristics (Median (min-max), N patients or % per group)Procedural characteristics were well-balanced between the two groups except for unsuccessful reperfusionMitoCare – HEALTH-F
9 Study Results: Co-primary Endpoint Mean +/- SEM. Analysis of AUC by ANCOVA. N = 163MitoCare – HEALTH-F
10 MRI Endpoints Placebo TRO40303 N/gp P (*) Main MRI endpoint: Myocardial salvage index (MSI)0.58 ( )0.52 ( )43/500.1000Infarct Size/Left Ventricle0.15 ( )0.17 ( )0.1034Infarct Size (gr)20.01 ( )21.88 ( )0.1650Microvascular Obstruction0.02 ( )0.02 ( )0.8512LV End Diastolic Volume (ml)( )( )54/570.9966LV End Systolic Volume (ml)93.1 ( )96.25 ( )0.6485LV Ejection Fraction0.48 ( )0.46 ( )0.1526Mixed model of ANCOVAMitoCare – HEALTH-F
12 Additional Secondary Endpoint: Echocardiography at D30 PlaceboTRO40303 ANCOVA (Time to PCI and culprit artery in the model, center as random effect)P valueLV end Diastolic Volume (ml)0.8789LV end Systolic Volume (ml)0.8048LV end Ejection Fraction (%)0.2784Data presented as mean +/- SEMNumber patients analysed = 105 for LVEDV; 104 for LVESD; 139 for LVEFMitoCare – HEALTH-F
13 Safety No difference in AE’s in both study arms CEC adjudicated SAE’s: Number of eventsPlaceboTRO40303Total number of events1126Cardiogenic shock24Death13Heart FailureMyocardial InfarctionRevascularization9Ventricular Arrhythmia56PlaceboTRO40303Number of patients with at least one event8 (10%)21 (24.7%)Fischer exact Test: P=0.013MitoCare – HEALTH-F
14 MITOCARE - Conclusions The MITOCARE trial did not show any protective effect of TRO compared to placebo in preventing reperfusion injury in STEMI patients treated with primary PCIA high standard of care accounted for the relatively small infarct size after primary PCI, leaving little room for improvementThere were more adjudicated events in the TRO40303-group than in the placebo-groupThis 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 infarctMitoCare – HEALTH-F
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