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-F 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-F 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 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-F 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-F Study Flow-Chart ITT Population N=163 Safety Population N= patients entered in the eCRF 1 patient did not meet the inclusion criteria 167 patients randomized 81 assigned to Placebo86 assigned to TRO patient did not meet the inclusion criteria 85 received TRO 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 (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-F (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-F Mean +/- SEM. Analysis of AUC by ANCOVA. N = 163
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) LV end Systolic Volume (ml) LV end Ejection Fraction (%) MitoCare – HEALTH-F
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-F 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
MITOCARE Clinical Sites Aalborg, DK: Svend Eggert Jensen, Jan Ravkilde, Hans-Henrik Tilsted, Bent Raungaard, Jens Aaroe, Anna-Marie Bloch Münster, Ernest-Torben Wilhem Fründ, Carsten Wiberg Simonsen, Charlotte Schmidt Skov, Kasper Villefrance. Bergen, NO: Jan-Erik Nordrehaug, Erlend Eriksen, Vegard Tuseth, Erik JS Packer, Liv Himle, Marion Birkeland Hammer, Terje H Larsen. Créteil, FR: Jean-Luc Dubois-Randé, Emmanuel Teiger, Philippe Le Corvoisier, Romain Gallet, Stephane Champagne, Pierre-François Lesault, Barnabas Gellen, Gauthier Mouillet, Dionyssis Pongas, Dalila Bitari, Marianne Lescouzeres, Bourhis Marie-Laure, Jean-François Deux. Oslo, NO: Sigrun Halvorsen, Trygve Sørdahl Hall, Margido Husvik, Maren Tandsaether, Tone Pedersen, Anette Vold, Pavel Hoffmann. Lund, SE: David Erlinge, Matthias Götberg, Sasha Koul, Fredrik Scherstén, Jesper van der Pals, Jan Harnek, Gustav Smith, Jasminka Holmqvist, Patrik Gilje, Stefan Jovinge, Mariam B Choudhary, Marcus Carlsson, Ewa Mattsson, Anna Duckert, Gunilla Brolin. Paris, FR: Nicolas Danchin, Etienne Puymirat, Eric Durand, Salvatore Battaglia, Christian Spaulding, Jean-Yves Pagny, Rahal Saliha, Sylvie Marinier, Mousseaux Elie, Nadège Goudet. Stavanger, NO: Alf Inge Larsen, Jorunn Nilsen, Stein Ørn, G. Greve. Marseille, FR: Jean-Louis Bonnet, Marc Lambert, Jacques Quilici, Thomas Cuissier, Pierre-Julien Moro, Fiacchetti Claudine, Alexis Jacquier, Monique Bernard, Frank Kober. Odense, DK: Henrik Steen Hansen, Mikkel Hougaard, Helle Cappelen, Jens Karstoft. Marseille, FR: Franck Paganelli, Olfa Helal, Isabelle Bouvin. Sponsor Chief Medical Officer: Jean-louis Abitbol, Pascal Longlade, Wilfried Hauke, Trophos, Marseille, FR International Study Coordinator: Carole Perez, Séverine Pitel, Valérie Cuvier, Trophos, Marseille, FR Data Monitoring Committee: Lars Køber, Tabassome Simon, Alain Leizorovicz. Safety and Ethics Monitoring Committee :Emmanuelle Rial-Sebbag, Thomas Roche. Clinical Events Committee: Claes Held, Christopher Varenhorst, Ziad Hijazi Statistics and data management: Eric Vicaut, Hélène Rousseau, Hôpital Fernand Widal, Paris, FR Central Biomarker Laboratory and Bio-bank: Huseyin Firat, Firalis, Huningue, FR Central ECG reading: Peter Clemmensen, Rigshospitalet, Copenhagen, DK Central MRI reading: Håkan Arheden, Henrik Engstrøm, Magnus Carlsson, Einar Heiberg, IMACOR AB, Lund, SE eCRF: Gilles Sonou, Mobile Health, Paris, FR Additional Contributors / Core Labs / DMSB Thanks to: