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 PCI
Dan Atar, MD, Professor of Cardiology Dept. of Cardiology B, Oslo University Hospital Ulleval, and Faculty of Medicine, University of Oslo, Norway.
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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.
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4. Cardiac Magnetic Resonance Echocardiography
Study Design
V1 / D30
Follow-up
Echocardiography
Safety Assessment V0
Inclusion and PCI
TRO 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
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5. 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
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6. Study Flow-Chart Safety Population N=165 ITT Population N=163
168 patients entered in the eCRF
1 patient did not meet the inclusion criteria
167 patients randomized
81 assigned to Placebo
86 assigned to TRO40303
85 received TRO40303
80 received Placebo
80 underwent PCI
83 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
Safety Population N=165
ITT Population N=163
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7. Baseline Characteristics
(Median (min-max), N patients or % per group)
Placebo,
n = 80
TRO40303,
n = 83
Age
60.0 (37-84)
63.8 (40-86)
Men/Women
63/17
73/10
BMI, kg/m2
26.7 (20-39) (n=74)
27.5 (20-45) (n=77)
Hypertension
25 (31.3%)
24 (28.9%)
Dyslipidemia
17 (21.3%)
9 (10.8%)
Diabetes Mellitus
7 (8.8%)
5 (6.0%)
Anterior/Posterior Infarction: / /51
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)

8. Procedural Characteristics
(Median (min-max), N patients or % per group)
Procedural characteristics were well-balanced between the two groups except for unsuccessful reperfusion
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9. Study Results: Co-primary Endpoint
Mean +/- SEM. Analysis of AUC by ANCOVA. N = 163
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10. MRI Endpoints Placebo TRO40303 N/gp P (*)
Main MRI endpoint: Myocardial salvage index (MSI)
0.58 ( )
0.52 ( )
43/50
0.1000
Infarct Size/Left Ventricle
0.15 ( )
0.17 ( )
0.1034
Infarct Size (gr)
20.01 ( )
21.88 ( )
0.1650
Microvascular Obstruction
0.02 ( )
0.02 ( )
0.8512
LV End Diastolic Volume (ml)
( )
( )
54/57
0.9966
LV End Systolic Volume (ml)
93.1 ( )
96.25 ( )
0.6485
LV Ejection Fraction
0.48 ( )
0.46 ( )
0.1526
Mixed model of ANCOVA
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11. MRI Endpoints

12. Additional Secondary Endpoint: Echocardiography at D30
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
Data presented as mean +/- SEM
Number patients analysed = 105 for LVEDV; 104 for LVESD; 139 for LVEF
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13. Safety No difference in AE’s in both study arms CEC adjudicated SAE’s:
Number of events
Placebo
TRO40303
Total number of events 11 26
Cardiogenic shock 2 4
Death 1 3
Heart Failure
Myocardial Infarction
Revascularization 9
Ventricular Arrhythmia 5 6
Placebo
TRO40303
Number of patients with at least one event
8 (10%)
21 (24.7%)
Fischer exact Test: P=0.013
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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 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
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16. MITOCARE Clinical Sites
Thanks to:
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.
Additional Contributors / Core Labs / DMSB
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

17. Thank you for your attention17