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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.

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Disclosures: ENTIRE TRIAL SPONSORED BY EU-FP7 GRANT

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Disclosures entire trial sponsored by eu fp7 grant

MITOCARE STUDYMulticenter, 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, andFaculty of Medicine, University of Oslo, Norway.

MitoCare – HEALTH-F2-2010-261034


Disclosures entire trial sponsored by eu fp7 grant

Disclosures:ENTIRE TRIAL SPONSORED BY EU-FP7 GRANT

Dan Atar, MD, Professor of Cardiology Dept. of Cardiology B, Oslo University Hospital Ulleval, andFaculty of Medicine, University of Oslo, Norway.


Disclosures entire trial sponsored by eu fp7 grant

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 201310 interventional sites in Denmark, France, Norway, Sweden.

MitoCare – HEALTH-F2-2010-261034


Study design

Study Design

TRO40303 Dose 6 mg /kg, N = 90

Drug/placebo given as IV bolus by large peripheral vein, during PCI, just before balloon inflation.

Placebo, N = 90

Hospitalization

V1 / D30

Follow-up

V0

Inclusion and PCI

D1

(24h)

D2

(48h)

D3-D5

(72h)

Echocardiography

Safety Assessment

Troponin I, CK:

at T0 (baseline) , 6h, 12h, 18h, 24h, 36h, 48h and 72h after stenting

Cardiac Magnetic Resonance Echocardiography

at 720h after stenting

MitoCare – HEALTH-F2-2010-261034


Key inclusion exclusion c riteria

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

Study Flow-Chart

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

1 patient did not meet the inclusion criteria

1 patient did not meet the inclusion criteria

80 received Placebo

85 received TRO40303

1 patient had a CABG instead of PCI

1 patient had a dissection of coronary artery

80 underwent PCI

83 underwent PCI

Safety Population N=165

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

ITT Population N=163

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

MitoCare – HEALTH-F2-2010-261034


Baseline characteristics

Baseline Characteristics

(Median (min-max), N patients or % per group)

Anterior/Posterior Infarction: 33/47 31/51

  • 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)


Disclosures entire trial sponsored by eu fp7 grant

Procedural Characteristics

Procedural characteristics were well-balanced between the two groups except for unsuccessful reperfusion

(Median (min-max), N patients or % per group)

MitoCare – HEALTH-F2-2010-261034


Disclosures entire trial sponsored by eu fp7 grant

Study Results: Co-primary Endpoint

  • Mean +/- SEM. Analysis of AUC by ANCOVA. N = 163

MitoCare – HEALTH-F2-2010-261034


Mri endpoints

MRI Endpoints

Mixed model of ANCOVA

MitoCare – HEALTH-F2-2010-261034


Mri endpoints1

MRI Endpoints


Disclosures entire trial sponsored by eu fp7 grant

Additional Secondary Endpoint: Echocardiography at D30

Placebo

TRO40303

  • Data presented as mean +/- SEM

  • Number patients analysed = 105 for LVEDV; 104 for LVESD; 139 for LVEF

MitoCare – HEALTH-F2-2010-261034


Disclosures entire trial sponsored by eu fp7 grant

Safety

No difference in AE’s in both study arms

CEC adjudicated SAE’s:

Fischer exact Test: P=0.013

MitoCare – HEALTH-F2-2010-261034


Mitocare conclusions

MITOCARE - Conclusions

  • 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 – HEALTH-F2-2010-261034


Mitocare clinical sites

Thanks to:

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.

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, HôpitalFernandWidal, 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


Disclosures entire trial sponsored by eu fp7 grant

Thank you for your attention


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