STEM-AMI OUTCOME TRIAL STem cElls Mobilization in Acute Myocardial Infarction Outcome Trial   A national, multicentre, randomised, open-label, Phase III study Dott. Luca Deferrari U.O. Cardiologia IRCCS San Martino, Genova

What is G-CSF? Granulocyte Colony Stimulating Factor Glycoprotein Growth factor Cytokine Produced by endothelium, macrophages and other immune cells G-CSF receptor present on precursor cells in the bone marrow Initiates proliferation and differentiation into mature granulocytes Stimulates bone marrow cell release into circulation

Two important G-CSF uses MOST COMMON: Post chemotherapy febrile neutropenia Potent inducer of hematopoietic stem cell mobilization for stem cell transplantation

Side effects associated with G-CSF

STEM–AMI Outcome trial: rationale

STEM–AMI Outcome trial: rationale

STEM–AMI Outcome trial: rationale

STEM –AMI Outcome trial: rationale

STEM–AMI Outcome trial: rationale

STEM–AMI Outcome trial: rationale

STEM–AMI Outcome trial: rationale

STEM-AMI OUTCOME TRIAL STUDY OBJECTIVES To demonstrate that G-CSF in addition to state of the art treatment is safe and significantly improves clinical outcome in patients with reduced left ventricular EF (≤45%) after successful reperfusion for large anterior acute myocardial infarction

STEM-AMI OUTCOME TRIAL DESIGN Phase III, randomized, open label. 1530 Patients (50 centres) will be randomized to standard therapy + G-CSF or standard therapy alone in 1:1 ratio. Accrual time 3 years. Follow-up time 2 years. TREATMENT FILGRASTIM 5 µg/kg will be administered subcutaneously bis in die for 6 days (from Day 1 to Day 6), starting within 24 h after PCI and reperfusion.

STEM-AMI OUTCOME TRIAL PRIMARY EFFICACY END POINT Clinical outcome will be assessed by the composite endpoint of: death or recurrence of MI or hospitalization due to heart failure SAFETY ENDPOINTS Incidence and severity of bleeding complications Incidence of malignancy Incidence and intensity of AEs and SAEs

STEM-AMI OUTCOME TRIAL INCLUSION CRITERIA Patients affected by acute anterior STEMI undergoing primary PCI (or PCI-rescue with persistent occlusion of coronary artery) Time symptom-to-balloon ≥3 h and ≤12h (or ≤24 h if symptoms persist) TIMI flow post PCI ≥2 Evidence of LV dysfunction (EF biplane ≤ 45%) ≤ 24 h after revascularization Men and women aged ≥18 years and ≤ 75 years, Informed consent must be signed before proceeding with any study procedure.

STEM-AMI OUTCOME TRIAL EXCLUSION CRITERIA Previous anterior MI Recent MI (within 1 month) Known previous LV dysfunction (EF <45%), Angiographic evidence of coronary anatomy not suitable for PCI Valve disease requiring surgical correction History of previous cardiac surgery or PCI on LAD within 6 months Previous or current documented history of leukemia, myeloproliferative or myelodisplastic disorder, malignant disease Haemoglobin <10 mg/dl White blood cells (WBC) >25.000 mm3 Platelet <50.000 mm3 Sepsis Known HIV infection Immune system diseases Interstitial lung disease Serious concomitant medical conditions (other than ischemic heart disease) Pregnancy and breast feeding Documented alcohol and drug abuse Anticipated poor compliance Current participation in a clinical trial with other investigational products or cell therapy EMOCROMO Hb <10 g/dl Globuli bianchi >25.000/mm3 Piastrine <50.000/mm3 ANAMNESI EXTRACARDIACA Malattie mieloproliferative, leucemia Neoplasie HIV Patologia autoimmune Interstiziopatia polmonare Gravidanza o allattamento Abuso di alcool e/o droghe Scarsa compliance ANAMNESI CARDIOLOGICA Pregresso IMA anteriore IMA nel mese precedente Nota disfunzione VSx (FE ≤ 45% ) Valvulopatia con indicazione CCH Pregressa CCH nei 6 mesi precedenti Pregressa PCI su IVA nei 6 mesi precedenti

STEM-AMI OUTCOME TRIAL Assessment I Assessment II Assessment III Assessment IV Assessment V Assessment VI Day -1/0 In hospital phase 1 month 6 months 12 months 24 months

STEM-AMI OUTCOME TRIAL ASSESMENT I DAY -1/0 Screening and randomization Obtain written informed consent Documented acute anterior STEMI Documented primary PCI/PCI-rescue (symptom to ballon time) TIMI flow post-PCI registration Evidence of Echo Simpson biplane EF ≤45%, EDV and ESV Hemochrome (hemoglobin, platelets, WBC) Pregnancy test (if necessary) Determine patient’s eligibility for enrollment Randomization to study treatment group

STEM-AMI OUTCOME TRIAL ASSESMENT II DAY 0-7 In Hospital phase G-CSF administration Hemochrome (WBC count) Documentation of ADRs/SAEs ECG ECHO: EF (Echo Simpson biplane), EDV and ESV

STEM-AMI OUTCOME TRIAL ASSESMENT III DAY 30 1-month visit Clinical Evaluation Documentation of ADRs/SAEs ECG

STEM-AMI OUTCOME TRIAL ASSESMENT IV DAY 180 6-months visit Clinical Evaluation Documentation of ADRs/SAEs ECG ECHO: EF (Echo Simpson biplane), EDV and ESV

STEM-AMI OUTCOME TRIAL ASSESMENT V DAY 365 12-months visit Phone interview Documentation of ADRs/SAEs

STEM-AMI OUTCOME TRIAL ASSESMENT V DAY 730 24-months visit Clinical Evaluation Documentation of ADRs/SAEs ECG ECHO: EF (Echo Simpson biplane), EDV and ESV

STEM-AMI OUTCOME TRIAL Egregi Dottori, Con la presente, comunichiamo che oggi, 8 novembre 2013, è stato arruolato il primo paziente dello Studio STEM-AMI Outcome dall'Ospedale San Gerardo di Monza. Cordialmente Segreteria Organizzativa Centro di Coordinamento Centro Studi ANMCO Grazie per l’attenzione