title: The combined effect of subcutaneous granulocyte- colony stimulating factor and myocardial contrast echocardiography with intravenous infusion of sulfur hexafluoride on post-infarction left ventricular function, the RIGENERA 2.0 trial: study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Several clinical trials and recent meta-analyses have demonstrated that administration of recombinant human granulocyte-colony stimulating factor (G-CSF) is safe and, only in patients with large acute myocardial infarction (AMI), is associated with an improvement in left ventricular ejection fraction. Moreover, the mobilization and engraftment of the bone marrow-derived cells may differ significantly among patients, interfering with the restoration of left ventricular function after treatment. Therefore, the clinical potential application of the G-CSF has not yet been fully elucidated.
  
  
  METHODS
  The RIGENERA 2.0 trial is a multicenter, phase II, placebo-controlled, randomized, open-label, with blinded evaluation of endpoints (PROBE) trial in which 120 patients with an acute ST-elevation myocardial infarction (STEMI) undergoing successful revascularization but with residual myocardial dysfunction will be enrolled. In cases where there is a left ventricular ejection fraction (LVEF) ≤ 45% the patient will be electronically randomized (1:1 ratio) to receive either subcutaneous recombinant human G-CSF (group 1) or placebo (group 2) both added on top of optimal standard of care. Both groups will undergo myocardial contrast echocardiography with intravenous infusion of sulfur hexafluoride (MCE) whilst undergoing the echocardiogram. The primary efficacy endpoint is the evaluation of the LVEF at 6 months after AMI assessed by cardiac magnetic resonance. Secondary efficacy endpoints are the evaluation of LVEF at 6 months after AMI assessed by echocardiography, left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) assessed by cardiac magnetic resonance and echocardiography at 6 months, together with the incidence of major adverse clinical events (MACE) defined as death, myocardial infarction, sustained cardiac arrhythmias, cardiogenic shock, stroke and re-hospitalization due to heart failure at 1 year.
  
  
  CONCLUSIONS
  The RIGENERA 2.0 trial will test whether G-CSF administration and MCE, through the enhancement of the bone marrow-derived cells homing in the myocardium, determines an improvement in regional and global contractile function, myocardial perfusion and infarct extension in patients with large AMI. The results of the present study are expected to envision routine clinical use of this safe, affordable and reproducible approach in patients with successful revascularization after AMI.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT02502747 (29 June 2015); EudraCT: 2015-002189-21 (10 July 2015).
authors.affiliation: Dipartimento di Scienze Cardiovascolari, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy. antoniomarialeone@gmail.com.
authors.forename: Antonio Maria
authors.initials: AM
authors.lastname: Leone
authors.affiliation: Dipartimento di Scienze Cardiovascolari, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy. domenico.damario@gmail.com.
authors.forename: Domenico
authors.initials: D
authors.lastname: D'Amario
authors.affiliation: Istituto di Ematologia, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy. lteofili@rm.unicatt.it.
authors.forename: Luciana
authors.initials: L
authors.lastname: Teofili
authors.affiliation: Dipartimento di Scienze Cardiovascolari, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy. eloisa.basile1@gmail.com.
authors.forename: Eloisa
authors.initials: E
authors.lastname: Basile
authors.affiliation: Dipartimento di Scienze Cardiovascolari, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cannata
authors.affiliation: Dipartimento di Scienze Cardiovascolari, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy. francesca.graziani4@gmail.com.
authors.forename: Francesca
authors.initials: F
authors.lastname: Graziani
authors.affiliation: Dipartimento Cardio-Toraco-Vascolare, Università di Pisa, Via Paradisa, 2, Pisa, 56124, Italy. mario.marzilli@med.unipi.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Marzilli
authors.affiliation: MEBIC, Università San Raffaele, Via di Val Cannuta, 247 - 00166, Rome, Italy. matteoantonio.russo@uniroma1.it.
authors.forename: Antonio Matteo
authors.initials: AM
authors.lastname: Russo
authors.affiliation: Dipartimento di Scienze Cardiologiche Toraciche e Vascolari, Università di Padova, Via Giustiniani, 2, Padova, 35128, Italy. giuseppe.tarantini.1@unipd.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tarantini
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università di Ferrara, Corso Giovecca, 203, Ferrara, 44100, Italy. claudio.ceconi@unife.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceconi
authors.affiliation: Istituto di Ematologia, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy. iclsm@rm.unicatt.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Leone
authors.affiliation: Dipartimento di Scienze Cardiovascolari, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy. carlotrani@rm.unicatt.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Trani
authors.affiliation: Dipartimento di Scienze Cardiovascolari, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy. arebuzzi@rm.unicatt.it.
authors.forename: Antonio Giuseppe
authors.initials: AG
authors.lastname: Rebuzzi
authors.affiliation: Dipartimento di Scienze Cardiovascolari, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, Rome, 00168, Italy. fcrea@rm.unicatt.it.
authors.forename: Filippo
authors.initials: F
authors.lastname: Crea
mesh_terms: D002985:Clinical Protocols; D004452:Echocardiography; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D007902:Length of Stay; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000503:physiopathology*; D013459:Sulfur Hexafluoride / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D013459:Sulfur Hexafluoride