title: Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I): A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction.
abstract: BACKGROUND
  Despite aggressive pharmacotherapy and stenting, there is a residual risk of major adverse cardiovascular events among patients with acute coronary syndrome. High-density lipoprotein (HDL) has been a major target for secondary acute coronary syndrome prevention; however, a better understanding of the physiologic function of HDL has demonstrated that a high cholesterol efflux capacity, rather than high HDL concentrations alone, may be critical to improving outcomes. CSL112, a reconstituted, infusible human apolipoprotein A-I, has been demonstrated to increase cholesterol efflux capacity and to have a protective effect in experimental models of atherosclerotic cardiovascular disease.
  
  
  METHODS
  The AEGIS-I trial (ClinicalTrials.govNCT02108262) is a phase 2b, multicenter, randomized, placebo-controlled, dose-ranging clinical trial to evaluate the hepatic and renal safety of multiple administrations of 2 doses of CSL112 among subjects with acute myocardial infarction (AMI). Approximately 1,200 subjects (400 per treatment group) with either normal renal function or mild renal impairment will be enrolled up to 7 days after an AMI and will be stratified by renal function and randomized in a 1:1:1 ratio to either 1 of 2 doses of CSL112 (either 2 g or 6 g) or placebo as a weekly 2-hour infusion over the course of 4 consecutive weeks. The coprimary safety endpoints will be the incidence of hepatic and renal toxicity, defined as either confirmed ALT >3 × ULN, total bilirubin >2 × ULN, serum creatinine ≥1.5×baseline value, or a new requirement for renal replacement therapy through the end of the active treatment period.
  
  
  CONCLUSIONS
  The AEGIS-I trial will characterize the safety profile of CSL112, a reconstituted formulation of apolipoprotein A-I, and will assess if administration to patients with a recent AMI is associated with a clinically significant alteration in either liver or kidney function when compared with placebo.
authors.affiliation: PERFUSE Study Group, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical, Harvard Medical School, Boston, MA. Electronic address: mgibson@bidmc.harvard.edu.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Gibson
authors.affiliation: PERFUSE Study Group, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical, Harvard Medical School, Boston, MA.
authors.forename: Serge
authors.initials: S
authors.lastname: Korjian
authors.affiliation: Duke Clinical Research Institute, Department of Medicine, Duke University, Durhman, NC.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Tricoci
authors.affiliation: PERFUSE Study Group, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical, Harvard Medical School, Boston, MA.
authors.forename: Yazan
authors.initials: Y
authors.lastname: Daaboul
authors.affiliation: Duke Clinical Research Institute, Department of Medicine, Duke University, Durhman, NC.
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
authors.affiliation: INSERM-Unité 1148, France Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, France Université Paris-Diderot, Sorbonne-Paris Cité, France National Heart and Lung Institute, Imperial College London, UK Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, United Kingdom.
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Steg
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH.
authors.forename: A Michael
authors.initials: AM
authors.lastname: Lincoff
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Columbia University Medical Center and the Cardiovascular Research Foundation, New York, NY.
authors.forename: Roxana
authors.initials: R
authors.lastname: Mehran
authors.affiliation: CSL Behring, LLC, King of Prussia, PA.
authors.forename: Denise
authors.initials: D
authors.lastname: D'Andrea
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor str. 68, Budapest, Hungary.
authors.forename: Bela
authors.initials: B
authors.lastname: Merkely
authors.affiliation: Department of Cardiology, Warsaw Medical University, Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Zarebinski
authors.affiliation: Department of Cardiology, Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands.
authors.forename: Ton Oude
authors.initials: TO
authors.lastname: Ophius
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000008:administration & dosage* / Q000009:adverse effects; D008099:Liver / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D012107:Research Design
chemical_list: C584257:CSL112; D008075:Lipoproteins, HDL