title: Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial.
abstract: BACKGROUND
  Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease.
  
  
  METHODS
  This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893.
  
  
  RESULTS
  527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001).
  
  
  CONCLUSIONS
  Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease.
  
  
  BACKGROUND
  Astellas Pharma Global Development, Basilea Pharmaceutica International.
authors.affiliation: Department of Hematology, Universitaire Ziekenhuizen Leuven, KU Leuven, Belgium.
authors.forename: Johan A
authors.initials: JA
authors.lastname: Maertens
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Issam I
authors.initials: II
authors.lastname: Raad
authors.affiliation: Department of Medicine, John Hopkins University, Baltimore, MD, USA; Department of Oncology, John Hopkins University, Baltimore, MD, USA.
authors.forename: Kieren A
authors.initials: KA
authors.lastname: Marr
authors.affiliation: The University of Texas Health Science Center San Antonio and South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Patterson
authors.affiliation: Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.affiliation: Department of Internal Medicine, Clinical Trials Centre Cologne, ZKS Köln, Center for Integrated Oncology CIO Köln Bonn, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), German Centre for Infection Research, University of Cologne, Cologne, Germany.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.affiliation: Departments of Medical Microbiology and Infectious Diseases, and Internal Medicine, the University of Manitoba, Winnipeg, Canada; Infection Control Services, CancerCare Manitoba, Winnipeg, Canada.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bow
authors.affiliation: The Chaim Sheba Medical Center, Tel-Hashomer, and Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel.
authors.forename: Galia
authors.initials: G
authors.lastname: Rahav
authors.affiliation: Division of Infectious Diseases, John Hopkins University, Baltimore, MD, USA.
authors.forename: Dionysios
authors.initials: D
authors.lastname: Neofytos
authors.affiliation: Division of Infectious Diseases, Jules Bordet Institute, Brussels, Belgium.
authors.forename: Mickael
authors.initials: M
authors.lastname: Aoun
authors.affiliation: University of Alabama at Birmingham and Veterans Affairs Medical Center, Birmingham, AL, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Baddley
authors.affiliation: Infectious Disease Unit, Tel Aviv Sourasky Medical Center and The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Giladi
authors.affiliation: University of Würzburg Medical Center, Würzburg, Germany.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Heinz
authors.affiliation: Department of Oncology and Hematology, Hôpitaux Universitaires de Strasbourg and Université de Strasbourg, France.
authors.forename: Raoul
authors.initials: R
authors.lastname: Herbrecht
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: William
authors.initials: W
authors.lastname: Hope
authors.affiliation: Klinik für Hämatologie und Onkologie, Klinikum Neuperlach, Munich, Germany.
authors.forename: Meinolf
authors.initials: M
authors.lastname: Karthaus
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Dong-Gun
authors.initials: DG
authors.lastname: Lee
authors.affiliation: Université Paris Descartes, Centre d'Infectiologie Necker Pasteur, Hôpital Necker Enfants Malades, IHU Imagine and Institut Pasteur, Centre National de Référence Mycoses Invasives et Antifongiques, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lortholary
authors.affiliation: University of Minnesota and Veterans Affairs Medical Center, Minneapolis, MN, USA.
authors.forename: Vicki A
authors.initials: VA
authors.lastname: Morrison
authors.affiliation: Infectious Diseases Unit, Rambam Health Care Campus, and the Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Oren
authors.affiliation: Algemeen Ziekenhuis Sint-Jan Brugge-Oostende, Belgium.
authors.forename: Dominik
authors.initials: D
authors.lastname: Selleslag
authors.affiliation: Department of Medicine, John Hopkins University, Baltimore, MD, USA.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Shoham
authors.affiliation: University of California Davis Medical Center, Davis, CA, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Thompson
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Misun
authors.initials: M
authors.lastname: Lee
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Rochelle M
authors.initials: RM
authors.lastname: Maher
authors.affiliation: Basilea Pharmaceutica International, Basel, Switzerland.
authors.forename: Anne-Hortense
authors.initials: AH
authors.lastname: Schmitt-Hoffmann
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Bernhardt
authors.initials: B
authors.lastname: Zeiher
authors.affiliation: Julius-Maximilians-University, Department of Internal Medicine II, Infectious Diseases, Würzburg, Germany. Electronic address: andrew.ullmann@uni-wuerzburg.de.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ullmann
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy / Q000401:mortality; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy* / Q000401:mortality; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D065819:Voriconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole; D065819:Voriconazole