Johan A Maertens1, Issam I Raad2, Kieren A Marr3, Thomas F Patterson4, Dimitrios P Kontoyiannis5, Oliver A Cornely6, Eric J Bow7, Galia Rahav8, Dionysios Neofytos9, Mickael Aoun10, John W Baddley11, Michael Giladi12, Werner J Heinz13, Raoul Herbrecht14, William Hope15, Meinolf Karthaus16, Dong-Gun Lee17, Olivier Lortholary18, Vicki A Morrison19, Ilana Oren20, Dominik Selleslag21, Shmuel Shoham22, George R Thompson23, Misun Lee24, Rochelle M Maher24, Anne-Hortense Schmitt-Hoffmann25, Bernhardt Zeiher24, Andrew J Ullmann26. 1. Department of Hematology, Universitaire Ziekenhuizen Leuven, KU Leuven, Belgium. 2. Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 3. Department of Medicine, John Hopkins University, Baltimore, MD, USA; Department of Oncology, John Hopkins University, Baltimore, MD, USA. 4. The University of Texas Health Science Center San Antonio and South Texas Veterans Health Care System, San Antonio, TX, USA. 5. Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6. 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. 7. Departments of Medical Microbiology and Infectious Diseases, and Internal Medicine, the University of Manitoba, Winnipeg, Canada; Infection Control Services, CancerCare Manitoba, Winnipeg, Canada. 8. The Chaim Sheba Medical Center, Tel-Hashomer, and Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel. 9. Division of Infectious Diseases, John Hopkins University, Baltimore, MD, USA. 10. Division of Infectious Diseases, Jules Bordet Institute, Brussels, Belgium. 11. University of Alabama at Birmingham and Veterans Affairs Medical Center, Birmingham, AL, USA. 12. Infectious Disease Unit, Tel Aviv Sourasky Medical Center and The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 13. University of Würzburg Medical Center, Würzburg, Germany. 14. Department of Oncology and Hematology, Hôpitaux Universitaires de Strasbourg and Université de Strasbourg, France. 15. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK. 16. Klinik für Hämatologie und Onkologie, Klinikum Neuperlach, Munich, Germany. 17. Division of Infectious Diseases, Department of Internal Medicine, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea. 18. 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. 19. University of Minnesota and Veterans Affairs Medical Center, Minneapolis, MN, USA. 20. Infectious Diseases Unit, Rambam Health Care Campus, and the Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 21. Algemeen Ziekenhuis Sint-Jan Brugge-Oostende, Belgium. 22. Department of Medicine, John Hopkins University, Baltimore, MD, USA. 23. University of California Davis Medical Center, Davis, CA, USA. 24. Astellas Pharma Global Development, Northbrook, IL, USA. 25. Basilea Pharmaceutica International, Basel, Switzerland. 26. Julius-Maximilians-University, Department of Internal Medicine II, Infectious Diseases, Würzburg, Germany. Electronic address: andrew.ullmann@uni-wuerzburg.de.
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. FINDINGS: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). INTERPRETATION: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. FUNDING: Astellas Pharma Global Development, Basilea Pharmaceutica International.
RCT Entities:
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. FINDINGS: 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). INTERPRETATION: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. FUNDING: Astellas Pharma Global Development, Basilea Pharmaceutica International.
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