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

Johan A. Maertens, Issam I. Raad, Kieren A. Marr, Thomas F. Patterson, Dimitrios P. Kontoyiannis, Oliver A. Cornely, Eric J. Bow, Galia Rahav, Dionysios Neofytos, Mickael Aoun, John W. Baddley, Michael Giladi, Werner J. Heinz, Raoul Herbrecht, William Hope, Meinolf Karthaus, Dong Gun Lee, Olivier Lortholary, Vicki A. Morrison, Ilana OrenDominik Selleslag, Shmuel Shoham, George R. Thompson, Misun Lee, Rochelle M. Maher, Anne Hortense Schmitt-Hoffmann, Bernhardt Zeiher, Andrew J. Ullmann

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402 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)760-769
Number of pages10
JournalThe Lancet
Volume387
Issue number10020
DOIs
StatePublished - Feb 20 2016

Bibliographical note

Funding Information:
Isavuconazole was co-developed by Astellas Pharma US and Basilea Pharmaceutica International. We acknowledge the contributions of the medical director of the SECURE trial, Neddie Zadeikis (Astellas Pharma Global Development during the conduct of the study) in the design and conduct of the study. Editorial assistance was provided by Radhika Bhatia, of Envision Scientific Solutions, funded by Astellas Pharma Global Development.

Funding Information:
JAM reports grants and personal fees from Bio-Rad, personal fees and non-financial support from Astellas and Basilea, and grants, personal fees and non-financial support from Gilead Sciences, Merck Sharp and Dohme, and Pfizer, Inc. during the conduct of the study. IIR participated in an International Speakers' Bureau for Pfizer, outside the submitted work. KAM reports personal fees from Astellas during the conduct of the study; personal fees from Chimerix, Cidara, Genentech and Merck, and grants and personal fees from Astellas, outside the submitted work. In addition, KAM has a patent (diagnostics for aspergillosis) licensed to MycoMed Technologies. TFP reports personal fees from Astellas during the conduct of the study; grants from Astellas, personal fees from Pfizer, Scynexis, Toyama, and Viamet, and grants and personal fees from Merck, outside the submitted work. OAC is supported by the German Federal Ministry of Research and Education, has received research grants from 3M, Actelion, Astellas, AstraZeneca, Basilea, Bayer, Celgene, Cubist/Optimer, Duke University (NIH UM1AI104681), Genzyme, Gilead, GSK, Leeds University, Merck/MSD, Miltenyi, Pfizer, Quintiles, Viropharma, is a consultant to Anacor, Astellas, Basilea, Cidara, Da Volterra, Daiichi Sankyo, F2G, Genentech, Gilead, Merck/MSD, Merck Serono, Pfizer, Sanofi Pasteur, Scynexis, Seres, Summit, Vical, Vifor, and received lecture honoraria from Astellas, Basilea, Gilead, Merck/MSD, and Pfizer. EJB was a member of the Data Review Committee for Astellas, after the conduct of the study; EJB also reports personal fees from Cidara, Gilead, GLY-Pharma, and Pfizer, outside the submitted work. GR reports grants from Astellas during the conduct of the study, and grants from Pfizer, MSD, Gilead, and AstraZeneca, outside the submitted work. DN reports personal fees from Astellas during the conduct of the study; personal fees from Astellas and Roche Molecular Diagnostics, outside the submitted work; DN is currently an employee of Roche Diagnostics. JWB reports personal fees from Astellas, Merck, and Pfizer, outside the submitted work. WJH reports personal fees from Astellas, Basilea, and Gilead Sciences, and grants and personal fees from MSD Sharp & Dohme/Merck, and Pfizer, outside the submitted work. RH reports personal fees from Astellas, Basilea, Gilead Sciences, MSD, and Schering-Plough, and grants and personal fees from Pfizer during the conduct of the study. WH reports grants and personal fees from Astellas, F2G, and Pfizer, outside the submitted work. MK reports participation on advisory boards for Astellas and Pfizer, outside the submitted work. D-GL reports grants and personal fees from Astellas, Gilead Sciences, MSD, Pfizer, and Yuhan, outside the submitted work. OL reports grants from Astellas during the conduct of the study, and personal fees from Gilead, Pfizer, and Merck, outside the submitted work. VAM was a member of the Data Review Committee for Astellas, after the conduct of the study. DS reports grants from Astellas during the conduct of the study; grants, personal fees and non-financial support from Pfizer, as well as personal fees and non-financial support from MSD, outside the submitted work. SS reports grants from Astellas during the conduct of the study; grants from Astellas, Chimerix, Merck, Pfizer, Scynexis, and Viropharma, and personal fees from the Mycoses Study Group Education and Research Consortium, outside the submitted work. GRT was a member of the Data Review Committee, after the conduct of the study; he reports grants from Pfizer and Merck, outside the submitted work. AJU received personal fees and fees for travel, speakers' bureau and consultancy from Basilea, and grants, personal fees, and fees for travel, speakers' bureau and consultancy from Astellas during the conduct of the study; grants, personal fees and fees for travel, speakers' bureau and consultancy from MSD, Gilead Sciences and Pfizer, and personal fees from Boehringer Ingelheim, outside the submitted work. ML, RMM, and BZ are employees of Astellas Pharma Global Development, Inc. A-HS-H is an employee of Basilea Pharmaceutica International Ltd. DPK, MA, MG, and IO declare no competing interests.

Funding Information:
Isavuconazole was co-developed by Astellas Pharma US and Basilea Pharmaceutica International. We acknowledge the contributions of the medical director of the SECURE trial, Neddie Zadeikis (Astellas Pharma Global Development during the conduct of the study) in the design and conduct of the study. Editorial assistance was provided by Radhika Bhatia, of Envision Scientifi c Solutions, funded by Astellas Pharma Global Development.

Publisher Copyright:
© 2016 Elsevier Ltd.

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