Maertens, Johan A., Raad, Issam I., Marr, Kieren A., Patterson, Thomas F., Kontoyiannis, Dimitrios P., Cornely, Oliver A., Bow, Eric J., Rahav, Galia, Neofytos, Dionysios ORCID: 0000-0001-6970-2869, Aoun, Mickael, Baddley, John W., Giladi, Michael, Heinz, Werner J., Herbrecht, Raoul ORCID: 0000-0002-9381-4876, Hope, William ORCID: 0000-0001-6187-878X, Karthaus, Meinolf, Lee, Dong-Gun ORCID: 0000-0003-4655-0641, Lortholary, Olivier, Morrison, Vicki A., Oren, Ilana, Selleslag, Dominik, Shoham, Shmuel, Thompson, George R., III, Lee, Misun, Maher, Rochelle M., Schmitt-Hoffmann, Anne-Hortense, Zeiher, Bernhardt and Ullmann, Andrew J. (2016). 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. Lancet, 387 (10020). S. 760 - 770. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-547X

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Maertens, Johan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raad, Issam I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marr, Kieren A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patterson, Thomas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kontoyiannis, Dimitrios P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cornely, Oliver A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bow, Eric J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rahav, GaliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neofytos, DionysiosUNSPECIFIEDorcid.org/0000-0001-6970-2869UNSPECIFIED
Aoun, MickaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baddley, John W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giladi, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinz, Werner J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herbrecht, RaoulUNSPECIFIEDorcid.org/0000-0002-9381-4876UNSPECIFIED
Hope, WilliamUNSPECIFIEDorcid.org/0000-0001-6187-878XUNSPECIFIED
Karthaus, MeinolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Dong-GunUNSPECIFIEDorcid.org/0000-0003-4655-0641UNSPECIFIED
Lortholary, OlivierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morrison, Vicki A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oren, IlanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Selleslag, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shoham, ShmuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thompson, George R., IIIUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, MisunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maher, Rochelle M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt-Hoffmann, Anne-HortenseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeiher, BernhardtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullmann, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-284332
DOI: 10.1016/S0140-6736(15)01159-9
Journal or Publication Title: Lancet
Volume: 387
Number: 10020
Page Range: S. 760 - 770
Date: 2016
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1474-547X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PHARMACODYNAMIC TARGET DETERMINATION; LIPOSOMAL AMPHOTERICIN-B; CELL TRANSPLANT PATIENTS; MYCOSES STUDY-GROUP; EUROPEAN-ORGANIZATION; PULMONARY ASPERGILLOSIS; CLINICAL-PRACTICE; THERAPY; INFECTIONS; CANCERMultiple languages
Medicine, General & InternalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28433

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