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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. [ABSTRACT FROM AUTHOR]