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 Richard Thompson, Misun Lee, Rochelle M. Maher, Anne Hortense Schmitt-Hoffmann, Bernhardt Zeiher, Andrew J. Ullmann

Research output: Contribution to journalArticle

288 Citations (Scopus)

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

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Aspergillus
Fungi
Therapeutics
Drug-Related Side Effects and Adverse Reactions
Pharmaceutical Preparations
isavuconazole
Non-Randomized Controlled Trials
Voriconazole
Safety
Triazoles
Mortality
Subcutaneous Tissue
Prodrugs
Stem Cell Transplantation
Population

ASJC Scopus subject areas

  • Medicine(all)

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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. / 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; Aoun, Mickael; Baddley, John W.; Giladi, Michael; Heinz, Werner J.; Herbrecht, Raoul; Hope, William; Karthaus, Meinolf; Lee, Dong Gun; Lortholary, Olivier; Morrison, Vicki A.; Oren, Ilana; Selleslag, Dominik; Shoham, Shmuel; Thompson, George Richard; Lee, Misun; Maher, Rochelle M.; Schmitt-Hoffmann, Anne Hortense; Zeiher, Bernhardt; Ullmann, Andrew J.

In: The Lancet, Vol. 387, No. 10020, 20.02.2016, p. 760-769.

Research output: Contribution to journalArticle

Maertens, JA, Raad, II, Marr, KA, Patterson, TF, Kontoyiannis, DP, Cornely, OA, Bow, EJ, Rahav, G, Neofytos, D, Aoun, M, Baddley, JW, Giladi, M, Heinz, WJ, Herbrecht, R, Hope, W, Karthaus, M, Lee, DG, Lortholary, O, Morrison, VA, Oren, I, Selleslag, D, Shoham, S, Thompson, GR, Lee, M, Maher, RM, Schmitt-Hoffmann, AH, Zeiher, B & Ullmann, AJ 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', The Lancet, vol. 387, no. 10020, pp. 760-769. https://doi.org/10.1016/S0140-6736(15)01159-9
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 ; Aoun, Mickael ; Baddley, John W. ; Giladi, Michael ; Heinz, Werner J. ; Herbrecht, Raoul ; Hope, William ; Karthaus, Meinolf ; Lee, Dong Gun ; Lortholary, Olivier ; Morrison, Vicki A. ; Oren, Ilana ; Selleslag, Dominik ; Shoham, Shmuel ; Thompson, George Richard ; Lee, Misun ; Maher, Rochelle M. ; Schmitt-Hoffmann, Anne Hortense ; Zeiher, Bernhardt ; Ullmann, Andrew J. / 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. In: The Lancet. 2016 ; Vol. 387, No. 10020. pp. 760-769.
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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. Funding Astellas Pharma Global Development, Basilea Pharmaceutica International.",
author = "Maertens, {Johan A.} and Raad, {Issam I.} and Marr, {Kieren A.} and Patterson, {Thomas F.} and Kontoyiannis, {Dimitrios P.} and Cornely, {Oliver A.} and Bow, {Eric J.} and Galia Rahav and Dionysios Neofytos and Mickael Aoun and Baddley, {John W.} and Michael Giladi and Heinz, {Werner J.} and Raoul Herbrecht and William Hope and Meinolf Karthaus and Lee, {Dong Gun} and Olivier Lortholary and Morrison, {Vicki A.} and Ilana Oren and Dominik Selleslag and Shmuel Shoham and Thompson, {George Richard} and Misun Lee and Maher, {Rochelle M.} and Schmitt-Hoffmann, {Anne Hortense} and Bernhardt Zeiher and Ullmann, {Andrew J.}",
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TY - JOUR

T1 - Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE)

T2 - A phase 3, randomised-controlled, non-inferiority trial

AU - Maertens, Johan A.

AU - Raad, Issam I.

AU - Marr, Kieren A.

AU - Patterson, Thomas F.

AU - Kontoyiannis, Dimitrios P.

AU - Cornely, Oliver A.

AU - Bow, Eric J.

AU - Rahav, Galia

AU - Neofytos, Dionysios

AU - Aoun, Mickael

AU - Baddley, John W.

AU - Giladi, Michael

AU - Heinz, Werner J.

AU - Herbrecht, Raoul

AU - Hope, William

AU - Karthaus, Meinolf

AU - Lee, Dong Gun

AU - Lortholary, Olivier

AU - Morrison, Vicki A.

AU - Oren, Ilana

AU - Selleslag, Dominik

AU - Shoham, Shmuel

AU - Thompson, George Richard

AU - Lee, Misun

AU - Maher, Rochelle M.

AU - Schmitt-Hoffmann, Anne Hortense

AU - Zeiher, Bernhardt

AU - Ullmann, Andrew J.

PY - 2016/2/20

Y1 - 2016/2/20

N2 - 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.

AB - 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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