Elsevier

The Lancet

Volume 387, Issue 10020, 20–26 February 2016, Pages 760-769
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(15)01159-9Get rights and content

Summary

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.

Introduction

Invasive mould disease represents a challenge, especially in patients with haematological malignant disease and haemopoietic stem cell transplantation, solid organ transplant recipients, and patients in intensive-care units.1 Invasive mould disease still accounts for substantial mortality in these patients.1, 2

The available range of antifungal drugs that are active against mould disease has shortcomings. Polyenes, once the mainstay of anti-mould therapy, now have a limited role because of toxicity concerns and the requirement for intravenous administration.3 Echinocandins have an excellent safety profile; however, there is relatively little experience in their use for the primary treatment of invasive mould disease.4, 5 Posaconazole is licensed for the salvage treatment of invasive mould disease,6 but data to support its first-line use are lacking. Voriconazole has been endorsed by international guidelines as primary treatment for invasive aspergillosis,2, 7, 8 as well as some other mould infections.9 However, drug interactions, pharmacokinetic variability, short-term acute toxicities (including photopsia, visual hallucinations, and abnormalities in liver function), long-term toxicities (such as skin carcinogenesis and fluorosis), concerns about β-cyclodextrin administration in the setting of impaired renal function, and recommendations for therapeutic drug monitoring have been problematic for patients.10

Research in Context

Evidence before this study

We searched PubMed without time or language limitation with the search criteria (“invasive”[All Fields] AND (“aspergillosis”[MeSH Terms] OR “aspergillosis”[All Fields])) AND ((“mortality”[Subheading] OR “mortality”[All Fields] OR “mortality”[MeSH Terms])) AND ((“registries”[MeSH Terms] OR “registries”[All Fields] OR “trial”[All Fields])), up to October, 2015. 55 references were found, of which 36 were categorised as clinical trials. By excluding prevention trials and studies in patients with Candida infections only, 15 clinical trials or cohorts or registries were identified, with nine studies before 2003. Mortality in all trials was similarly high. Only one study was well powered, prospective, and randomised-controlled prior to the beginning of the trial. Overall 10 studies were non-randomised or uncontrolled in nature; four studies were identified in patients refractory or intolerant to therapy; three trials included only patients with non-haematological disease (mainly solid organ transplant recipients). The only study published before 2003 was that by Herbrecht and colleagues (2002), which showed significantly improved outcomes, including survival advantage of voriconazole compared with conventional amphotericin B.

Added value of this study

SECURE is a prospective, double-blind, randomised, global trial demonstrating that the novel triazole isavuconazole is non-inferior to voriconazole for the primary treatment of invasive aspergillosis and disease caused by other moulds. Additionally, isavuconazole was well tolerated compared with voriconazole, with significantly fewer study drug-related adverse events and adverse events of the skin, eye, and hepatobiliary systems.

Implications of all the available evidence

Voriconazole is the current gold standard for treatment of invasive aspergillosis but is limited by drug–drug interactions and safety concerns. Moreover, many non-Aspergillus moulds, such as the agents of mucormycosis, are often resistant to voriconazole. This trial offers strong evidence that isavuconazole is an appropriate alternative to voriconazole for the primary treatment of invasive aspergillosis and other mould disease.

The water-soluble prodrug isavuconazonium sulfate was developed to facilitate intravenous administration without the need for potentially nephrotoxic excipients such as β-cyclodextrin. Isavuconazole, the active moiety, displays excellent bioavailability (roughly 98%)11 after oral administration without any clinically relevant food effects. Isavuconazole is a broad-spectrum triazole that has demonstrated potent activity in animal models of invasive aspergillosis,12 mucormycosis,13 invasive candidiasis,14 and cryptococcosis.15 Isavuconazonium sulfate was approved in 2015 by the US Food and Drug Administration (FDA) for the treatment of invasive aspergillosis and invasive mucormycosis,16 and by the European Medicines Agency for the treatment of invasive aspergillosis and of mucormycosis when amphotericin B is inappropriate.17

We conducted a phase 3, double-blind trial to compare the efficacy and safety of intravenous and oral formulations of isavuconazole to voriconazole for the primary treatment of invasive mould disease caused by Aspergillus spp or other filamentous fungi (the SECURE trial).

Section snippets

Study design and participants

This was a phase 3, randomised, double-blind, international, multicentre, non-inferiority study of isavuconazole versus voriconazole for the primary treatment of invasive mould disease, conducted from 2007 to 2013. Enrolment was suspended from January, 2009, to March, 2011, to allow for completion of non-clinical toxicity studies and licensing activities.

Patients 18 years or older were eligible if they were considered to have invasive mould disease by meeting the criteria for proven, probable,

Results

Between March 7, 2007, and March 28, 2013, we recruited patients from 102 centres from 26 countries located across North and South America, Europe, the Middle East, southeast Asia, east Asia, and Pacific regions. 532 patients gave consent, of whom 527 were randomly assigned. 11 patients did not receive any study drug (five did not meet entry criteria, four withdrew consent, and two died), and were excluded from the ITT population, which included 516 patients (n=258 for each treatment group;

Discussion

In this double-blind, randomised trial, we compared the efficacy and safety of intravenous and oral formulations of two mould-active azoles for the treatment of invasive aspergillosis and other mould infections. Our study demonstrates that isavuconazole is non-inferior to voriconazole in patients suspected of having invasive mould disease, but showed significantly fewer drug-related adverse events and fewer drug discontinuations.

Our primary analysis, 42-day mortality in the ITT population, met

References (32)

  • A Schmitt-Hoffmann et al.

    Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers

    Antimicrob Agents Chemother

    (2006)
  • AJ Lepak et al.

    Isavuconazole (BAL4815) pharmacodynamic target determination in an in vivo murine model of invasive pulmonary aspergillosis against wild-type and cyp51 mutant isolates of Aspergillus fumigatus

    Antimicrob Agents Chemother

    (2013)
  • G Luo et al.

    Isavuconazole therapy protects immunosuppressed mice from mucormycosis

    Antimicrob Agents Chemother

    (2014)
  • AJ Lepak et al.

    Isavuconazole pharmacodynamic target determination for Candida species in an in vivo murine disseminated candidiasis model

    Antimicrob Agents Chemother

    (2013)
  • A Espinel-Ingroff et al.

    Multicenter study of isavuconazole MIC distributions and epidemiological cutoff values for the Cryptococcus neoformans-Cryptococcus gattii species complex using the CLSI M27-A3 broth microdilution method

    Antimicrob Agents Chemother

    (2015)
  • US Astellas Pharma

    Cresemba (isavuconazonium sulfate) prescribing information

  • Cited by (0)

    View full text