ArticlesIsavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis
Introduction
Mucormycosis, an opportunistic invasive fungal disease, which is classically associated with diabetic ketoacidosis and iron overload1 is increasingly encountered in immunocompromised individuals, especially those receiving treatment for haematological malignancies or undergoing transplantation.2, 3 The outlook in these populations is particularly poor, with fatality rates of 52–91%.1, 2, 3, 4 Present guidelines recommend antifungal treatment, surgical debridement, and correction of underlying predisposing disorders.5 Although amphotericin B and posaconazole show in-vitro activity against Mucorales moulds, their clinical use is often restricted.6, 7 Nephrotoxicity remains a common adverse effect of amphotericin B,8 and posaconazole has mainly been studied in the salvage setting.9, 10
Isavuconazonium sulfate is a water-soluble prodrug, which is rapidly hydrolysed to the triazole isavuconazole after oral or intravenous administration. Isavuconazole has high oral bioavailability, linear pharmacokinetics, and is active against a broad range of clinically important fungi, including moulds of the order Mucorales. Isavuconazole inhibits ergosterol biosynthesis, which results in accumulation of toxic sterols and cell death.11
We present the results of a single-arm open-label trial of isavuconazole treatment of mucormycosis, and a case-control analysis. The primary objective of the open-label trial was to assess the efficacy of isavuconazole; the case-control analysis evaluated the mortality outcomes recorded with isavuconazole compared with amphotericin B.
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Patients and study design
VITAL was a single-arm open-label trial done in 34 centres worldwide (appendix) that assessed the efficacy and safety of isavuconazole for the treatment of invasive aspergillosis in patients with renal impairment and for the treatment of rare invasive fungal diseases. The study prespecified a category for mucormycosis primary treatment, defined as 4 days or less of previous systemic antifungals. Patients were also eligible if they were intolerant or refractory to other antifungals. Patients
Results
From April 22, 2008, to Oct 6, 2008, six patients consented to participate in the VITAL study. Enrolment was suspended between Jan 23, 2009, and April 3, 2011, to conduct additional non-clinical safety studies and transfer sponsorship from Basilea Pharmaceutica International to Astellas Pharma Global Development. From April 20, 2011, to June 21, 2013, another 143 patients consented to participate in the study (figure 1). Of 37 patients with mucormycosis only, 32 had proven and five had probable
Discussion
The VITAL study showed that isavuconazole was active as primary or salvage (refractory or intolerant to other antifungals) treatment for mucormycosis, with overall end-of-treatment complete and partial response of 32% for primary treatment and 36% for treatment of mucormycosis refractory to other antifungals (table 3). These response rates are similar to those reported for liposomal amphotericin B.22 The stringent response criteria used in the VITAL study might underestimate the relevant
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