www.thelancet.com/infection Published online March 8, 2016 http://dx.doi.org/10.1016/S1473-3099(16)00071-2 1 Articles Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis Francisco M Marty, Luis Ostrosky-Zeichner, Oliver A Cornely, Kathleen M Mullane, John R Perfect, George R Thompson III, George J Alangaden, Janice M Brown, David N Fredricks, Werner J Heinz, Raoul Herbrecht, Nikolai Klimko, Galina Klyasova, Johan A Maertens, Sameer R Melinkeri, Ilana Oren, Peter G Pappas, Zdeněk Ráčil, Galia Rahav, Rodrigo Santos, Stefan Schwartz, J Janne Vehreschild, Jo-Anne H Young, Ploenchan Chetchotisakd, Sutep Jaruratanasirikul, Souha S Kanj, Marc Engelhardt, Achim Kauold, Masanori Ito, Misun Lee, Carolyn Sasse, Rochelle M Maher, Bernhardt Zeiher, Maria J G T Vehreschild, for the VITAL and FungiScope Mucormycosis Investigators* Summary Background Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. Methods In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response—ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)—according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all- cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. Findings Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19–179, range 2–882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). Interpretation Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. Funding Astellas Pharma Global Development, Basilea Pharmaceutica International. Introduction Mucormycosis, an opportunistic invasive fungal disease, which is classically associated with diabetic ketoacidosis and iron overload 1 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%. 1–4 Present guidelines recommend antifungal treatment, surgical debridement, and correction of underlying predisposing disorders. 5 Although ampho- tericin 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. Methods 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 Lancet Infect Dis 2016 Published Online March 8, 2016 http://dx.doi.org/10.1016/ S1473-3099(16)00071-2 See Online/Comment http://dx.doi.org/10.1016/ S1473-3099(16)00127-4 *Additional VITAL and FungiScope Mucormycosis Investigators are listed in the appendix Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA, USA (F M Marty MD); University of Texas Medical School at Houston and Memorial Hermann Texas Medical Center, University of Texas, Houston, TX, USA (L Ostrosky-Zeichner MD); Department I of Internal Medicine, Clinical Trials Centre Cologne, ZKS Köln, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany (Prof O A Cornely MD); Department of Medicine (K M Mullane DO) and Division of Infectious Diseases (K M Mullane), University of Chicago, IL, USA; Department of Medicine (J R Perfect MD) and Division of Infectious Diseases (J R Perfect), Duke University, Durham, NC, USA; Departments of Medicine (G R Thompson III MD) and Division of Infectious Diseases and Medical Microbiology and Immunology (G R Thompson III), University of California, Davis, CA, USA; Division of Infectious Diseases, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA (G J Alangaden MD); Division of Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, CA, USA (J M Brown MD); Vaccine and