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.

Astellas Pharma Global Development Northbrook IL USA

Basilea Pharmaceutica International Basel Switzerland

Deenanath Mangeshkar Hospital and Research Centre Erandawane Pune India

Department 1 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

Department 1 of Internal Medicine University Hospital of Cologne and German Centre for Infection Research partner site Bonn Cologne Cologne Germany

Department of Hematology University Hospital Gasthuisberg Leuven Belgium

Department of Internal Medicine American University of Beirut Medical Center Beirut Lebanon

Department of Medicine Duke University Durham NC USA

Department of Medicine Songklanagarind Hospital Prince of Songkla University Hat Yai Thailand

Department of Medicine University of Chicago IL USA

Department of Medicine University of Minnesota Minneapolis MN USA

Department of Oncology and Hematology Hautepierre Hospital University of Strasbourg Strasbourg France

Departments of Medicine University of California Davis CA USA

Division of Blood and Marrow Transplantation Stanford University Medical Center Stanford CA USA

Division of Infectious Disease and Tropical Medicine Srinagarind Hospital Khon Kaen University Khon Kaen Thailand

Division of Infectious Diseases and Medical Microbiology and Immunology University of California Davis CA USA

Division of Infectious Diseases Brigham and Women's Hospital Boston MA USA

Division of Infectious Diseases Department of Internal Medicine Henry Ford Hospital Detroit MI USA

Division of Infectious Diseases Duke University Durham NC USA

Division of Infectious Diseases University of Alabama at Birmingham AL USA

Division of Infectious Diseases University of Chicago IL USA

Division of Infectious Diseases University of Minnesota Minneapolis MN USA

Federal University of Minas Gerais Belo Horizonte Minas Gerais Brazil

Infectious Disease Unit Sheba Medical Center Tel Hashomer Israel

Medizinische Klinik 3 Charité Campus Benjamin Franklin Berlin Germany

National Research Center for Hematology Moscow Russia

North Western State Medical University St Petersburg Russia

Unit of Infectious Diseases Rambam Health Care Campus Haifa Israel

University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

University of Texas Medical School at Houston and Memorial Hermann Texas Medical Center University of Texas Houston TX USA

University of Würzburg Medical Centre Würzburg Germany

Vaccine and Infectious Disease Division Fred Hutchinson Cancer Research Center Seattle WA USA

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$a Marty, Francisco M $u Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA.

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$a Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis / $c FM. Marty, L. Ostrosky-Zeichner, OA. Cornely, KM. Mullane, JR. Perfect, GR. Thompson, GJ. Alangaden, JM. Brown, DN. Fredricks, WJ. Heinz, R. Herbrecht, N. Klimko, G. Klyasova, JA. Maertens, SR. Melinkeri, I. Oren, PG. Pappas, Z. Ráčil, G. Rahav, R. Santos, S. Schwartz, JJ. Vehreschild, JA. Young, P. Chetchotisakd, S. Jaruratanasirikul, SS. Kanj, M. Engelhardt, A. Kaufhold, M. Ito, M. Lee, C. Sasse, RM. Maher, B. Zeiher, MJ. Vehreschild, . ,

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$a 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.

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$a Ostrosky-Zeichner, Luis $u University of Texas Medical School at Houston and Memorial Hermann Texas Medical Center, University of Texas, Houston, TX, USA.

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$a Cornely, Oliver A $u 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. Electronic address: oliver.cornely@uk-koeln.de.

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$a Mullane, Kathleen M $u Department of Medicine, University of Chicago, IL, USA; Division of Infectious Diseases, University of Chicago, IL, USA.

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$a Perfect, John R $u Department of Medicine, Duke University, Durham, NC, USA; Division of Infectious Diseases, Duke University, Durham, NC, USA.

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$a Thompson, George R $u Departments of Medicine, University of California, Davis, CA, USA; Division of Infectious Diseases and Medical Microbiology and Immunology, University of California, Davis, CA, USA.

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$a Alangaden, George J $u Division of Infectious Diseases, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA. $7 gn_A_00003282

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$a Brown, Janice M $u Division of Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, CA, USA.

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$a Fredricks, David N $u Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

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$a Heinz, Werner J $u University of Würzburg Medical Centre, Würzburg, Germany.

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$a Herbrecht, Raoul $u Department of Oncology and Hematology, Hautepierre Hospital, University of Strasbourg, Strasbourg, France.

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$a Maertens, Johan A $u Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium.

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$a Ráčil, Zdeněk $u University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.

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$a Young, Jo-Anne H $u Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Division of Infectious Diseases, University of Minnesota, Minneapolis, MN, USA.

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$a Chetchotisakd, Ploenchan $u Division of Infectious Disease and Tropical Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand.

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$a Jaruratanasirikul, Sutep $u Department of Medicine, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand.

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