title: Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated.
  
  
  BACKGROUND
  Astellas Pharma Global Development, Basilea Pharmaceutica International.
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA.
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authors.affiliation: University of Texas Medical School at Houston and Memorial Hermann Texas Medical Center, University of Texas, Houston, TX, USA.
authors.forename: Luis
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authors.affiliation: 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.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.affiliation: Department of Medicine, University of Chicago, IL, USA; Division of Infectious Diseases, University of Chicago, IL, USA.
authors.forename: Kathleen M
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authors.affiliation: Department of Medicine, Duke University, Durham, NC, USA; Division of Infectious Diseases, Duke University, Durham, NC, USA.
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authors.initials: JR
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authors.affiliation: 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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authors.affiliation: University of Würzburg Medical Centre, Würzburg, Germany.
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authors.affiliation: Department of Oncology and Hematology, Hautepierre Hospital, University of Strasbourg, Strasbourg, France.
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authors.affiliation: Unit of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel.
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authors.affiliation: Division of Infectious Diseases, University of Alabama at Birmingham, AL, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Pappas
authors.affiliation: University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Zdeněk
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authors.lastname: Rahav
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authors.forename: Rodrigo
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authors.affiliation: Medizinische Klinik III, Charité, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Stefan
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authors.lastname: Schwartz
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, and German Centre for Infection Research, partner site Bonn-Cologne, Cologne, Germany.
authors.forename: J Janne
authors.initials: JJ
authors.lastname: Vehreschild
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Division of Infectious Diseases, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jo-Anne H
authors.initials: JH
authors.lastname: Young
authors.affiliation: Division of Infectious Disease and Tropical Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Ploenchan
authors.initials: P
authors.lastname: Chetchotisakd
authors.affiliation: Department of Medicine, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand.
authors.forename: Sutep
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authors.lastname: Jaruratanasirikul
authors.affiliation: Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
authors.forename: Souha S
authors.initials: SS
authors.lastname: Kanj
authors.affiliation: Basilea Pharmaceutica International, Basel, Switzerland.
authors.forename: Marc
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authors.lastname: Engelhardt
authors.affiliation: Basilea Pharmaceutica International, Basel, Switzerland.
authors.forename: Achim
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authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Masanori
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authors.lastname: Ito
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Misun
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authors.lastname: Lee
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Sasse
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Rochelle M
authors.initials: RM
authors.lastname: Maher
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, USA.
authors.forename: Bernhardt
authors.initials: B
authors.lastname: Zeiher
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, and German Centre for Infection Research, partner site Bonn-Cologne, Cologne, Germany.
authors.forename: Maria J G T
authors.initials: MJGT
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mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy / Q000401:mortality; D005260:Female; D005658:Fungi; D006801:Humans; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis / Q000188:drug therapy*; D009570:Nitriles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole