Isavuconazole (BAL8557) for Primary Treatment of Invasive Aspergillosis

A Phase III, Double Blind, Randomized Study to Evaluate Safety and Efficacy of BAL8557 Versus Voriconazole for Primary Treatment of Invasive Fungal Disease Caused by Aspergillus Species or Other Filamentous Fungi.

The purpose of this study is to compare the efficacy and safety of isavuconazole versus voriconazole in the treatment of patients with invasive aspergillosis.

Study Overview

• Status: Completed
• Conditions: Aspergillosis; Invasive Fungal Infection
• Intervention / Treatment: Drug: Isavuconazole; Drug: Voriconazole

Detailed Description

Acute invasive fungal infections caused by aspergillus, zygomycetes and other filamentous fungi remain life threatening diseases. Early treatment with highly effective anti-fungals reduces mortality. This study investigates the efficacy and safety of isavuconazole in the treatment of invasive fungal diseases, caused by Aspergillus or other filamentous fungi.

• Study Type: Interventional
• Enrollment (Actual): 527
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
  • Buenos Aires, Argentina, C1039AAO
  • Buenos Aires, Argentina, C1157ADP
  • Capital Federal, Argentina, C1180AAV
  • Capital Federal, Argentina, C1405DCS
  • Ciudad Autonoma, Argentina, 1181
    • Hospital Italiano de Buenos Aires
  • Ciudad Autonoma, Argentina, 1426
    • Instituto Médico Especializado Alexander Fleming
• Australia
  • Perth, Australia, 6000
  • South Brisbane, Australia, 4101
    • Mater Medical Centre
  • Woolloongabba, Australia, 4102
• Belgium
  • Brugge, Belgium, 8000
    • AZ St Jan
  • Brussels, Belgium, 1000
    • Institut Jules Bordet
  • Bruxelles, Belgium, 1070
    • Ulb Hospital Erasme
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Leuven, Belgium, 3000
    • Universitaire Ziekenhuizen Leuven
• Brazil
  • Belo Horizonte, Brazil, 30150-221
    • Santa Casa de Misericordia de Belo Horizonte
  • Belo Horizonte, Brazil, 30110-908
    • Felicio Rocho
  • Curitiba, Brazil, 80060-150
    • Hospital das Clínicas da UFPR
  • Ribeirão Preto, Brazil, 14048-900
    • Hospital de Clinicas da FMUSP - Ribeirao Preto
  • Rio de Janeiro, Brazil, 21941-913
    • Hospital Universitario Clementino Fraga Filho
• Canada
  • Hamilton, Canada, L8V 1C3
    • Hamilton Health Sciences - Henderson Site
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital - General Campus
• Chile
  • Santiago, Chile
  • Temuco, Chile, 4780000
    • Hospital Dr. Hernan Henriquez Aravena
  • Valdivia, Chile, 5090000
• China
  • Beijing, China, 100083
    • 3rd Hospital, Peking University
  • Changchun, China, 130021
    • The 1st Hospital, Jilin University
  • Changsha, China, 410013
    • The Third Xiangya Hospital of Central South University
  • Chengdu, China, 610041
    • West China Hospital of Sichuan University
  • Fuzhou, China, 350001
    • The Affiliated Union Hospital of Fujian Medical University
  • Hangzhou, China, 310003
    • The First Affiliated Hospital, Med. School, Zhejiang Uni.
  • Nanjing, China, 310009
    • The First Affiliated Hospital of Nanjing Medical University
  • Nanning, China, 530021
    • The 1st Affiliated Hospital of Guangxi Medical University
  • Shanghai, China, 200040
    • Huashan Hospital, Insitute of Antibiotics
  • Shanghai, China, 200233
    • No.6 Renmin Hosp. of Shanghai City
  • Shanghai, China, 200433
    • Chang Hai Hospital
  • Wuhan, China, 430022
    • Wuhan Union Hospital
• Egypt
  • Alexandria, Egypt, 21131
    • Alexandria University Hospital
  • Cairo, Egypt, 11796
    • National Cancer Institute
  • Cairo, Egypt, 12655
    • Nasser Institute
• France
  • Dijon, France, 21079
  • Nantes Cedex, France, 44035
    • CHU de Nantes - Hopital Hotel Dieu
  • Nantes Cedex 01, France, 44093
    • Hotel Dieu
  • Strasbourg, France, 67098
    • Hôpital Hautepierre
  • Vandoeuvre les Nancy, France, 54511
    • Hôpital de Brabois Adultes
• Germany
  • Aachen, Germany, 52074
    • Universitaetsklinikum Aachen
  • Berlin, Germany, 12200
    • Charité Universitaetsmedizin Berlin- Campus Charité Mitte
  • Köln, Germany, 50937
    • Universitaet Koeln
  • Leipzig, Germany, 04289
    • Universitaetsklinik Leipzig
  • Luebeck, Germany, 23538
  • Muenchen, Germany, 81737
    • Klinikum Schwabing
  • Würzburg, Germany, 97080
    • Medizinische klinik und Polyklinik II
• Hungary
  • Budapest, Hungary, 1094
  • Györ, Hungary, 9024
    • Petz Aladár Megyei Oktató Kórház
  • Szeged, Hungary, 6720
    • Szegedi Tudomanyegyetem
• India
  • Andh Prad
    • Hyderabad, Andh Prad, India, 500033
      • Apollo Hospitals
  • Gujarat
    • Ahmedabad, Gujarat, India, 380052
      • Sterling Hospital
  • Karna
    • Mangalore, Karna, India, 575001
      • Kasturba Medical College and Hospital
    • Manipal, Karna, India, 576104
      • Shirdi Sai Baba Cancer Hospital K. M. C. Hospital
  • Mahara
    • Mumbai, Mahara, India, 400012
      • Tata Memorial Hopital, Department of Anesthesia
    • Pune, Mahara, India, 411004
      • Deenanath Mangeshkar Hospital & Research Centre
    • Pune, Mahara, India, 411004
      • Sahyadri Hospital
  • Uttar Prad
    • Noida, Uttar Prad, India, 201301
• Israel
  • Haifa, Israel, 31096
    • Rambam Health Care Campus
  • Jerusalem, Israel, 91200
    • Hadassah Universtiy Hospital - Ein Kerem
  • Petah Tikva, Israel, 49100
    • Rabin MC
  • Ramat-Gan, Israel, 52621
    • Chaim Sheba Medical Center
  • Tel Aviv, Israel, 64239
    • Sourasky MC Ichilov Hospital Tel Aviv
• Italy
  • Firenze, Italy, 50134
    • Unità Funzionale di Ematologia; Azienda Ospedaliera Universitaria Careggi
  • Milano, Italy, 20162
    • Azienda Ospedaliera Ospedale Niguarda CA' Granda
• Korea, Republic of
  • Incheon, Korea, Republic of, 405-760
    • Gachon University Gil Hospital
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 120-752
  • Seoul, Korea, Republic of, 137-701
    • The Catholic University of Korea, St. Mary's Hospital
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
  • Kuala Lumpur, Malaysia, 68000
• Mexico
  • Mexico, Mexico, 06726
  • Monterrey, Mexico, 64040
    • Hospital Universitario Dr Jose Eleuterio Gonzalez
• Netherlands
  • Nijmegen, Netherlands, 6525
• New Zealand
  • Palmerston North, New Zealand, 4442
• Poland
  • Warszawa, Poland, 02-097
    • Samodzielny Publiczny Centralny Szpital Kliniczny
• Russian Federation
  • Moscow, Russian Federation, 125167
    • State Institution "Hematology Research Center" RAMS
  • Petrozavodsk, Russian Federation, 185019
    • Republican Hospital Named After V.A. Baranov
  • St. Petersburg, Russian Federation, 197089
  • St. Petersburg, Russian Federation, 194291
    • St-Petersburg MA Postgraduate Education
  • St. Petersburg, Russian Federation, 194291
    • Leningrad Regional Hospital
• Spain
  • Salamanca, Spain, 37007
• Switzerland
  • Zurich, Switzerland, 8091
• Thailand
  • Hat Yai, Thailand, 90110
    • Songklanagarind Hospital
  • Khon Kaen, Thailand, 40002
  • Muang, Thailand, 30000
    • Maharat Nakhon Ratchasima Hospital
  • Muang, Thailand, 40002
    • Srinagarind Hospital
  • Muang, Thailand, 50200
    • Maharaj Nakorn Chiang Mai Hospital
  • Songkla, Thailand, 90110
• Turkey
  • Istanbul, Turkey, 34662
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0006
      • University Of Alabama
  • California
    • San Francisco, California, United States, 94143
      • University of California at San Francisco
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago, Division of Infectious Diseases
    • Springfield, Illinois, United States, 62703
      • Springfield Clinic LLP
    • Springfield, Illinois, United States, 62703
      • Indiana BMT
  • Indiana
    • Indianapolis, Indiana, United States, 46280
      • Infectious Disease of Indiana
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Womens Hospital
    • Worcester, Massachusetts, United States, 01655
  • New York
    • Albany, New York, United States, 12208
      • Upstate Infectious Diseases Association LLP
  • Ohio
    • Lima, Ohio, United States, 45801
      • Regional Infection Diseases Infusion Center Inc.
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have proven, probable or possible invasive fungal disease caused by Aspergillus species or other filamentous fungi
• Female patients must be non-lactating and at no risk for pregnancy

Exclusion Criteria:

• Patients with invasive fungal infections other than Aspergillus species or other filamentous fungi
• Evidence of hepatic dysfunction at Baseline or moderate to severe renal dysfunction
• Patients with chronic aspergillosis, or aspergilloma or allergic bronchopulmonary aspergillosis
• Patients who have received more than 4 days of systemic antifungal therapy other than fluconazole within the 7 days prior to the first administration of study medication
• Patients previously enrolled in a Phase III study with isavuconazole
• Patients with a body weight </= 40 kg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Isavuconazole; Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days.	Drug: Isavuconazole; Loading doses were administered as IV infusion and maintenance doses were administered as IV infusion or oral (capsules).; Other Names: ASP9766; BAL8557
Active Comparator: Voriconazole; Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.	Drug: Voriconazole; Loading doses were administered as IV infusion and maintenance doses were administered as IV infusion or oral (capsules).; Other Names: VFend

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality Through Day 42	All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 42 from any cause. Participants with unknown survival status through Day 42 were included as deaths in the calculation.	Through Day 42

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC)	The DRC was an independent, blinded committee consisting of experts in the field of infectious disease who assessed patients' outcomes. The overall response was based on the DRC-assessed clinical, mycological and radiological responses. Success was defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings, the eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline and a > 50% improvement in radiological response from Baseline (or improvement of at least 25% from Baseline for the Day 42 analysis or End of Treatment if it occurred prior to Day 42). End of treatment (EOT) is the last day of study drug administration. For the Day 42 and Day 84 analyses, any visits that the DRC assessed as Not Done were considered a failure for that visit. A death before Day 42 was also considered a failure, even if the DRC assessed the participant to be a success prior to death.	Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
All-cause Mortality Through Day 84	All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 84 from any cause. Participants with unknown survival status through Day 84 were included as deaths in the calculation.	Through Day 84
Percentage of Participants With an Overall Outcome of Success Evaluated by Investigator	Overall response based on investigators' assessments was not derived as it was not deemed necessary because participants overall response status was determined by the DRC. All investigators' assessments of clinical, mycological and radiological responses are analyzed separately (see Outcome Measures 8-10).	Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Percentage of Participants With a Clinical Response Assessed by the DRC	Blinded assessments of clinical symptoms and physical findings of invasive fungal disease were performed by the independent DRC. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening. Participants with no attributable signs and symptoms present at Baseline and no symptoms attributable to invasive fungal disease (IFD) developed post-baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration.	Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Percentage of Participants With a Mycological Response Assessed by the DRC	Blinded mycological assessments of the participant's invasive fungal disease status were performed by the independent DRC using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline were classified as "Not Applicable". End of treatment is the last day of study drug administration.	Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Percentage of Participants With a Radiological Response Assessed by the DRC	Independent reviews of radiology assessments were completed by radiology experts which were provided to the independent, blinded DRC. Blinded radiological assessments were performed by the DRC. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Participants without any radiology at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration.	Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Percentage of Participants With a Clinical Response Assessed by the Investigator	Assessment of clinical symptoms and physical findings of invasive fungal disease were performed by the investigator. Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening, or if results were unavailable or the participant was unevaluable. Participants with no attributable signs and symptoms present at Baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration.	Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Percentage of Participants With a Mycological Response Assessed by the Investigator	Mycological assessments of the participant's invasive fungal disease status were performed by the investigator using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site. Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline, or no mycological follow-up results available or indeterminate results were classified as "Not Applicable". End of treatment is the last day of study drug administration.	Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Percentage of Participants With a Radiological Response Assessed by the Investigator	Radiological assessments were performed by the investigator. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Failure is defined as a < 25% improvement at any time or results not available. Participants with no signs on radiological images at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration.	Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days.
Number of Participants With Adverse Events, Reported by System Organ Class		From the first study drug administration until 28 days after the last dose of study drug. The median duration of study drug administration was 45 days.

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Collaborators: Basilea Pharmaceutica International Ltd

Publications and helpful links

General Publications

• Kovanda LL, Kolamunnage-Dona R, Neely M, Maertens J, Lee M, Hope WW. Pharmacodynamics of Isavuconazole for Invasive Mold Disease: Role of Galactomannan for Real-Time Monitoring of Therapeutic Response. Clin Infect Dis. 2017 Jun 1;64(11):1557-1563. doi: 10.1093/cid/cix198. Erratum In: Clin Infect Dis. 2017 Oct 15;65(8):1431-1433.
• Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, Bow EJ, Rahav G, Neofytos D, Aoun M, Baddley JW, Giladi M, Heinz WJ, Herbrecht R, Hope W, Karthaus M, Lee DG, Lortholary O, Morrison VA, Oren I, Selleslag D, Shoham S, Thompson GR 3rd, Lee M, Maher RM, Schmitt-Hoffmann AH, Zeiher B, Ullmann AJ. 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. Lancet. 2016 Feb 20;387(10020):760-9. doi: 10.1016/S0140-6736(15)01159-9. Epub 2015 Dec 10.

Helpful Links

• Link to results on Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2007
• Primary Completion (Actual): March 28, 2013
• Study Completion (Actual): March 28, 2013

Study Registration Dates

• First Submitted: December 18, 2006
• First Submitted That Met QC Criteria: December 18, 2006
• First Posted (Estimate): December 19, 2006

Study Record Updates

• Last Update Posted (Actual): April 5, 2019
• Last Update Submitted That Met QC Criteria: March 25, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Phase III; Isavuconazole; ASP9766; BAL8557; Invasive fungal disease; Filamentous fungi; Aspergillus species
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Invasive Fungal Infections; Aspergillosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Isavuconazole; Voriconazole
• Other Study ID Numbers: 9766-CL-0104; WSA-CS-004 (Other Identifier: Basilea Protocol ID); 2006-003868-59 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Access to anonymized individual participant level data collected during the trial, in addition to study-related supporting documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)