Isavuconazole (BAL8557) in the Treatment of Candidemia and Other Invasive Candida Infections

A Phase III, Double-blind, Randomized Study to Evaluate the Safety and Efficacy of BAL8557 Versus a Caspofungin Followed by Voriconazole Regimen in the Treatment of Candidemia and Other Invasive Candida Infections

The purpose of the study is to compare the safety and efficacy of isavuconazole versus caspofungin followed by voriconazole in the treatment of candidemia and other invasive Candida infections.

Study Overview

• Status: Completed
• Conditions: Mycoses; Candidemia; Candidiasis, Invasive
• Intervention / Treatment: Drug: Isavuconazole; Drug: Caspofungin; Drug: Voriconazole

Detailed Description

Candida infections, representing approximately 80% of all major systemic fungal infections, are the fourth most common cause of nosocomial bloodstream infections, with a mortality rate of 40%. Isavuconazole is not yet approved for the treatment of fungal infections. This study investigates the efficacy and safety of intravenous and oral isavuconazole. Patients are randomized to isavuconazole and the reference regimen. Patients with a positive blood- or deep tissue culture of candida fungi can be included.

• Study Type: Interventional
• Enrollment (Actual): 450
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Capital Federal, Argentina, C1280AEB
    • Hospital Britanico de Buenos Aires
  • Capital Federal, Argentina, C1405DCS
    • Hospital General de Agudos Dr. Carlos G. Durand
  • Ciudad Autonoma, Argentina, 1181
    • Hospital Italiano de Buenos Aires
  • Ciudad Autonoma, Argentina, 1426
    • Instituto Médico Especializado Alexander Fleming
  • La Boca, Argentina, 1157
    • Hospital General de Agudos Dr. Cosme Argerich
• Australia
  • Fremantle, Australia, 6160
    • Fremantle Hospital
  • South Brisbane, Australia
    • Mater Adult Hospital
  • Westmead, Australia
    • Westmead Hospital
  • Woolloongabba, Australia, 4102
    • Princess Alexandra Hospital
• Belgium
  • Brussels, Belgium, 1000
    • Institut Jules Bordet
  • Brussels, Belgium, 1090
    • Universitair Ziekenhuis Brussel
  • Bruxelles, Belgium, 1070
    • ULB Hôpital Erasme
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Leuven, Belgium, 3000
    • Universitaire Ziekenhuizen Leuven
• Brazil
  • Belo Horizonte, Brazil, 30150-221
    • Santa Casa de Misericórdia de Belo Horizonte
  • Belo Horizonte, Brazil, 30110-908
    • Hospital Felicio Rocho
  • Belo Horizonte, Brazil, 30130-100
    • Hospital das Clinicas da Universidade Federal de Minas Gerai
  • Curitiba, Brazil, 80060-150
    • Hospital das Clínicas da UFPR
  • Curitiba, Brazil, 80810-040
    • Hospital Nossa Senhora Das Gracas
  • Porto Alegre, Brazil
    • Irmandade da Santa Casa de Misericórdia de Porto Alegre
  • Porto Alegre, Brazil, 90610-000
    • Hospital Sao Lucas - PUCRS
  • Rio de Janeiro, Brazil, 21941-913
    • Hospital Universitario Clementino Fraga Filho
  • Santa Maria, Brazil, 97105-900
    • Hospital Universitário de Santa Maria
  • São Paulo, Brazil, 04020-002
    • Universidade Federal de São Paulo - UNIFESP
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8V 1C3
      • Hamilton Health Sciences - Henderson Site
    • Kingston, Ontario, Canada, K7L 3N6
      • Queen's University
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital - General Campus
    • Toronto, Ontario, Canada, M5G 2N2
      • University Health Network - Toronto General Hospital
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve - Rosemont
• Chile
  • Puente Alto Santiago, Chile
    • Hospital Dr. Sótero del Río
  • Santiago, Chile
    • Hospital del Salvador
  • Temuco, Chile, 4780000
    • Hospital Dr. Hernan Henriquez Aravena
• China
  • Chengdu, China, 610041
    • West China Hospital of Sichuan University
  • Shanghai, China, 200040
    • HuaShan Hospital Fudan University
• France
  • Strasbourg, France, 67048
    • Hôpital Hautepierre
  • Vandoeuvre les Nancy, France, 54511
    • Hôpital de Brabois Adultes
• Germany
  • Berlin, Germany, 10117
    • Charité Campus Mitte
  • Freiburg, Germany
    • Universitaetsklinikum Freiburg
  • Koeln, Germany, 50937
    • Universitaet Koeln
  • Leipzig, Germany, 04289
    • Universitaetsklinik Leipzig
  • Leipzig, Germany, 04129
    • Klinikum St. Georg
  • Luebeck, Germany
    • Universitaetsklinikum Leipzig
  • Wuerzburg, Germany, 97080
    • Universitaetsklinikum Wuerzburg
• Hungary
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Orvos- es Egeszsegtudomanyi Centrum
  • Györ, Hungary, 9024
    • Petz Aladár Megyei Oktató Kórház
• India
  • Chennai, India
    • Apollo Hospitals Educational & Research Foundation
  • Hyderabad, India, 500082
    • Nizam's Institute of Medical Sciences
  • Kolkata, India, 700098
    • AMRI Hospital
  • Vellore Tamilnadu, India
    • Christian Medical College & Hospital
  • Delhi
    • New Delhi, Delhi, India, 110017
      • Max Super Speciality Hospital
    • Noida, Delhi, India, 201301
      • Metro Centre for Respiratory Diseases
  • Karna
    • Mangalore, Karna, India, 575001
      • Kasturba Medical College and Hospital
    • Manipal, Karna, India, 576104
      • Kasturba Medical College K. M. C. Hospital
  • Kerala
    • Cochin, Kerala, India, 682041
      • Amrita Institute of Medical Science
  • Mahara
    • Pune, Mahara, India, 411004
      • Deenanath Mangeshkar Hospital and Research Centre
• Israel
  • Afula, Israel, 18101
    • Ha Emek Medical Center
  • Haifa, Israel, 31096
    • Rambam Health Care Campus
  • Holon, Israel, 58100
    • Wolfson Medical Center
  • Jerusalem, Israel, 91200
    • Hadassah Universtiy Hospital - Ein Kerem
  • Kfar-Saba, Israel, 44281
    • Sapir Medical Center, Meir Hospital
  • Petah, Israel, 49100
    • Rabin MC
  • Ramat Gan, Israel, 52621
    • Chaim Sheba Medical Center
  • Tel Aviv, Israel, 64239
    • Sourasky MC Ichilov Hospital Tel Aviv
• Italy
  • Bologna, Italy, 40138
    • Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Ma
  • Brescia, Italy, 25126
    • Azienda Ospedaliera Spedali Civili di Brescia
  • Genova, Italy, 16132
    • Azienda Ospedaliero Universitaria San Martino
  • Genova, Italy, 16128
    • Ente Ospedaliero Ospedeli Galliera
  • Verona, Italy, 37134
    • Azienda Ospedaliera di Verona-Ospedale Civile Maggiore
• Lebanon
  • Beirut, Lebanon, 11-0236
    • AUB Medical Center
  • Beirut, Lebanon, 5244
    • Rafik Hariri Uni Hospital
• Malaysia
  • Ampang, Malaysia, 68000
    • Hospital Ampang
  • Kuala Lumpur, Malaysia, 56000
    • Pusat Perubatan Universiti Kebangsaan Malaysia
• Mexico
  • Guadalajara, Mexico, 44280
    • Hospital Civil De Guadalajara Fray Antonio Alcalde
  • Guadalajara, Mexico, 44340
    • Hospital Civil de Guadalajara Dr Juan I Menchaca
  • Mexico, Mexico, 14000
    • Instituto Nacional de Ciencias Médicas y Nutrición Salvador
  • Monterrey, Mexico, 64460
    • Hospital Universitario Dr Jose Eleuterio Gonzalez
• New Zealand
  • Auckland, New Zealand
    • Auckland City Hospital
  • Hamilton, New Zealand
    • Waikato Urology Research LTD
• Philippines
  • Cavite City, Philippines
    • De La Salle Health Sciences Institute- DLSUMC
  • Manila, Philippines
    • Philippine General Hospital
• Russian Federation
  • Moscow, Russian Federation, 115478
    • S.I. Russian Oncological Research Center n.a. N.N. Blokhin
  • Moscow, Russian Federation, 125167
    • State Institution "Hematology Research Center" RAMS
• Singapore
  • Singapore, Singapore, 308433
    • National Neuroscience Institute
  • Singapore, Singapore, 169608
    • Singapore General Hospital - Parent
• South Africa
  • Lyttelton Centurion, South Africa, 0157
    • Unitas Hospital
• Spain
  • Barcelona, Spain, 08003
    • Hospital Del Mar
• Switzerland
  • Geneva, Switzerland
    • Hopitaux Universitaires de Geneve - HUG
  • Zurich, Switzerland
    • Universitaetsspital Zuerich
• Thailand
  • Bangkoknoi, Thailand, 10700
    • Siriraj Hospital
  • Hat Yai, Thailand, 90110
    • Songklanagarind Hospital
  • Muang, Thailand, 30000
    • Maharat Nakhon Ratchasima Hospital
  • Muang, Thailand, 40002
    • Srinagarind Hospital
  • Muang, Thailand, 50200
    • Maharaj Nakorn Chiang Mai Hospital
  • Ratchathewi, Thailand, 10400
    • Ramathibodi Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0006
      • University of Alabama at Birmingham
  • California
    • Palm Desert, California, United States, 92211
      • Somero Research Corporation
    • Sacramento, California, United States, 95817
      • University of California Davis Health System
    • San Francisco, California, United States, 94143
      • University of California at San Francisco
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Idaho Falls Infectious Diseases PLLC
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Hospital
    • Springfield, Illinois, United States, 62701
      • Springfield Clinic LLP
  • Indiana
    • Indianapolis, Indiana, United States, 46280
      • Infectious Disease of Indiana
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • UMass Memorial Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Montana
    • Butte, Montana, United States, 59701
      • Mercury Street Medical Group
  • New Jersey
    • Neptune, New Jersey, United States, 07753
      • Jersey Shore University Medical Center
  • New York
    • New York, New York, United States, 10065
      • New York Presbyterian Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Lima, Ohio, United States, 45801
      • Regional Infection Diseases Infusion Center Inc.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Health Sciences

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 with candidemia or with an invasive Candida infection
• Presence of fever, hypothermia or other appropriate local sign of infection
• Female patients must be non-lactating and at no risk of pregnancy

Exclusion Criteria:

• Patients with a sole diagnosis of mucocutaneous candidiasis, i.e. oropharyngeal, esophageal or genital candidiasis; or candidal lower urinary tract infection or Candida isolated solely from respiratory tract specimens
• Patients with candidemia who failed a previous antifungal therapy for the same infection
• Patients previously enrolled in a phase III study with isavuconazole
• Patients with a body weight <40kg

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 (ISA); Participants received 3 intravenous (IV) loading doses of 200 mg of isavuconazole on days 1 and 2, followed by an IV maintenance dose of 200 mg once daily from day 3 to day 56. On day 11 at the discretion of the investigator, non-neutropenic patients could switch from IV to oral therapy. Oral therapy consisted of 200 mg isavuconazole twice daily.	Drug: Isavuconazole; Administered by intravenous infusion.; Other Names: ASP9766; BAL8557
Active Comparator: Caspofungin (CAS)/Voriconazole; Participants received 1 intravenous (IV) loading dose of 70 mg CAS on day 1, followed by an IV maintenance dose of 50 mg CAS from day 2 to day 56. On day 11 at the discretion of the investigator, non-neutropenic patients could switch from IV CAS to oral voriconazole comprising of a loading dose of 400 mg twice daily (BID) on the first day of oral therapy followed by standard dosing of 200 mg BID thereafter.	Drug: Caspofungin; Administered by intravenous infusion.; Other Names: Cancidas; Drug: Voriconazole; Administered by intravenous infusion.; Other Names: VFend

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Overall Response of Success at the End of Intravenous Therapy (EOIV) as Determined by the Data Review Committee (DRC) Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use	A Data Review Committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication) without the use of alternative systemic antifungal therapy (AFT) within 48 hours after the last dose of IV study medication.	End of Intravenous Treatment (EOIV) (Days 11-56)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Overall Response of Success at Follow Up Visit 1 (FU1-2 Weeks After End of Treatment (EOT)) as Determined by the DRC Based on the Assessments of Clinical, Mycological Responses and Antifungal Therapy (AFT)	A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication), without the use of alternative systemic AFT within 48 hours after the last dose of IV study medication.	End of Treatment (EOT) (Day 56) and FU1 (2 weeks after end of treatment)
Percentage of Participants With Overall Response of Success at EOT and Follow Up Visit 2 (FU2) as Determined by the DRC Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use at EOT and FU2	A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication), without the use of alternative systemic antifungal therapy AFT within 48 hours after the last dose of IV study medication (for EOT analysis) or for continued treatment of the primary infection, or for recurrent or emergent infection by FU2, with no recurrent or emergent infection by FU2 (for FU2 analysis).	EOT (Day 56) and FU2 (6 weeks after end of treatment)
Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC)	A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial).	EOIV (Days 11-56), EOT (Day 56), FU1 (2 weeks after end of treatment) and FU2 (6 weeks after end of treatment)
Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC)	A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as mycological response (Eradication or Presumed Eradication).	EOIV (Days 11-56), EOT (Day 56), FU1 (2 weeks after end of treatment) and FU2 (6 weeks after end of treatment)
Percentage of Participants With Mycological Response of Success at Day 7 and EOT as Determined by The Investigator	Success was defined as mycological response (eradication or presumed eradication).	Day 7 and EOT (Day 56)
Percentage of Participants With Clinical Response of Success at Day 7 and EOT as Determined by The Investigator	Investigators defined clinical response as success if participants exhibited complete or partial clinical response after evaluation of clinical signs and symptoms.	Day 7 and EOT (Day 56)
All-Cause Mortality (ACM) at Day 14 and Day 56	All-cause mortality is represented as the percentage of participants who died on or before the analysis day. Participants who were lost to follow-up (i.e., unknown survival status) before the analysis day were counted as death. All-cause mortality was examined on Day 14 and Day 56.	Day 14 and Day 56
Time to First Confirmed Negative Culture	The first confirmed negative blood culture was defined as the first negative blood culture on or after first dose followed by a second negative blood culture at least 24 hours apart without any positive blood cultures in between. A participant without a confirmed negative blood culture was censored on the participant's last visit day. This endpoint was analyzed for mITT participants with candidemia only using the Kaplan-Meier method. Only participants with at least one positive blood culture on or prior to first dose and the culture not resolved prior to first dose were included in this analysis	Day 1 up to FU1 (2 weeks after EOT (Day 56))

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Collaborators: Basilea Pharmaceutica

Publications and helpful links

General Publications

• Kullberg BJ, Viscoli C, Pappas PG, Vazquez J, Ostrosky-Zeichner L, Rotstein C, Sobel JD, Herbrecht R, Rahav G, Jaruratanasirikul S, Chetchotisakd P, Van Wijngaerden E, De Waele J, Lademacher C, Engelhardt M, Kovanda L, Croos-Dabrera R, Fredericks C, Thompson GR. Isavuconazole Versus Caspofungin in the Treatment of Candidemia and Other Invasive Candida Infections: The ACTIVE Trial. Clin Infect Dis. 2019 May 30;68(12):1981-1989. doi: 10.1093/cid/ciy827.
• McCormack PL. Isavuconazonium: first global approval. Drugs. 2015 May;75(7):817-22. doi: 10.1007/s40265-015-0398-6.

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2007
• Primary Completion (Actual): March 3, 2015
• Study Completion (Actual): March 3, 2015

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): February 15, 2019
• Last Update Submitted That Met QC Criteria: January 31, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Isavuconazole; ASP9766; BAL8557; Candidemia; Invasive Candida infections; Phase III study; Candidemia and other invasive candida infections
• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections and Mycoses; Sepsis; Invasive Fungal Infections; Fungemia; Infections; Candidiasis; Candidemia; Candidiasis, Invasive; Mycoses; 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; Caspofungin; Isavuconazole; Voriconazole
• Other Study ID Numbers: 9766-CL-0105; WSA-CS-008 (Other Identifier: Basilea Pharmaceutica Ltd); 2006-003951-18 (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)