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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    2006-003951-18
    Trial protocol
    BE   DE   HU   ES   NL   IT   GB  
    Global end of trial date
    03 Mar 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    9766-CL-0105
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00413218
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Astellas Study Drug Name: Isavuconazonium sulfate (BAL8557/ASP9766)
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc.
    Sponsor organisation address
    One Astellas Way, Northbrook, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to compare the efficacy of treatment with isavuconazole versus caspofungin in participants with candidemia or other invasive Candida infections and examine safety and tolerability of treatment with isavuconazole versus caspofungin/voriconazole regimen.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP). Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Mar 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 15
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Belgium: 39
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    China: 2
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    India: 26
    Country: Number of subjects enrolled
    Israel: 72
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Lebanon: 4
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Philippines: 3
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Thailand: 82
    Country: Number of subjects enrolled
    United States: 56
    Worldwide total number of subjects
    450
    EEA total number of subjects
    102
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    276
    From 65 to 84 years
    157
    85 years and over
    17

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were stratified by geographical region (North America; Western Europe plus Australia and New Zealand; or Other Regions) and baseline neutropenic status (presence vs absence) defined as absolute neutrophil count (ANC) < 0.5 x 10^9/L [< 500/mm^3] for ≥ 10 days.

    Pre-assignment
    Screening details
    Consenting male and female participants aged ≥ 18 with candidemia or an invasive Candida infection who had a positive blood or tissue culture obtained within 96 hours prior to randomization and meeting the inclusion/exclusion criteria were enrolled in the study.

    Pre-assignment period milestones
    Number of subjects started
    450
    Number of subjects completed
    440

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Participants didn't meet incl/excl: 4
    Reason: Number of subjects
    Participants didn't take study drug: 6
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    Participants were randomized 1:1 to receive either isavuconazole or caspofungin in a blinded way. The sponsor, contract research organization (CRO) staff, investigators, participants and study coordinator(s) were blinded to randomization of study drug.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Isavuconazole (ISA)
    Arm description
    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 participants could switch from IV to oral therapy. Oral therapy consisted of 200 mg isavuconazole once daily.
    Arm type
    Experimental

    Investigational medicinal product name
    Isavuconazole
    Investigational medicinal product code
    BAL8557
    Other name
    Pharmaceutical forms
    Powder for infusion, Capsule
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Isavuconazole for IV administration was provided as lyophilized powder for IV infusion. Isavuconazole (200 mg) was dissolved in 250 mL of a compatible infusion solution.

    Arm title
    Caspofungin (CAS)/Voriconazole
    Arm description
    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 participants 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.
    Arm type
    Active comparator

    Investigational medicinal product name
    Voriconazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For oral therapy, over-encapsulated voriconazole tablets were provided. Each tablet contained 200 mg of voriconazole.

    Investigational medicinal product name
    Caspofungin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Caspofungin for IV administration was provided as a lyophilized powder. Caspofungin (50 or 70 mg) was dissolved in 250 mL of a compatible infusion solution.

    Number of subjects in period 1 [1]
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole
    Started
    221
    219
    Completed
    120
    131
    Not completed
    101
    88
         Missing
             1
             -
         Adverse event, serious fatal
             57
             56
         Admin/Other
             20
             14
         Consent withdrawn by subject
             9
             1
         Lost to follow-up
             14
             17
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Four hundred and fifty participants were randomized in the study however 10 participants did not receive treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Isavuconazole (ISA)
    Reporting group description
    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 participants could switch from IV to oral therapy. Oral therapy consisted of 200 mg isavuconazole once daily.

    Reporting group title
    Caspofungin (CAS)/Voriconazole
    Reporting group description
    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 participants 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.

    Reporting group values
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole Total
    Number of subjects
    221 219
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58 ± 17.54 57.9 ± 16.88 -
    Gender categorical
    Units:
        Male
    143 126 269
        Female
    78 93 171

    End points

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    End points reporting groups
    Reporting group title
    Isavuconazole (ISA)
    Reporting group description
    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 participants could switch from IV to oral therapy. Oral therapy consisted of 200 mg isavuconazole once daily.

    Reporting group title
    Caspofungin (CAS)/Voriconazole
    Reporting group description
    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 participants 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.

    Subject analysis set title
    Intent to Treat (ITT)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The intent to treat (ITT) population consisted of all randomized participants who received at least one dose of study drug. For the ITT, data were analyzed by the treatment group that participants were randomized to.

    Subject analysis set title
    Modified Intent to Treat (mITT)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The modified intent to treat (mITT) population consisted of ITT participants who had documented invasive candidiasis or candidemia at baseline based on the assessment of the independent blinded Data Review Committee (DRC).

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis set (SAF) consisted of all participants who received at least one dose of study drug. For the SAF data were analyzed according to the first dose of study drug participants received even if it was different from what they were randomized to.

    Primary: 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

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    End point title
    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
    End point description
    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 [Crude rates of overall response were calculated within treatment group]. 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. The isavuconazole and caspofungin group included participants who switched to oral isavuconazole and oral voriconazole. The mITT population was used for this analysis.
    End point type
    Primary
    End point timeframe
    Day 7 and End of Intravenous Therapy (EOIV) (up to 56 days)
    End point values
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole
    Number of subjects analysed
    199
    201
    Units: Percentage of participants
    number (not applicable)
        Success
    60.3
    71.1
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS)
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified Cochran-Mantel-Haenszel (CMH) method with the strata of geographical region and baseline neutropenic status. The 95% CI for treatment group is based on a binomial distribution and the 95% CI for the treatment difference is calculated based on a normal approximation.
    Comparison groups
    Caspofungin (CAS)/Voriconazole v Isavuconazole (ISA)
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -10.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.9
         upper limit
    -1.8
    Notes
    [1] - The lower bound of the 95% CI for the adjusted treatment difference was compared to the protocol prespecified NIM value of -15%. If the lower bound were greater than -15%, isavuconazole would be declared as noninferior to caspofungin.

    Secondary: 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)

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    End point title
    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)
    End point description
    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 based on the DRC assessments of clinical and mycological responses as well as alternative systemic antifungal therapy (AFT) use and recurrent or emergent infection. The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole. The mITT population was used for this analysis.
    End point type
    Secondary
    End point timeframe
    2 weeks after last dose of study drug
    End point values
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole
    Number of subjects analysed
    199
    201
    Units: Percentage of participants
    number (not applicable)
        Success
    54.8
    57.2
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS)
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -2.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.2
         upper limit
    6.8
    Notes
    [2] - If the noninferiority for the primary efficacy endpoint were met, the noninferiority for the key secondary endpoint would be established if the lower limit of the 95% CI were greater than -15%.

    Secondary: 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

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    End point title
    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
    End point description
    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 (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). N= represents actual number of participants used in the analysis. The mITT population was used for this analysis.
    End point type
    Secondary
    End point timeframe
    EOT (up to Day 56) and FU2 (6 weeks after last dose of study drug)
    End point values
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole
    Number of subjects analysed
    199
    201
    Units: Percentage of Participants
    number (not applicable)
        EOT [N=122; 145]
    61.3
    72.1
        FU2 [N=86; 97]
    43.2
    48.3
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [EOT]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference %
    Point estimate
    -10.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.9
         upper limit
    -1.9
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [FU2]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference %
    Point estimate
    -5.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15
         upper limit
    4.2

    Secondary: Percentage of Participants with Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC)

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    End point title
    Percentage of Participants with Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC)
    End point description
    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). The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole. The mITT population was used for this analysis.
    End point type
    Secondary
    End point timeframe
    EOIV, EOT (up to Day 56) and 2 weeks after last dose of study drug and 6 weeks after last dose of study drug
    End point values
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole
    Number of subjects analysed
    199
    201
    Units: Percentage of participants
    number (not applicable)
        Success- End of Intravenous Treatment (EOIV)
    76.4
    84.1
        Success- End of Treatment (EOT)
    76.4
    84.6
        Success- Follow-up Visit 1 (FU1)
    67.8
    67.7
        Success- Follow-up Visit 2 (FU2)
    52.8
    58.2
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [EOIV]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -8.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.4
         upper limit
    -0.9
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [EOT]
    Statistical analysis description
    TThe adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -8.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.8
         upper limit
    -1.5
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [FU1]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.1
         upper limit
    8.3
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [FU2]
    Statistical analysis description
    TThe adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -5.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.3
         upper limit
    3.6

    Secondary: Percentage of Participants with Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC)

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    End point title
    Percentage of Participants with Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC)
    End point description
    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). The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole. The mITT population was used for this analysis.
    End point type
    Secondary
    End point timeframe
    EOIV (up to the maximum duration of therapy of 56 days), EOT (up to day 56), 2 weeks after last dose of study drug, and 6 weeks after last dose of study drug
    End point values
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole
    Number of subjects analysed
    199
    201
    Units: Percentage of participants
    number (not applicable)
        Success-EOIV
    70.9
    85.6
        Success-EOT
    71.9
    87.6
        Success-FU1
    66.8
    65.7
        Success-FU2
    51.8
    56.7
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [EOIV]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -14.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.7
         upper limit
    -7
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [EOT]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -15.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.5
         upper limit
    -8.4
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [FU1]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.1
         upper limit
    9.6
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [FU2]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -5.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.7
         upper limit
    4.3

    Secondary: Percentage of Participants with Mycological Response of Success at Day 7 and EOT as Determined by The Investigator

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    End point title
    Percentage of Participants with Mycological Response of Success at Day 7 and EOT as Determined by The Investigator
    End point description
    The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole.Success was defined as mycological response (Eradication or Presumed Eradication). The mITT population was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Day 7 and EOT (up to Day 56)
    End point values
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole
    Number of subjects analysed
    199
    201
    Units: Percentage of participants
    number (not applicable)
        Day 7
    61.3
    72.1
        EOT
    72.9
    81.1
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [EOT]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -8.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.5
         upper limit
    -0.4
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [Day 7]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -11.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.4
         upper limit
    -2.5

    Secondary: Percentage of Participants with Clinical Response of Success at Day 7 and EOT as Determined by The Investigator

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    End point title
    Percentage of Participants with Clinical Response of Success at Day 7 and EOT as Determined by The Investigator
    End point description
    The isavuconazole and caspofungin group included participants who switched to oral isavuconazol and voriconazole. Success was defined as clinical response (complete or partial). The mITT population was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Day 7 and EOT (up to Day 56)
    End point values
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole
    Number of subjects analysed
    199
    201
    Units: Percentage of Participants
    number (not applicable)
        Day 7
    54.3
    64.7
        EOT
    70.9
    78.6
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [Day 7]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Difference (%)
    Point estimate
    -11.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.3
         upper limit
    -1.9
    Statistical analysis title
    Adjusted Treatment Difference (ISA-CAS) [EOT]
    Statistical analysis description
    The adjusted treatment difference (ISA-CAS) was calculated by a stratified CMH method with the strata of geographical region and baseline neutropenic status. The 95% CI for the adjusted treatment difference was calculated based on a normal approximation.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    -8.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.3
         upper limit
    0.1

    Secondary: All-Cause Mortality (ACM) at Day 14 and Day 56

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    End point title
    All-Cause Mortality (ACM) at Day 14 and Day 56
    End point description
    All-cause mortality is represented as the percentage of participants who died on or before the landmark day as well as participants who were lost to follow-up (i.e., unknown survival status) before the analysis day were counted as death. All-cause mortality rate was examined at day 14 and day 56. The mITT population was used for this analysis.
    End point type
    Secondary
    End point timeframe
    Day 14 and Day 56
    End point values
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole
    Number of subjects analysed
    199
    201
    Units: Percentage of participants
    number (not applicable)
        Day 14 All-cause Mortality
    14.6
    12.4
        Day 56 All-cause Mortality
    30.7
    29.9
    Statistical analysis title
    All-cause Mortality - Day 56
    Statistical analysis description
    Adjusted treatment difference (Isavuconazole-Caspofungin) is calculated by a stratified CMH method with the strata of geographical regions, and baseline neutropenic status. The 95% CI for treatment group is based on a binomial distribution and the 95% CI for the treatment difference is calculated based on a normal approximation.The ITT population was used for this analysis.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.1
         upper limit
    10
    Statistical analysis title
    All-cause Mortality - Day 14
    Statistical analysis description
    Adjusted treatment difference (Isavuconazole-Caspofungin) is calculated by a stratified CMH method with the strata of geographical regions, and baseline neutropenic status. The 95% CI for treatment group is based on a binomial distribution and the 95% CI for the treatment difference is calculated based on a normal approximation. The ITT population was used for this analysis.
    Comparison groups
    Isavuconazole (ISA) v Caspofungin (CAS)/Voriconazole
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Adjusted Treatment Difference (%)
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    8.9

    Secondary: Time to First Confirmed Negative Culture

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    End point title
    Time to First Confirmed Negative Culture
    End point description
    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 was included in this analysis
    End point type
    Secondary
    End point timeframe
    Days 3, 7, 10, 14 and 21
    End point values
    Isavuconazole (ISA) Caspofungin (CAS)/Voriconazole
    Number of subjects analysed
    120
    119
    Units: Days
        median (confidence interval 95%)
    4 (3 to 6)
    3 (3 to 4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 - Day 56 + FU2 (1 Week)
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAE) is an adverse event which has started after first study drug administration until 28 days after the last dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Caspofungin (CAS)/Voriconazole
    Reporting group description
    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 participants 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.

    Reporting group title
    Isavuconazole (ISA)
    Reporting group description
    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 once daily.

    Serious adverse events
    Caspofungin (CAS)/Voriconazole Isavuconazole (ISA)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    106 / 220 (48.18%)
    112 / 220 (50.91%)
         number of deaths (all causes)
    68
    66
         number of deaths resulting from adverse events
    Vascular disorders
    Arterial thrombosis limb
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 220 (0.45%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematoma
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 220 (0.45%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Shock haemorrhagic
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hodgkin's disease refractory
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to liver
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sarcoma
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    7 / 220 (3.18%)
    5 / 220 (2.27%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 5
         deaths causally related to treatment / all
    0 / 5
    1 / 3
    Necrosis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain herniation
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Donor site complication
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug toxicity
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme abnormal
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 220 (0.91%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 220 (0.00%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    6 / 220 (2.73%)
    4 / 220 (1.82%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 6
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Cardiac Failure
         subjects affected / exposed
    2 / 220 (0.91%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Congenital, familial and genetic disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 220 (0.45%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 220 (0.45%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 220 (0.91%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    2 / 220 (0.91%)
    4 / 220 (1.82%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulmonary necrosis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 220 (0.45%)
    5 / 220 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Respiratory failure
         subjects affected / exposed
    8 / 220 (3.64%)
    12 / 220 (5.45%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 13
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 220 (1.36%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia Hemolytic Autoimmune
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 220 (0.91%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Basilar artery thrombosis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic encephalopathy
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoxic encephalopathy
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intracranial haematoma
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 220 (0.91%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 220 (0.91%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peritonitis
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 220 (1.36%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrectasia
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 220 (0.91%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Renal failure acute
         subjects affected / exposed
    3 / 220 (1.36%)
    10 / 220 (4.55%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 10
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Renal failure chronic
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 220 (0.91%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatosplenomegaly
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic complication
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 220 (1.36%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    2 / 220 (0.91%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 220 (0.00%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    4 / 220 (1.82%)
    3 / 220 (1.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Candida endophthalmitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral aspergillosis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fungal infection
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Klebsiella infection
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 220 (0.45%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Lung abscess
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mediastinitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Meningitis bacterial
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenic sepsis
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pneumonia
         subjects affected / exposed
    6 / 220 (2.73%)
    2 / 220 (0.91%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    9 / 220 (4.09%)
    16 / 220 (7.27%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 16
         deaths causally related to treatment / all
    0 / 5
    0 / 8
    Septic shock
         subjects affected / exposed
    11 / 220 (5.00%)
    19 / 220 (8.64%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 19
         deaths causally related to treatment / all
    0 / 6
    0 / 12
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 220 (0.91%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Wound abscess
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Caspofungin (CAS)/Voriconazole Isavuconazole (ISA)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    167 / 220 (75.91%)
    162 / 220 (73.64%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 220 (5.45%)
    9 / 220 (4.09%)
         occurrences all number
    13
    9
    Hypotension
         subjects affected / exposed
    27 / 220 (12.27%)
    22 / 220 (10.00%)
         occurrences all number
    29
    30
    Phlebitis
         subjects affected / exposed
    15 / 220 (6.82%)
    14 / 220 (6.36%)
         occurrences all number
    20
    14
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    11 / 220 (5.00%)
    4 / 220 (1.82%)
         occurrences all number
    12
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    11 / 220 (5.00%)
    5 / 220 (2.27%)
         occurrences all number
    11
    5
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    9 / 220 (4.09%)
    18 / 220 (8.18%)
         occurrences all number
    10
    20
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 220 (5.91%)
    10 / 220 (4.55%)
         occurrences all number
    14
    11
    Dyspnoea
         subjects affected / exposed
    14 / 220 (6.36%)
    15 / 220 (6.82%)
         occurrences all number
    14
    18
    Pleural effusion
         subjects affected / exposed
    12 / 220 (5.45%)
    11 / 220 (5.00%)
         occurrences all number
    12
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 220 (8.18%)
    13 / 220 (5.91%)
         occurrences all number
    21
    14
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    6 / 220 (2.73%)
    11 / 220 (5.00%)
         occurrences all number
    6
    15
    Oedema peripheral
         subjects affected / exposed
    16 / 220 (7.27%)
    15 / 220 (6.82%)
         occurrences all number
    17
    17
    Pyrexia
         subjects affected / exposed
    41 / 220 (18.64%)
    38 / 220 (17.27%)
         occurrences all number
    73
    56
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    7 / 220 (3.18%)
    11 / 220 (5.00%)
         occurrences all number
    8
    11
    Agitation
         subjects affected / exposed
    13 / 220 (5.91%)
    5 / 220 (2.27%)
         occurrences all number
    15
    5
    Insomnia
         subjects affected / exposed
    10 / 220 (4.55%)
    12 / 220 (5.45%)
         occurrences all number
    10
    13
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 220 (9.09%)
    16 / 220 (7.27%)
         occurrences all number
    23
    17
    Constipation
         subjects affected / exposed
    24 / 220 (10.91%)
    32 / 220 (14.55%)
         occurrences all number
    31
    34
    Diarrhoea
         subjects affected / exposed
    41 / 220 (18.64%)
    33 / 220 (15.00%)
         occurrences all number
    49
    37
    Nausea
         subjects affected / exposed
    30 / 220 (13.64%)
    21 / 220 (9.55%)
         occurrences all number
    37
    28
    Vomiting
         subjects affected / exposed
    37 / 220 (16.82%)
    33 / 220 (15.00%)
         occurrences all number
    49
    44
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    10 / 220 (4.55%)
    14 / 220 (6.36%)
         occurrences all number
    19
    15
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    6 / 220 (2.73%)
    13 / 220 (5.91%)
         occurrences all number
    6
    15
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    18 / 220 (8.18%)
    18 / 220 (8.18%)
         occurrences all number
    21
    19
    Hypomagnesaemia
         subjects affected / exposed
    29 / 220 (13.18%)
    18 / 220 (8.18%)
         occurrences all number
    31
    22
    Hyponatraemia
         subjects affected / exposed
    14 / 220 (6.36%)
    12 / 220 (5.45%)
         occurrences all number
    16
    12
    Hypokalaemia
         subjects affected / exposed
    44 / 220 (20.00%)
    41 / 220 (18.64%)
         occurrences all number
    50
    49
    Hypophosphataemia
         subjects affected / exposed
    9 / 220 (4.09%)
    15 / 220 (6.82%)
         occurrences all number
    11
    15
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    9 / 220 (4.09%)
    11 / 220 (5.00%)
         occurrences all number
    9
    12
    Staphylococcal bacteraemia
         subjects affected / exposed
    9 / 220 (4.09%)
    13 / 220 (5.91%)
         occurrences all number
    10
    13
    Urinary tract infection bacterial
         subjects affected / exposed
    12 / 220 (5.45%)
    7 / 220 (3.18%)
         occurrences all number
    12
    7

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jan 2007
    Protocol Amendment 1, dated January 09, 2007, changed the study drug name from BAL4815 to isavuconazole. The number of study sites was increased from 100 to 180. The inclusion/exclusion criteria were amended and further clarified. The timing of the first oral maintenance dose was clarified. The use of 70 mg caspofungin was clarified. The setting of treatment administration after the first 48 hours was specified. The number of plasma samples for pharmacokinetic profiling was reduced from 8 to 7. The measures taken to prevent unblinding of the IDMSB were specified. The information on drug-drug interactions in healthy volunteers was updated. The list of concomitant medications that should be used with caution was updated. The time windows for visits starting at day 7 were amended. A statement was added that in case of cultures with voriconazole- or caspofungin-resistant species during the study period, patients were allowed to remain in the study provided they showed clinical improvement; otherwise, they would be considered failures and withdrawn from the study.
    12 Feb 2007
    Protocol Amendment 2, dated February 12, 2007, amended and further clarified the inclusion/exclusion criteria. The dose of 70 mg caspofungin was clarified to be a maintenance dose for patients receiving concomitant efavirenz, nevirapine, dexamethasone or phenytoin (in addition to patients with a body weight > 80 kg). A prohibition on switching patients from oral therapy back to intravenous therapy was added. Isolate re-evaluation in a central laboratory was limited to specific positive cultures. Dose adaptation of caspofungin was allowed. The interval between IV infusions of isavuconazole and caspofungin was amended to 8 hours. The schedule of assessments was updated with a blood sample collection for biomarkers and a footnote specifying the day for pharmacokinetic assessments. The site’s informed consent log was added. Circumstances for analyzing the biomarker sample were specified. Day 14 was specified as the preferred day for pharmacokinetic sample collection. Reporting of serious adverse events (SAEs) in patients who were consented but not randomized was clarified. The interim analysis text was updated.
    07 Apr 2008
    Protocol Amendment 3, dated April 7, 2008, amended and exclusion criterion 11 was revised to exclude patients who received more than 48 hours of prior systemic AFT within 96 hours prior to randomization.
    27 May 2010
    Protocol Amendment 4, dated May 27, 2010, reflected the change in study sponsorship; Basilea Pharmaceuticals was replaced with Astellas Pharma Global Development, Inc.The inclusion/exclusion criteria were amended and further clarified. Secondary and exploratory efficacy variables were added. Isavuconazole dosing was clarified. Criteria were added to extend therapy if needed for deep-seated infections. Additional medications were added to the list of prohibited concomitant medications or the list of concomitant medications to be used with caution. Patient withdrawal criteria were clarified. Study procedures were amended, clarified and added. The collection of trough samples and pharmacokinetic samples was specified. The statistical power, sample size, type I and type II error were clarified. The P value for evidence of superiority of isavuconazole was amended. The safety population criteria were amended. The pharmacokinetic population was amended and the pharmacokinetic analysis was updated.
    17 Nov 2010
    Protocol Amendment 5, dated November 17, 2010, updated the primary study variable and amended the secondary objective and the exploratory objectives and variables. The interim analysis was omitted from the protocol because it was not a requirement and the IDSMB’s ongoing review of blinded safety data ensured the continuing safety of patients. The inclusion/exclusion criteria were amended and further clarified. The timing of the first IV maintenance dose was clarified. The collection times of pharmacokinetic trough samples were amended. The number of patients included in IDSMB review was corrected. Guidance to determine neutropenia resolution and additional guidance for oral therapy dosing were provided. Follow-up visit 3 and biomarker sampling were removed. Laboratory tests were added and creatinine clearance calculation was amended.
    15 Jul 2013
    Protocol Amendment 6, dated July 15, 2013, amended the primary study objective of the study to assess the efficacy of treatment with isavuconazole vs caspofungin instead of comparing the efficacy of isavuconazole vs caspofungin and voriconazole. The primary efficacy variable was amended to overall response at EOIV instead of overall response at FU1. Protocol Amendment 6 further amended the secondary study objectives and the secondary efficacy variables and implemented a DRC. The statistical power, sample size, type I and type II error were amended and the justification for the sample size was included. The inclusion/exclusion criteria were amended and further clarified. The safety and pharmacokinetic variables were amended and further clarified. The collection of pharmacokinetic trough samples was clarified. Sample collection and analysis for the pharmacokinetic sub-study were clarified. The safety analysis was clarified. The requirement for dialysis was removed as a treatment endpoint for this study. More detailed instructions regarding participant counseling and compliance with oral study drug for recording drug accountability were provided. Additional medications were added to the list of prohibited concomitant medications or the list of concomitant medications to be used with caution. The requirement for blood culture sampling through day 9 and the collection of radiology reports were removed. Additional laboratory tests were included. The requirements for electrocardiogram (ECG) collection and the purpose of the central line were clarified. The optional genotype analysis was clarified.
    09 Sep 2014
    Protocol Amendment 8, dated September 09, 2014, reduced the sample size to change the power of the study from 90% to 86%. With the assumption that the overall response rate remained 70% for both arms, a revised sample size of 438 ITT patients (or 350 mITT patients) provided at least 86% power to demonstrate that the non-inferiority of isavuconazole to caspofungin with the chosen noninferiority margin (NIM) of 15%.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Jan 2009
    Enrollment in the clinical study was suspended in January 2009 pending further characterization of newly identified impurities. After successful completion of the studies, regulatory notifications and transfer of sponsorship from Basilea to Astellas, resumption of enrollment occurred in March 2011.
    01 Mar 2011

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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