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    Clinical Trial Results:
    A Phase 3 Randomized Study of the Efficacy and Safety of Posaconazole versus Voriconazole for the Treatment of Invasive Aspergillosis in Adults and Adolescents (Phase 3; Protocol No. MK-5592-069)

    Summary
    EudraCT number
    		 2011-003938-14
    Trial protocol
    		 ES   DE   BE   LT   PT   GB   EE   IT   PL   GR   FR   HU   CZ   HR   RO  
    Global end of trial date
    10 Sep 2019

    Results information
    Results version number
    		 v1
    This version publication date
    26 Aug 2020
    First version publication date
    26 Aug 2020
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    P06200
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01782131
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Registration: MK-5592-069
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the safety and efficacy of posaconazole (POS) versus voriconazole (VOR) in the treatment of adults and adolescents with invasive aspergillosis (IA). The primary hypothesis is that the all-cause mortality through Day 42 in the POS treatment group is non-inferior to that in the VOR treatment group.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Sep 2013
    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
    Belgium: 84
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Chile: 5
    Country: Number of subjects enrolled
    China: 62
    Country: Number of subjects enrolled
    Colombia: 51
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Israel: 59
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 39
    Country: Number of subjects enrolled
    Mexico: 29
    Country: Number of subjects enrolled
    Peru: 6
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Russian Federation: 36
    Country: Number of subjects enrolled
    Serbia: 4
    Country: Number of subjects enrolled
    Singapore: 14
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Turkey: 30
    Country: Number of subjects enrolled
    United States: 35
    Worldwide total number of subjects
    585
    EEA total number of subjects
    172
    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)
    5
    Adults (18-64 years)
    417
    From 65 to 84 years
    161
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 After a screening phase of up to 7 days, 585 participants were enrolled/randomized, but only 575 began treatment (288 in the posaconazole [POS] group and 287 in the voriconazole [VOR] group).

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Assessor, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Posaconazole
    Arm description
    		 Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Voriconazole
    Arm description
    		 Participants received 6 mg/kg voriconazole (VOR) IV BID on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Posaconazole Voriconazole
    Started
    293
    292
    Completed
    288
    287
    Not completed
    5
    5
         Randomized but not treated
    5
    5
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Posaconazole
    Arm description
    		 Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Posaconazole
    Investigational medicinal product code
    Other name
    SCH 056592 MK-5592 Noxafil®
    Pharmaceutical forms
    Tablet, Infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    POS IV: Day 1b: 300 mg BID, Day 2-84: 300 mg QD; POS oral: Day 1b: 300 mg BID, Day 2-84: 300 mg QD

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Matching placebo received for Posaconazole

    Arm title
    		 Voriconazole
    Arm description
    		 Participants received 6 mg/kg voriconazole (VOR) IV BID on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Voriconazole
    Investigational medicinal product code
    Other name
    VFEND®
    Pharmaceutical forms
    Capsule, Infusion
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    VOR IV: Day 1b: 6 mg/kg per body weight administered BID, Day 2-84: 4 mg/kg per body weight administered BID; VOR oral: Day 1b: 300 mg BID, Day 2-84: 200 mg BID

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Matching placebo received for Voriconazole

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The All Patients as Treated population was used as the baseline population.
    Number of subjects in period 2 [2]
    		Posaconazole Voriconazole
    Started
    288
    287
    Completed
    184
    177
    Not completed
    104
    110
         Adverse event, serious fatal
    93
    96
         Consent withdrawn by subject
    10
    10
         Lost to follow-up
    1
    3
         Reason not provided
    -
    1
    Notes
    [2] - 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: The All Patients as Treated population was used as the baseline population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Posaconazole
    Reporting group description
    		 Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.

    Reporting group title
    Voriconazole
    Reporting group description
    		 Participants received 6 mg/kg voriconazole (VOR) IV BID on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.

    Reporting group values
    		 Posaconazole Voriconazole Total
    Number of subjects
    		 288 287
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.5 ( 16.7 ) 53.0 ( 15.9 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 116 115 231
        Male
    		 172 172 344
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 4 6 10
        Asian
    		 62 60 122
        Black or African American
    		 3 4 7
        Multiple
    		 25 25 50
        White
    		 194 192 386
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 48 57 105
        Not Hispanic or Latino
    		 220 219 439
        Unknown or Not Reported
    		 20 11 31

    End points

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    End points reporting groups
    Reporting group title
    Posaconazole
    Reporting group description
    		 Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.

    Reporting group title
    Voriconazole
    Reporting group description
    		 Participants received 6 mg/kg voriconazole (VOR) IV BID on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
    Reporting group title
    Posaconazole
    Reporting group description
    		 Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.

    Reporting group title
    Voriconazole
    Reporting group description
    		 Participants received 6 mg/kg voriconazole (VOR) IV BID on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.

    Primary: Percentage of Participants Who Died Through Day 42 in the Intention to Treat Population

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    End point title
    		 Percentage of Participants Who Died Through Day 42 in the Intention to Treat Population
    End point description
    The percentage of participants who died with posaconazole (POS) compared to voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) in the Intention to Treat (ITT) population through Day 42 was assessed. The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to ~42 days
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    288
    287
    Units: Percentage of Participants
        number (not applicable)
    15.3
    20.6
    Statistical analysis title
    		 All-Cause Mortality by Day 42 in ITT
    Statistical analysis description
    Based on Miettinen and Nurminen’s method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme. The p-Value is based on the one-sided non inferiority test. Non-inferiority of posaconazole vs. voriconazole is established if the upper limit of the 95% confidence interval is less than 10%.
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Estimated Difference in Percent
    Point estimate
    -5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.6
         upper limit
    		 1

    Secondary: Percentage of Participants Who Died Through Day 42 in the Full Analysis Set Population

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    End point title
    		 Percentage of Participants Who Died Through Day 42 in the Full Analysis Set Population
    End point description
    The percentage of participants who died with POS compared to VOR in the first line treatment of invasive aspergillosis (IA) in the Full Analysis Set (FAS) population through Day 42 was assessed. The analysis population consisted of all randomized participants who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions) and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to ~42 days
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    163
    171
    Units: Percentage of Participants
        number (not applicable)
    19.0
    18.7
    Statistical analysis title
    		 All-Cause Mortality by Day 42 in FAS
    Statistical analysis description
    Based on Miettinen and Nurminen’s method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme.
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Estimated Difference in Percent
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 8.8

    Secondary: Percentage of Participants Who Died Through Day 84 in the ITT Population

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    End point title
    		 Percentage of Participants Who Died Through Day 84 in the ITT Population
    End point description
    The percentage of participants who died with posaconazole (POS) compared to voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) in the ITT population through Day 84 was assessed. The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to ~84 days
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    288
    287
    Units: Percentage of Participants
        number (not applicable)
    28.1
    30.7
    Statistical analysis title
    		 All-Cause Mortality by Day 84 in ITT
    Statistical analysis description
    Based on Miettinen and Nurminen’s method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme.
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Estimated Difference in Percent
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.9
         upper limit
    		 4.9

    Secondary: Percentage of Participants Who Died Through Day 84 in the FAS Population

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    End point title
    		 Percentage of Participants Who Died Through Day 84 in the FAS Population
    End point description
    The percentage of participants who died with POS compared to VOR in the first line treatment of invasive aspergillosis (IA) in the FAS population through Day 84 was assessed. The analysis population consisted of all randomized participants who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions) and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to ~84 days
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    163
    171
    Units: Percentage of Participants
        number (not applicable)
    34.4
    31.0
    Statistical analysis title
    		 All-Cause Mortality by Day 84 in FAS
    Statistical analysis description
    Based on Miettinen and Nurminen’s method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme.
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percent
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 13.1

    Secondary: Percentage of Participants Achieving Global Clinical Response at Week 12 in the FAS Population

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    End point title
    		 Percentage of Participants Achieving Global Clinical Response at Week 12 in the FAS Population
    End point description
    The global clinical response of posaconazole (POS) compared to voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) was assessed. The percentage of participants achieving adjudicated complete and partial global clinical response at Week 12 was reported. Complete response was classified as survival with resolution of fungal disease evidence; Partial response was survival and improvement of fungal disease. The analysis population consisted of all randomized participants who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG] definitions) and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks (± 4 weeks)
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    163
    171
    Units: Percentage of Participants
        number (not applicable)
    42.3
    46.2
    Statistical analysis title
    		 Global Clinical Response at Week 12 in FAS
    Statistical analysis description
    Based on Miettinen and Nurminen’s method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme.
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Estimated Difference in Percent
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.9
         upper limit
    		 7.1

    Secondary: Percentage of Participants Achieving Global Clinical Response at Week 6 in the FAS Population

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    End point title
    		 Percentage of Participants Achieving Global Clinical Response at Week 6 in the FAS Population
    End point description
    The global clinical response of posaconazole (POS) compared to voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) was assessed. The percentage of participants achieving adjudicated complete and partial global clinical response at Week 6 was reported. Complete response was classified as survival with resolution of fungal disease evidence; Partial response was survival and improvement of fungal disease. The analysis population consisted of all randomized participants who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG] definitions) and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 6 weeks (± 2 weeks)
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    163
    171
    Units: Percentage of Participants
        number (not applicable)
    44.8
    45.6
    Statistical analysis title
    		 Global Clinical Response at Week 6 in FAS
    Statistical analysis description
    Based on Miettinen and Nurminen’s method stratified by the risk for mortality/poor outcome (high risk, not high risk) and using Cochran-Mantel-Haenszel weighting scheme.
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Estimated Difference in Percent
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.2
         upper limit
    		 10.1

    Secondary: Time to Death, All Causes (Kaplan-Meier Estimate of Number of Participants Experiencing a Qualifying Event) in the FAS Population

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    End point title
    		 Time to Death, All Causes (Kaplan-Meier Estimate of Number of Participants Experiencing a Qualifying Event) in the FAS Population
    End point description
    The time to death (all causes) in participants with proven or probable IA receiving POS versus VOR was assessed at Day 114. The Kaplan-Meier estimate reports the number of participants who experienced death (all causes) through Day 114 or ~16 weeks. Participants who did not have any endpoint event until last visit or who were lost to follow-up and had no event were censored at the time of last available information (last study visit). For Day 42 and Day 84, missing or 'unable to determine' responses were considered as failures (dead). The analysis population consisted of all randomized participants who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions) and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to ~16 weeks (± 2 weeks)
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    163
    171
    Units: Participants
    number (not applicable)
        Day 42 (missing responses were included as dead)
    31
    32
        Day 84 (missing responses were included as dead)
    56
    53
        Day 114
    64
    56
    Statistical analysis title
    		 Time to Death, All Causes
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.2767 [2]
    Method
    		 Kaplan-Meier
    Parameter type
    		 Survival Rate in Percent
    Point estimate
    60.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 52.8
         upper limit
    		 67.8
    Notes
    [1] - From product-limit (Kaplan-Meier) method for censored data.
    [2] - Based on Stratified Log-Rank method stratified by the risk for mortality/poor outcome (high risk, not high risk).

    Secondary: Number of Participants Who Died Due to Invasive Aspergillosis Through Day 42 in the FAS Population

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    End point title
    		 Number of Participants Who Died Due to Invasive Aspergillosis Through Day 42 in the FAS Population
    End point description
    The number of participants who died due to IA receiving POS versus VOR through Day 42 was assessed. The analysis population consisted of all randomized participants who died by Day 42 and who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions), and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    31
    32
    Units: Participants
        number (not applicable)
    16
    10
    Statistical analysis title
    		 Died due to IA by Day 42 in FAS
    Statistical analysis description
    Based on Miettinen and Nurminen’s method.
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percent
    Point estimate
    20.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 42.7

    Secondary: Number of Participants Who Died Due to Invasive Aspergillosis Through Day 84 in the FAS Population

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    End point title
    		 Number of Participants Who Died Due to Invasive Aspergillosis Through Day 84 in the FAS Population
    End point description
    The number of participants who died due to IA receiving POS versus VOR in the FAS population through Day 84 was assessed. The analysis population consisted of all randomized participants who died by Day 84 and who have been classified as having proven or probable IA (based upon independent adjudication assessment using the modified 2008 European Organization for Research and Treatment of Cancer/Mycoses study group [EORTC/MSG] definitions), and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 84 days
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    56
    50
    Units: Participants
        number (not applicable)
    22
    14
    Statistical analysis title
    		 Died due to IA by Day 84 in FAS
    Statistical analysis description
    Based on Miettinen and Nurminen’s method.
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percent
    Point estimate
    11.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 28.6

    Secondary: Percentage of Participants with Tier 1 Treatment Emergent Adverse Events

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    End point title
    		 Percentage of Participants with Tier 1 Treatment Emergent Adverse Events
    End point description
    The percentage of participants with Tier 1 treatment-emergent adverse events (TEAEs) was determined. The Tier 1 TEAEs included hepatic safety (elevated aspartate serum transaminase [AST] or alanine serum transaminase [ALT] value ≥3x upper limit of normal (ULN) and an elevated total bilirubin value ≥2x ULN and, at the same time, an alkaline phosphatase value <2 ULN); central nervous system (CNS) and visual disturbances (eye disorders, nervous system disorders, psychiatric disorders), dermatologic reactions, and adrenal insufficiency or temporally associated TEAEs of hypotension. The analysis population consisted of all participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to ~16 weeks (± 2 weeks)
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    288
    287
    Units: Percentage of Participants
    number (not applicable)
        Abnormal Hepatic Laboratory Value
    3.8
    3.5
        CNS and Visual Disturbances
    32.3
    35.9
        Dermatologic Reactions
    16.3
    19.2
        Adrenal Insufficiency or Temporal Hypotension
    8.0
    7.0
    Statistical analysis title
    		 Abnormal Hepatic Laboratory Value
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8305
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percent
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 3.6
    Statistical analysis title
    		 CNS and Visual Disturbances
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3633
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percent
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.3
         upper limit
    		 4.2
    Statistical analysis title
    		 Dermatologic Reactions
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3724
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percent
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.1
         upper limit
    		 3.4
    Statistical analysis title
    		 Adrenal Insufficiency or Temporal Hypotension
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6431
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percent
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 5.5

    Secondary: Percentage of Participants with at Least One Adverse Event

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    End point title
    		 Percentage of Participants with at Least One Adverse Event
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product. The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to ~16 weeks (± 2 weeks)
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    288
    287
    Units: Percentage of Participants
        number (not applicable)
    97.6
    97.6
    Statistical analysis title
    		 One or More Adverse Events
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percent
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 2.8

    Secondary: Percentage of Participants with at Least One Drug Related Adverse Event

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    End point title
    		 Percentage of Participants with at Least One Drug Related Adverse Event
    End point description
    An AE was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product. The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to ~16 weeks (± 2 weeks)
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    288
    287
    Units: Percentage of Participants
        number (not applicable)
    29.9
    40.1
    Statistical analysis title
    		 Drug-Related Adverse Events
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percent
    Point estimate
    -10.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.9
         upper limit
    		 -2.4

    Secondary: Percentage of Participants with at Least One Serious Adverse Event

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    End point title
    		 Percentage of Participants with at Least One Serious Adverse Event
    End point description
    A serious adverse event (SAE) was an AE that resulted in death, was life threatening, required or prolonged an existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was another important medical event deemed such by medical or scientific judgment. The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to ~16 weeks (± 2 weeks)
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    288
    287
    Units: Percentage of Participants
        number (not applicable)
    61.8
    59.9
    Statistical analysis title
    		 Serious Adverse Events
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percent
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1
         upper limit
    		 9.8

    Secondary: Percentage of Participants with at Least One Serious Drug-Related Adverse Event

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    End point title
    		 Percentage of Participants with at Least One Serious Drug-Related Adverse Event
    End point description
    An SAE was an AE that resulted in death, was life threatening, required or prolonged an existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was another important medical event deemed such by medical or scientific judgment. The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to ~16 weeks (± 2 weeks)
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    288
    287
    Units: Percentage of Participants
        number (not applicable)
    5.6
    7.0
    Statistical analysis title
    		 Serious Drug-Related Adverse Events
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percent
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 2.7

    Secondary: Percentage of Participants who Discontinued Study Treatment due to an Adverse Event

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    End point title
    		 Percentage of Participants who Discontinued Study Treatment due to an Adverse Event
    End point description
    An AE was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product. The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to ~12 weeks
    End point values
    		 Posaconazole Voriconazole
    Number of subjects analysed
    288
    287
    Units: Percentage of Participants
        number (not applicable)
    32.3
    35.5
    Statistical analysis title
    		 Discontinued due to an Adverse Event
    Comparison groups
    Posaconazole v Voriconazole
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percent
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 4.5

    Secondary: Steady State Average Concentration (Cavg) of Posaconazole with Food Intake

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    End point title
    		 Steady State Average Concentration (Cavg) of Posaconazole with Food Intake [3]
    End point description
    The characterization of the pharmacokinetics (PK) parameters of POS was determined from plasma samples taken at steady-state after receiving oral tablet of POS. Steady-state Cavg, where Cavg is defined as area under the concentration time-curve from 0 to 24 hours (AUC0-24hr) divided by the dosing interval. No evaluation of food intake on the VOR capsule was presented. The analysis population consisted of all randomized participants in the POS group only who received at least one dose of study treatment. Per protocol, the VOR group was not included in the analysis population because the food intake evaluation was limited to the POS group.
    End point type
    Secondary
    End point timeframe
    Baseline, and at pre-dose on Day 7, Week 2, Week 4, Week 6, and Week 12
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The VOR group was not included in the analysis population because the food intake evaluation was limited to the POS group only.
    End point values
    		 Posaconazole
    Number of subjects analysed
    288
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1: N=58
    1625 ( 902.9 )
        Week 2: N=64
    1992 ( 1190 )
        Week 4: N=67
    1994 ( 956.3 )
        Week 6: N=65
    2005 ( 1333 )
        Week 12: N=49
    2169 ( 1255 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to ~16 weeks (± 2 weeks)
    Adverse event reporting additional description
    The analysis population consisted of all participants who received at least one dose of study treatment. The analysis population for the all-cause mortality included all randomized participants (n=293, n=292).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Posaconazole (POS)-300 mg
    Reporting group description
    		 Participants received posaconazole intravenously (IV) twice per day (BID) on Day 1, and then received posaconazole IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral posaconazole tablets QD for up to 12 weeks of treatment. Participants with renal insufficiency or without central venous catheter access started with posaconazole oral tablets BID on Day 1, and then QD for up to 12 weeks of treatment.

    Reporting group title
    Voriconazole (VOR)-6 mg, 4 mg/200 mg
    Reporting group description
    		 Participants received voriconazole IV BID on Day 1, and then received voriconazole IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with voriconazole capsules BID for up to 12 weeks of treatment. Participants with renal insufficiency or without central venous catheter access started treatment with oral voriconazole capsules BID on Day 1, and then BID for up to 12 weeks of treatment.

    Serious adverse events
    		 Posaconazole (POS)-300 mg Voriconazole (VOR)-6 mg, 4 mg/200 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    178 / 288 (61.81%)
    172 / 287 (59.93%)
         number of deaths (all causes)
    99
    99
         number of deaths resulting from adverse events
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    3 / 288 (1.04%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    3 / 288 (1.04%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Acute myeloid leukaemia
         subjects affected / exposed
    7 / 288 (2.43%)
    12 / 287 (4.18%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 12
         deaths causally related to treatment / all
    0 / 6
    0 / 12
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma recurrent
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell type acute leukaemia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blast crisis in myelogenous leukaemia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diffuse large B-cell lymphoma refractory
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemia recurrent
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocytic leukaemia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphoma
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neuroendocrine tumour of the lung
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (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
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Plasma cell myeloma
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Precursor T-lymphoblastic lymphoma/leukaemia refractory
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Primary mediastinal large B-cell lymphoma
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 288 (1.04%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    General physical health deterioration
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hypothermia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 288 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Oedema
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 288 (2.43%)
    5 / 287 (1.74%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Acute graft versus host disease
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute graft versus host disease in skin
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Engraftment syndrome
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Graft versus host disease in liver
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune reconstitution inflammatory syndrome
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney transplant rejection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    3 / 288 (1.04%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 288 (0.35%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    4 / 288 (1.39%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 288 (1.04%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary cavitation
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 288 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Pulmonary oedema
         subjects affected / exposed
    1 / 288 (0.35%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    10 / 288 (3.47%)
    7 / 287 (2.44%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 8
    0 / 4
    Psychiatric disorders
    Bipolar I disorder
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 288 (1.04%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         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
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Accessory cardiac pathway
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    4 / 288 (1.39%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (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 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral disorder
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    3 / 288 (1.04%)
    5 / 287 (1.74%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 5
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Headache
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wernicke's encephalopathy
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood disorder
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    3 / 288 (1.04%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    24 / 288 (8.33%)
    21 / 287 (7.32%)
         occurrences causally related to treatment / all
    0 / 32
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         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
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastritis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 288 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Melaena
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    3 / 288 (1.04%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative generalised
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    9 / 288 (3.13%)
    5 / 287 (1.74%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle twitching
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anal infection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Atypical pneumonia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (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
    5 / 288 (1.74%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Bacterial pericarditis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain abscess
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    6 / 288 (2.08%)
    6 / 287 (2.09%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Candida sepsis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis pharyngeal
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral aspergillosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Citrobacter sepsis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (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
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Corona virus infection
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis viral
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated cytomegaloviral infection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diverticulitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Emphysematous cholecystitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter pneumonia
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    3 / 288 (1.04%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Escherichia sepsis
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatosplenic candidiasis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         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 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 288 (1.04%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 288 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucormycosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Muscle abscess
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nocardiosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonia
         subjects affected / exposed
    23 / 288 (7.99%)
    12 / 287 (4.18%)
         occurrences causally related to treatment / all
    0 / 27
    0 / 12
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Pneumonia bacterial
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia cytomegaloviral
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonia fungal
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pseudomembranous colitis
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mycosis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Relapsing fever
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal graft infection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection fungal
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    10 / 288 (3.47%)
    7 / 287 (2.44%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    Sepsis syndrome
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    16 / 288 (5.56%)
    16 / 287 (5.57%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 16
         deaths causally related to treatment / all
    0 / 12
    0 / 11
    Sinusitis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinusitis fungal
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         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
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    4 / 288 (1.39%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 287 (0.35%)
         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
    1 / 288 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Posaconazole (POS)-300 mg Voriconazole (VOR)-6 mg, 4 mg/200 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    232 / 288 (80.56%)
    225 / 287 (78.40%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    28 / 288 (9.72%)
    23 / 287 (8.01%)
         occurrences all number
    33
    25
    Hypotension
         subjects affected / exposed
    17 / 288 (5.90%)
    19 / 287 (6.62%)
         occurrences all number
    20
    25
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    18 / 288 (6.25%)
    11 / 287 (3.83%)
         occurrences all number
    19
    11
    Chills
         subjects affected / exposed
    15 / 288 (5.21%)
    8 / 287 (2.79%)
         occurrences all number
    19
    8
    Fatigue
         subjects affected / exposed
    19 / 288 (6.60%)
    7 / 287 (2.44%)
         occurrences all number
    20
    8
    Oedema peripheral
         subjects affected / exposed
    32 / 288 (11.11%)
    24 / 287 (8.36%)
         occurrences all number
    35
    27
    Pyrexia
         subjects affected / exposed
    75 / 288 (26.04%)
    69 / 287 (24.04%)
         occurrences all number
    122
    127
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    30 / 288 (10.42%)
    24 / 287 (8.36%)
         occurrences all number
    32
    24
    Dyspnoea
         subjects affected / exposed
    27 / 288 (9.38%)
    24 / 287 (8.36%)
         occurrences all number
    28
    28
    Epistaxis
         subjects affected / exposed
    31 / 288 (10.76%)
    17 / 287 (5.92%)
         occurrences all number
    34
    17
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    8 / 288 (2.78%)
    16 / 287 (5.57%)
         occurrences all number
    9
    16
    Insomnia
         subjects affected / exposed
    18 / 288 (6.25%)
    16 / 287 (5.57%)
         occurrences all number
    19
    17
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    39 / 288 (13.54%)
    34 / 287 (11.85%)
         occurrences all number
    49
    46
    Aspartate aminotransferase increased
         subjects affected / exposed
    36 / 288 (12.50%)
    34 / 287 (11.85%)
         occurrences all number
    46
    41
    Blood alkaline phosphatase increased
         subjects affected / exposed
    21 / 288 (7.29%)
    28 / 287 (9.76%)
         occurrences all number
    23
    33
    Blood bilirubin increased
         subjects affected / exposed
    24 / 288 (8.33%)
    20 / 287 (6.97%)
         occurrences all number
    38
    24
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    13 / 288 (4.51%)
    17 / 287 (5.92%)
         occurrences all number
    17
    20
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    13 / 288 (4.51%)
    15 / 287 (5.23%)
         occurrences all number
    15
    21
    Platelet count decreased
         subjects affected / exposed
    15 / 288 (5.21%)
    11 / 287 (3.83%)
         occurrences all number
    21
    18
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    11 / 288 (3.82%)
    18 / 287 (6.27%)
         occurrences all number
    14
    23
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    21 / 288 (7.29%)
    12 / 287 (4.18%)
         occurrences all number
    22
    12
    Headache
         subjects affected / exposed
    34 / 288 (11.81%)
    24 / 287 (8.36%)
         occurrences all number
    45
    29
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 288 (7.99%)
    29 / 287 (10.10%)
         occurrences all number
    41
    46
    Febrile neutropenia
         subjects affected / exposed
    21 / 288 (7.29%)
    18 / 287 (6.27%)
         occurrences all number
    24
    22
    Thrombocytopenia
         subjects affected / exposed
    22 / 288 (7.64%)
    17 / 287 (5.92%)
         occurrences all number
    28
    23
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    27 / 288 (9.38%)
    24 / 287 (8.36%)
         occurrences all number
    31
    24
    Constipation
         subjects affected / exposed
    32 / 288 (11.11%)
    23 / 287 (8.01%)
         occurrences all number
    36
    26
    Diarrhoea
         subjects affected / exposed
    52 / 288 (18.06%)
    50 / 287 (17.42%)
         occurrences all number
    66
    57
    Nausea
         subjects affected / exposed
    65 / 288 (22.57%)
    50 / 287 (17.42%)
         occurrences all number
    83
    63
    Vomiting
         subjects affected / exposed
    52 / 288 (18.06%)
    38 / 287 (13.24%)
         occurrences all number
    64
    57
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    19 / 288 (6.60%)
    22 / 287 (7.67%)
         occurrences all number
    22
    32
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 288 (5.90%)
    9 / 287 (3.14%)
         occurrences all number
    21
    10
    Pain in extremity
         subjects affected / exposed
    19 / 288 (6.60%)
    13 / 287 (4.53%)
         occurrences all number
    20
    15
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    15 / 288 (5.21%)
    14 / 287 (4.88%)
         occurrences all number
    17
    16
    Pneumonia
         subjects affected / exposed
    14 / 288 (4.86%)
    15 / 287 (5.23%)
         occurrences all number
    14
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    25 / 288 (8.68%)
    14 / 287 (4.88%)
         occurrences all number
    25
    15
    Hypocalcaemia
         subjects affected / exposed
    15 / 288 (5.21%)
    13 / 287 (4.53%)
         occurrences all number
    25
    27
    Hypokalaemia
         subjects affected / exposed
    78 / 288 (27.08%)
    49 / 287 (17.07%)
         occurrences all number
    133
    72
    Hypomagnesaemia
         subjects affected / exposed
    29 / 288 (10.07%)
    18 / 287 (6.27%)
         occurrences all number
    48
    20
    Hyponatraemia
         subjects affected / exposed
    12 / 288 (4.17%)
    19 / 287 (6.62%)
         occurrences all number
    19
    26
    Hypophosphataemia
         subjects affected / exposed
    22 / 288 (7.64%)
    9 / 287 (3.14%)
         occurrences all number
    24
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2012
    Amendment 01: Primary reason for amendment was to clarify and simplify the study drug dosing by treatment arms in regard to the dosing for intravenous (IV) and oral posaconazole and voriconazole.
    01 Jul 2013
    Amendment 02: Primary reason for amendment was to exclude participants <18 years of age.
    14 Jan 2015
    Amendment 03: Primary reason for amendment was to allow the enrollment of adolescents outside of the EU (ie, in those regions with an approved indication for use of oral POS in the adolescent age population (≥13 years of age).
    12 Aug 2016
    Amendment 04: Primary reason for amendment was to change the primary study objective and endpoint of global clinical response at Week 6 (FAS population) to a key secondary study objective and endpoint. The all-cause mortality at Week 6 (ITT population) secondary objective and study endpoint was changed to the primary objective and study endpoint.
    22 Feb 2019
    Amendment 05: Primary reason for amendment was to clarify protocol and statistical analyses, including approximate sample size and power calculation, time windows used for assessment, and the elimination of 2 secondary objectives for which data analyses was no longer planned.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    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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