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    Clinical Trial Results:
    NAI114373: A Phase III international, randomized, double-blind, double-dummy study to evaluate the efficacy and safety of 300 mg or 600 mg of intravenous zanamivir twice daily compared to 75 mg of oral oseltamivir twice daily in the treatment of hospitalized adults and adolescents with influenza

    Summary
    EudraCT number
    		 2010-021621-12
    Trial protocol
    		 SK   DE   FR   GB   HU   NL   CZ   NO   DK   GR   BE   PL   ES   Outside EU/EEA  
    Global end of trial date
    18 Mar 2015

    Results information
    Results version number
    		 v1
    This version publication date
    10 Jul 2016
    First version publication date
    10 Jul 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    NAI114373
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, +1 8664357343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, +1 8664357343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of treatment with 600 mg of intravenous (IV) zanamivir twice daily compared to 75 mg of oral oseltamivir twice daily, and 600 mg IV zanamivir compared to 300 mg IV zanamivir twice daily on time to clinical response (TTCR).
    Protection of trial subjects
    N/A
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jan 2011
    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
    Korea, Republic of: 18
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Norway: 11
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Spain: 146
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Greece: 19
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    India: 44
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    Mexico: 19
    Country: Number of subjects enrolled
    New Zealand: 13
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Australia: 22
    Country: Number of subjects enrolled
    China: 18
    Country: Number of subjects enrolled
    United States: 151
    Country: Number of subjects enrolled
    South Africa: 13
    Worldwide total number of subjects
    626
    EEA total number of subjects
    285
    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)
    400
    From 65 to 84 years
    189
    85 years and over
    32

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Male and female adult and adolescent participants >=16 years of age hospitalized with documented influenza or suspected influenza were eligible for enrollment. A total of 626 participants were randomized, and 615 participants were included in the Intent-to-Treat Exposed (ITT-E) Population.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IV zanamivir 300 mg
    Arm description
    		 Participants >=16 years of age received intravenous (IV) zanamivir 300 milligrams (mg) twice daily, adjusted for renal function for 5–10 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    zanamivir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    300 mg twice daily, adjusted for renal function

    Arm title
    		 IV zanamivir 600 mg
    Arm description
    		 Participants >=16 years of age received IV zanamivir 600 mg twice daily, adjusted for renal function for 5–10 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    zanamivir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    600 mg twice daily, adjusted for renal function

    Arm title
    		 Oral oseltamivir 75 mg
    Arm description
    		 Participants >=16 years of age received oral oseltamvir 75 mg twice daily, adjusted for renal function for 5–10 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    oseltamivir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg twice daily, frequency adjusted for renal function

    Number of subjects in period 1 [1]
    		IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Started
    201
    209
    205
    Completed
    175
    178
    166
    Not completed
    26
    31
    39
         Adverse event, serious fatal
    12
    14
    11
         Physician decision
    3
    5
    10
         Consent withdrawn by subject
    6
    6
    8
         Adverse event, non-fatal
    2
    2
    1
         Lost to follow-up
    3
    4
    9
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Male and female adult and adolescent participants >=16 years of age hospitalized with documented influenza or suspected influenza were eligible for enrollment. A total of 626 participants were randomized, and 615 participants were included in the Intent-to-Treat Exposed (ITT-E) Population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IV zanamivir 300 mg
    Reporting group description
    		 Participants >=16 years of age received intravenous (IV) zanamivir 300 milligrams (mg) twice daily, adjusted for renal function for 5–10 days.

    Reporting group title
    IV zanamivir 600 mg
    Reporting group description
    		 Participants >=16 years of age received IV zanamivir 600 mg twice daily, adjusted for renal function for 5–10 days.

    Reporting group title
    Oral oseltamivir 75 mg
    Reporting group description
    		 Participants >=16 years of age received oral oseltamvir 75 mg twice daily, adjusted for renal function for 5–10 days.

    Reporting group values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg Total
    Number of subjects
    		 201 209 205 615
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.2 ± 18.88 57.3 ± 17.39 55.9 ± 18.7 -
    Gender categorical
    Units: Subjects
        Female
    		 82 86 117 285
        Male
    		 119 123 88 330
    Race
    Units: Subjects
        African American/African Heritage
    		 12 4 10 26
        American Indian or Alaskan Native
    		 3 2 4 9
        Asian - Central/South Asian Heritage
    		 10 15 13 38
        Asian - East Asian Heritage
    		 12 18 13 43
        Asian - South East Asian Heritage
    		 6 4 7 17
        Native Hawaiian or Other Pacific Islander
    		 2 1 0 3
        White - Arabic/North African Heritage
    		 4 3 3 10
        White -White/Caucasian/European Heritage
    		 150 162 154 466
        Unknown
    		 1 0 1 2
        Mixed Race
    		 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    IV zanamivir 300 mg
    Reporting group description
    		 Participants >=16 years of age received intravenous (IV) zanamivir 300 milligrams (mg) twice daily, adjusted for renal function for 5–10 days.

    Reporting group title
    IV zanamivir 600 mg
    Reporting group description
    		 Participants >=16 years of age received IV zanamivir 600 mg twice daily, adjusted for renal function for 5–10 days.

    Reporting group title
    Oral oseltamivir 75 mg
    Reporting group description
    		 Participants >=16 years of age received oral oseltamvir 75 mg twice daily, adjusted for renal function for 5–10 days.

    Primary: Median time to clinical response (TTCR) in participants with confirmed influenza

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    End point title
    		 Median time to clinical response (TTCR) in participants with confirmed influenza
    End point description
    Clinical response is defined as the resolution of at least 4 of the 5 vital signs (temperature, oxygen saturation, respiratory status, heart rate, systolic blood pressure) within the respective resolution criteria, maintained for at least 24 hours, or hospital discharge, whichever occurred first. The ITT-E Population is comprised of all randomized participants who received at least one dose of investigational product. The Influenza Positive Population (IPP) is comprised of all participants in the ITT-E Population with proven influenza infection. "-99999, 99999" indicates that full range data are not available.
    End point type
    Primary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [1]
    162 [2]
    163 [3]
    Units: Days to success
        median (full range (min-max))
    5.87 (-99999 to 99999)
    5.14 (-99999 to 99999)
    5.63 (-99999 to 99999)
    Notes
    [1] - IPP Population
    [2] - IPP Population
    [3] - IPP Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    IV zanamivir 300 mg v IV zanamivir 600 mg
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2496 [4]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [4] - Wilcoxon-sum test stratified by the randomization strata
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    IV zanamivir 600 mg v Oral oseltamivir 75 mg
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3912 [5]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [5] - Wilcoxon-sum test stratified by the randomization strata

    Primary: Percentage of participants with confirmed influenza acheiving a clinical response

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    End point title
    		 Percentage of participants with confirmed influenza acheiving a clinical response [6]
    End point description
    Clinical response is defined as the resolution of at least 4 of the 5 vital signs (temperature, oxygen saturation, respiratory status, heart rate, systolic blood pressure) within the respective resolution criteria, maintained for at least 24 hours, or hospital discharge, whichever occurred first.
    End point type
    Primary
    End point timeframe
    Up to 42 days
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [7]
    162 [8]
    163 [9]
    Units: Percentage of participants
        number (not applicable)
    85
    87
    77
    Notes
    [7] - IPP Population
    [8] - IPP Population
    [9] - IPP Population
    No statistical analyses for this end point

    Secondary: Combined time to clinical response (TTCR) and TTRI

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    End point title
    		 Combined time to clinical response (TTCR) and TTRI
    End point description
    Respiratory Status (RS) is a component of TTCR. Response criteria included the return to the pre-morbid oxygen requirement (participants with chronic oxygen use), a need for supplemental oxygen (administered by any modality: ventilator, non-invasive ventilation, facemask, facetent, nasal canula, etc.) to no need for supplemental oxygen, or a respiratory rate of =<24 breaths/minute (without supplemental oxygen). Data are presented as the percentage of participants acheiving respiratory improvement. This analysis utilizes the Wei-Johanson method.
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [10]
    162 [11]
    163 [12]
    Units: Percentage of participants
        number (not applicable)
    77
    78
    74
    Notes
    [10] - IPP Population
    [11] - IPP Population
    [12] - IPP Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    IV zanamivir 600 mg v IV zanamivir 300 mg
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.506
    Method
    		 Wei-Johnson method
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    IV zanamivir 600 mg v Oral oseltamivir 75 mg
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Wei-Johnson method
    Confidence interval

    Secondary: Number of participants with all cause and attributable mortality at Day 14, at Day 28, and at the End of Study Visit

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    End point title
    		 Number of participants with all cause and attributable mortality at Day 14, at Day 28, and at the End of Study Visit
    End point description
    The number of participants who died on or before Day 14, Day 28, and the End of Study Visit are summarized.
    End point type
    Secondary
    End point timeframe
    On or before Day 14, Day 28, End of Study Visit (assessed up to 42 days)
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [13]
    162 [14]
    163 [15]
    Units: Participants
    number (not applicable)
        Died on or before Study Day 14: all cause
    5
    8
    5
        Died on or before Study Day 28: all cause
    8
    9
    9
        Died while on-study: all cause
    10
    12
    10
        Died on or before Study Day 14: attributable
    3
    4
    4
        Died on or before Study Day 28: attributable
    5
    5
    5
        Died while on-study: attributable
    5
    6
    6
    Notes
    [13] - IPP Population
    [14] - IPP Population
    [15] - IPP Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Katz Activities of Daily Living (ADL) score and each ADL activity score

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    End point title
    		 Change from Baseline in the Katz Activities of Daily Living (ADL) score and each ADL activity score
    End point description
    The Katz ADL scores were collected for bathing, dressing, toileting, transferring, continence, and feeding activities and were assessed once daily during the treatment period/hospitalization and once at each Post-Treatment Clinic Visit. For the six individual activities, a score of 1 indicates independence, and a score of 0 indicates dependence. The total score is generated by adding the scores of all six activities. A total score of 6 indicates that the participant was independent; a total score of 0 indicates that the participant was very dependent. Baseline is defined as the pre-dose value collected on Study Day 1. Change from Baseline is defined as the difference at each time point (Day 5/6, and Day 10/11, and last day S/R if treatment was extended beyond 5 days) and the end of the study (post-treatment [PT] +28 Days) compared to Baseline. Only those participants available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [16]
    162 [17]
    163 [18]
    Units: Scores on the scale
    arithmetic mean (standard deviation)
        Total Score Day 5/6, n=149, 150, 139
    1.07 ± 1.959
    0.93 ± 1.782
    0.78 ± 1.837
        Total Score Day 10/11, n=16, 6, 12,
    0.88 ± 1.746
    0.5 ± 0.837
    -0.08 ± 3.029
        Total Score Last Day of S/R, n=5, 2, 8
    0.2 ± 2.49
    -3 ± 4.243
    0.75 ± 1.165
        Total Score PT+28 Day, n=138, 134, 120
    2.13 ± 2.234
    1.72 ± 2.342
    1.98 ± 2.142
        Bathing: DAY 5/6, n=149, 150, 139
    0.24 ± 0.488
    0.19 ± 0.429
    0.18 ± 0.438
        Bathing: DAY 10/11, n=16, 6, 12
    0.19 ± 0.403
    0 ± 0
    0 ± 0.426
        Bathing: Last Day of S/R, n=5, 2, 8
    0.2 ± 0.447
    -0.5 ± 0.707
    0 ± 0
        Bathing: PT + 28 DAYS, n=138, 134, 120
    0.43 ± 0.498
    0.34 ± 0.505
    0.39 ± 0.507
        Dressing DAY 5/6, n=149, 150, 139
    0.23 ± 0.481
    0.21 ± 0.438
    0.14 ± 0.427
        Dressing: Day 10/11, n=16, 6, 12
    0.13 ± 0.342
    0 ± 0
    -0.08 ± 0.515
        Dressing: Last Day of S/R, n=5, 2, 8
    0.2 ± 0.447
    -0.5 ± 0.707
    0.13 ± 0.354
        Dressing:PT+28 Day, n=138, 134, 120
    0.42 ± 0.495
    0.37 ± 0.515
    0.41 ± 0.494
        Toileting: DAY 5/6, n=149, 150, 139
    0.19 ± 0.456
    0.19 ± 0.439
    0.14 ± 0.409
        Toileting: Day 10/11, n=16, 6, 12
    0.13 ± 0.342
    0.33 ± 0.516
    0.08 ± 0.515
        Toileting: Last Day of S/R, n=5, 2, 8
    0.2 ± 0.447
    -0.5 ± 0.707
    0 ± 0.535
        Toileting: PT+28 Day, n=138, 134, 120
    0.4 ± 0.491
    0.32 ± 0.514
    0.37 ± 0.484
        Transferring: DAY 5/6, n=149, 150, 139
    0.28 ± 0.505
    0.23 ± 0.451
    0.17 ± 0.41
        Transferring: Day 10/11, n=16, 6, 12
    0.19 ± 0.403
    0.17 ± 0.408
    0.08 ± 0.515
        Transferring: Last Day of S/R, n=5, 2, 8
    0 ± 0.707
    -0.5 ± 0.707
    0.25 ± 0.463
        Transferring: PT+28 Day, n=138, 134, 120
    0.45 ± 0.499
    0.36 ± 0.526
    0.4 ± 0.492
        Continence: DAY 5/6, n=149, 150, 139
    0.07 ± 0.322
    0.05 ± 0.314
    0.07 ± 0.374
        Continence: Day 10/11, n=16, 6, 12
    0.13 ± 0.342
    0 ± 0
    -0.08 ± 0.669
        Continence: Last Day of S/R, n=5, 2, 8
    -0.2 ± 0.447
    -0.5 ± 0.707
    0.13 ± 0.354
        Continence: PT+28 Day, n=138, 134, 120
    0.22 ± 0.431
    0.16 ± 0.422
    0.23 ± 0.439
        Feeding: Day 5/6, n=149, 150, 139
    0.07 ± 0.331
    0.07 ± 0.309
    0.08 ± 0.382
        Feeding: Day 10/11, n=16, 6, 12
    0.13 ± 0.342
    0 ± 0
    -0.08 ± 0.669
        Feeding: Last Day of S/R, n=5, 2, 8
    -0.2 ± 0.447
    -0.5 ± 0.707
    0.25 ± 0.463
        Feeding: PT+28 Day, n=138, 134, 120
    0.21 ± 0.409
    0.17 ± 0.416
    0.19 ± 0.395
    Notes
    [16] - IPP Population
    [17] - IPP Population
    [18] - IPP Population
    No statistical analyses for this end point

    Secondary: Median time to return to pre-morbid functional status as measured by the Katz ADL score and each ADL activity score

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    End point title
    		 Median time to return to pre-morbid functional status as measured by the Katz ADL score and each ADL activity score
    End point description
    Pre-morbid functional status is defined as the best functional status in the 4 weeks prior to enrolment. Median time to return to pre-morbid functional status was assessed via the Katz ADL score (bathing, dressing, toileting, transferring, continence, and feeding activities). For the six individual activities, a score of 1 indicates independence, and a score of 0 indicates dependence. The total score is generated by adding the scores of all six activities. A total score of 6 indicates that the participant was independent; a total score of 0 indicates that the participant was very dependent. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles)
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [19]
    162 [20]
    163 [21]
    Units: Days
    median (full range (min-max))
        Total score; n=139, 138, 130
    2 (2 to 38)
    2 (2 to 37)
    2.5 (2 to 57)
        Bathing; n=135, 133, 126:
    2 (2 to 38)
    2 (2 to 37)
    2 (2 to 57)
        Dressing; n=138, 135, 126
    2 (2 to 38)
    2 (2 to 40)
    2 (2 to 57)
        Toileting; n=139, 136, 130
    2 (2 to 38)
    2 (2 to 31)
    2 (2 to 40)
        Transferring; n=140, 140, 133
    2 (2 to 38)
    2 (2 to 31)
    2 (2 to 40)
        Continence; n= 142, 143, 139
    2 (2 to 35)
    2 (2 to 33)
    2 (2 to 31)
        Feeding; n= 145, 148, 144
    2 (2 to 29)
    2 (2 to 32)
    2 (2 to 36)
    Notes
    [19] - IPP Population
    [20] - IPP Population
    [21] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants who returned to their pre-morbid functional status as assessed per the Katz ADL score and each ADL activity score at the end of the study

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    End point title
    		 Number of participants who returned to their pre-morbid functional status as assessed per the Katz ADL score and each ADL activity score at the end of the study
    End point description
    Pre-morbid functional status is defined as the best functional status in the 4 weeks prior to enrolment. The number of participants who returned to their pre-morbid functional status at the end of the study assessed per the Katz ADL score (bathing, dressing, toileting, transferring, continence and feeding activities) is summarized
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [22]
    162 [23]
    163 [24]
    Units: Participants
    number (not applicable)
        Total
    139
    138
    130
        Bathing
    135
    133
    126
        Dressing
    138
    135
    126
        Toileting
    139
    136
    130
        Transferring:
    140
    140
    133
        Continence
    142
    143
    139
        Feeding
    145
    148
    144
    Notes
    [22] - IPP Population
    [23] - IPP Population
    [24] - IPP Population
    No statistical analyses for this end point

    Secondary: Median time to return to the pre-morbid level of activity as measured by the 3-point scale

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    End point title
    		 Median time to return to the pre-morbid level of activity as measured by the 3-point scale
    End point description
    Median time to return to pre-morbid level of activity was assessed during the study i.e once daily during treatment/hospitalization and once at each post-treatment assessment and was measured using the 3-point scale (bed rest, limited ambulation, or unrestricted). Participants successed in pre-morbid functional status were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    138 [25]
    137 [26]
    135 [27]
    Units: Days
        median (full range (min-max))
    5 (2 to 34)
    4 (2 to 31)
    4 (1 to 57)
    Notes
    [25] - IPP Population
    [26] - IPP Population
    [27] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated clinical symptoms of influenza

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    End point title
    		 Number of participants with the indicated clinical symptoms of influenza
    End point description
    Influenza clinical symptoms included nasal symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, anorexia, dyspnea, headache, sore throat, nausea, and vomiting. Influenza symptoms were assessed once daily during inpatient/hospitalization and once at each post-treatment assessment
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [28]
    162 [29]
    163 [30]
    Units: Participants
    number (not applicable)
        Anorexia
    102
    112
    123
        Cough
    151
    150
    157
        Diarrhea
    64
    57
    66
        Dyspnea
    143
    145
    152
        Fatigue
    144
    144
    148
        Feverishness
    138
    145
    136
        Headache
    104
    102
    103
        Myalgias
    115
    117
    114
        Nasal symptoms (rhinorrhea, congestion)
    118
    123
    122
        Nausea
    57
    51
    77
        Sore throat
    94
    115
    97
        Vomiting
    27
    23
    45
    Notes
    [28] - IPP Population
    [29] - IPP Population
    [30] - IPP Population
    No statistical analyses for this end point

    Secondary: Median duration of clinical symptoms of influenza

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    End point title
    		 Median duration of clinical symptoms of influenza
    End point description
    Influenza clinical symptoms included nasal symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, anorexia, dyspnea, headache, sore throat, nausea, and vomiting. Influenza symptoms were assessed once daily during inpatient/hospitalization and once at each post-treatment assessment. Only those participants with clinical symptomps of influenza were analyzed (represented by n=X, X, X in the category titles)
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [31]
    162 [32]
    163 [33]
    Units: Days
    median (full range (min-max))
        Anorexia; n=102, 112, 123
    5 (1 to 39)
    3 (1 to 46)
    5 (1 to 55)
        Cough; n= 151, 150, 157
    14 (1 to 39)
    13 (1 to 46)
    15 (1 to 56)
        Diarrhea; n=64, 57, 66
    3 (1 to 29)
    2 (1 to 28)
    3 (1 to 23)
        Dyspnea; n=143, 145, 152
    7 (1 to 40)
    6 (1 to 43)
    8 (1 to 56)
        Fatigue; n= 144, 144, 148
    11 (1 to 41)
    11 (1 to 44)
    12 (1 to 56)
        Feverishness; n=138, 145, 136
    2 (1 to 28)
    2 (1 to 29)
    2.5 (1 to 56)
        Headache; n=104, 102, 103
    3 (1 to 33)
    3 (1 to 33)
    4 (1 to 56)
        Myalgias; n=115, 117, 114
    4 (1 to 39)
    3 (1 to 34)
    4 (1 to 56)
        Nasal symptoms; n=118, 123, 122
    6 (1 to 34)
    4 (1 to 43)
    5.5 (1 to 35)
        Nausea; n=57, 51, 77
    3 (1 to 34)
    2 (1 to 24)
    2 (1 to 28)
        Sore throat; n=94, 115, 97
    3 (1 to 28)
    2 (1 to 36)
    3 (1 to 35)
        Vomiting; n=27, 23, 45
    2 (1 to 19)
    1 (1 to 11)
    1 (1 to 20)
    Notes
    [31] - IPP Population
    [32] - IPP Population
    [33] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants with complications of influenza and associated antibiotic use

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    End point title
    		 Number of participants with complications of influenza and associated antibiotic use
    End point description
    The number of participants with complications of influenza and associated antibiotic use is summarized
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [34]
    162 [35]
    163 [36]
    Units: Participants
    number (not applicable)
        Associated use of any antibiotic
    22
    16
    29
        Any complication of influenza
    34
    33
    41
    Notes
    [34] - IPP Population
    [35] - IPP Population
    [36] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated ventilation status: modality of invasive and non-invasive ventilator support and oxygen supplementation

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    End point title
    		 Number of participants with the indicated ventilation status: modality of invasive and non-invasive ventilator support and oxygen supplementation
    End point description
    Ventilation status was assessed three times daily during the treatment period/hospitalization. Ventilation status was assessed once daily during inpatient/hospitization and once at each post-treatment clinic visit. The number of participants reported for machine-assisted: extracorporeal membrane oxygenation (ECMO), endotracheal mechanical ventilation, and supplemental oxygen delivery (SOD), no supplemental oxygen (O2) or ventilation support, Respiratory support at “any time (AT) on study” and at Baseline (Day 1) are summarized. Data for the "any time (AT) on study" time point was reported.
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [37]
    162 [38]
    163 [39]
    Units: Participants
    number (not applicable)
        Day 1, Machine-Assisted: ECMO
    0
    0
    0
        Day 1, Machine-Assisted: Endotracheal
    28
    25
    27
        Day 1, SOD
    96
    103
    87
        Day 1, No supplemental O2 or ventilation support
    32
    29
    37
        Day 1, Respiratory Support
    34
    29
    39
        AT on Study, Machine-Assisted: ECMO
    2
    0
    1
        AT on Study, Machine-Assisted: Endotracheal
    36
    31
    37
        AT on Study, SOD
    137
    137
    128
        AT on Study, No supplemental O2 or ventilation sup
    138
    135
    131
        AT on Study, Respiratory Support
    46
    37
    50
    Notes
    [37] - IPP Population
    [38] - IPP Population
    [39] - IPP Population
    No statistical analyses for this end point

    Secondary: Median time duration of invasive and non-invasive ventilator support and oxygen supplementation

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    End point title
    		 Median time duration of invasive and non-invasive ventilator support and oxygen supplementation
    End point description
    Ventilation status was assessed three times daily during the treatment period/hospitalization. Ventilation status was assessed once daily during inpatient/hospitization and once at each post-treatment clinic visit. Only those participants available with the indicated ventilator support or oxygen supplementation were analyzed (represented by n=X, X, X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [40]
    162 [41]
    163 [42]
    Units: Days
    median (full range (min-max))
        Ventilator Support, n=46, 37, 50
    9 (0 to 38)
    5.2 (0 to 36)
    8.2 (0 to 36)
        Oxygen Supplementation, n=137, 137, 128
    4.4 (0 to 38)
    4.2 (0 to 43)
    3.7 (0 to 36)
    Notes
    [40] - IPP Population
    [41] - IPP Population
    [42] - IPP Population
    No statistical analyses for this end point

    Secondary: Median time of duration of hospitalization and Intensive Care Unit (ICU) stay

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    End point title
    		 Median time of duration of hospitalization and Intensive Care Unit (ICU) stay
    End point description
    Hospital duration and ICU duration was assessed from the first day of dosing. Hospital duration was calculated as the discharge date minus the admission date + 1. Hospital duration while on study was the earlier of discharge, completion, or withdrawal minus the later of the admission date or the study start date + 1. ICU duration-Modified was calculatd as the original ICU duration minus ICU days prior to Study Day 1. Only those participants with the indicated hospitalization or ICU stay were analyzed (represented by n=X, X, X in the category titles)
    End point type
    Secondary
    End point timeframe
    Day 1 to the end of the study (assessed up to 42 days)
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [43]
    162 [44]
    163 [45]
    Units: Days
    median (full range (min-max))
        Hospitalization; n=163, 162, 163
    10 (1 to 108)
    8 (2 to 64)
    9 (1 to 58)
        Hospitalization while on study; n=163, 162, 163
    8 (1 to 39)
    6 (1 to 43)
    7 (1 to 39)
        Hospitalization-ICU; n=72, 56, 71
    8 (1 to 41)
    7.5 (1 to 36)
    8 (1 to 36)
        ICU Duration Modified; n=70, 54, 69
    7 (1 to 39)
    6 (1 to 36)
    7 (1 to 36)
    Notes
    [43] - IPP Population
    [44] - IPP Population
    [45] - IPP Population
    No statistical analyses for this end point

    Secondary: Median time to the absence of fever and improved respiratory status, oxygen saturation, heart rate, and systolic blood pressure

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    End point title
    		 Median time to the absence of fever and improved respiratory status, oxygen saturation, heart rate, and systolic blood pressure
    End point description
    The absence of fever is defined as a nonaxillary temperature recording <=36.6 degrees Celsius axillary, <= 37.2 degrees Celsius oral or <= 37.7 degrees Celsius core. Respiratory Status (RS) response criteria included the return to the pre-morbid oxygen requirement (participants with chronic oxygen use), or the need for supplemental oxygen (administered by any modality: ventilator, non-invasive ventilation, facemask, facetent, nasal canula, etc.) to no need for supplemental oxygen, or a respiratory rate =<24 breaths/minute (without supplemental oxygen). Oxygen saturation response criteria: >=95% (without supplemental oxygen). Heart rate response criteria: =<100 beats/minute. Systolic blood pressure response criteria: >=90 millimeters of mercury. Vital signs were assessed three times daily during the treatment period/hospitalization. Vital signs were assessed once daily during inpatient/hospitization and once at each post-treatment clinic visit.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [46]
    162 [47]
    163 [48]
    Units: Days
    median (full range (min-max))
        Fever
    1.6 (0 to 34)
    0.8 (0 to 14)
    1.5 (0 to 31)
        Oxygen Saturation; n=98, 108, 99
    5.3 (0 to 30)
    5.6 (0 to 32)
    4.5 (0 to 25)
        Respiratory status; n=126, 126, 121
    3.5 (0 to 31)
    3.6 (0 to 32)
    2.8 (0 to 21)
        Heart rate; n=156, 148, 155
    0.4 (0 to 28)
    0.4 (0 to 21)
    0.5 (0 to 24)
        Systolic blood pressure; n=156, 156, 154
    0.3 (0 to 23)
    0.3 (0 to 14)
    0.3 (0 to 16)
    Notes
    [46] - IPP Population
    [47] - IPP Population
    [48] - IPP Population
    No statistical analyses for this end point

    Secondary: Median time to virologic improvement

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    End point title
    		 Median time to virologic improvement
    End point description
    Virologic improvement is defined as a 2 log drop in viral load or sustained undetectable viral ribonucleic acid (RNA) (on two successive occasions) as measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) from nasopharyngeal samples. Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Days 6, 8, 10 and on the last day of randomized treatment. For participants who utilized the Switch (S)/Rescue (R) option, samples were taken on S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6, whichever was the last day of S/R treatment. Nasopharyngeal swabs were taken if the participant was symptomatic and continued to be hospitalized on the Post-Treatment +2, +5, +9, +16, and +28 Day assessment. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles). Data presented is for subjects positive at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [49]
    162 [50]
    163 [51]
    Units: Days
    median (full range (min-max))
        Influenza A and B; n=116, 122, 129
    3 (2 to 34)
    3 (2 to 35)
    3 (2 to 34)
        Influenza A/H1N1; n=47, 42, 48
    3 (2 to 13)
    3 (2 to 34)
    3 (2 to 34)
        Influenza A/H3N2, n=55, 58, 61
    3 (2 to 8)
    3 (2 to 35)
    3 (2 to 11)
        Influenza B; n=15, 20, 21
    5 (2 to 34)
    3 (2 to 21)
    3 (2 to 12)
    Notes
    [49] - IPP Population
    [50] - IPP Population
    [51] - IPP Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in quantitative virus culture from nasopharyngeal swabs positive at Baseline

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    End point title
    		 Change from Baseline in quantitative virus culture from nasopharyngeal swabs positive at Baseline
    End point description
    Nasopharyngeal swabs were collected daily from Baseline through Day5. If randomized treatment was continued beyond Day5, samples were taken on Treatment Day6, Day8, Day10, Day11, and the last day of randomized treatment. For participants who utilized the S/R option, samples were taken on S/R Day1, S/R Day3, S/R Day5, or S/R Day6, whichever was the last day of S/R treatment. Samples were taken if the participant was symptomatic and continued to be hospitalized on the Post-Treatment +2, +5, +9, +16 and +28Day assessment. Viral load as measured by RT-PCR was assessed in Quantitative Virus Culture, log10 50% Tissue Culture Infectious Dose (TCID50)/milliliter (mL). Change from Baseline was calculated as the post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles). "99999" :data are not available/analysis was not performed. Data presented is for participants positive at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 3, Day 5, Day 8, Day 10, Day 11 and/or last day of randomized treatment, if randomized treatment was extended beyond 5 days, and S/R Day 5/6 (up to Day 14) if applicable
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [52]
    162 [53]
    163 [54]
    Units: log10 TCID50/mL
    median (full range (min-max))
        Day 3 n=78, 76, 89
    -2.01 (-5 to 0.8)
    -2.01 (-4.8 to 1.3)
    -2.01 (-5.3 to 2.8)
        Day 5 n=66, 69, 80
    -2.51 (-5.5 to 0)
    -2.26 (-5.3 to 0)
    -2.26 (-5.3 to 2)
        Day 8 n=6, 7, 10
    -1.64 (-5.5 to 0)
    -2.01 (-4.3 to -0.3)
    -2.26 (-4.3 to 0)
        Day 10 n=4, 3, 4
    -3.76 (-5.5 to -0.3)
    -0.3 (-1.3 to -0.3)
    -2.26 (-3.8 to -1.3)
        Day 11 n=3,3, 4
    -3.01 (-5.5 to -0.3)
    -0.3 (-1.3 to -0.3)
    -2.26 (-3.8 to -1.3)
        S/R Day 5 n=0, 1, 1
    99999 (-99999 to 99999)
    -4.3 (-4.3 to -4.3)
    -3 (-3 to -3)
        S/R Day 6 n=1, 1, 1
    -2.5 (-2.5 to -2.5)
    -4.3 (-4.3 to -4.3)
    0 (0 to 0)
    Notes
    [52] - IPP Population
    [53] - IPP Population
    [54] - IPP Population
    No statistical analyses for this end point

    Secondary: Change from Baseline viral load (influenza A or B) from nasopharyngeal swabs positive at Baseline

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    End point title
    		 Change from Baseline viral load (influenza A or B) from nasopharyngeal swabs positive at Baseline
    End point description
    Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Day 6, Day 8, Day 10, Day 11, and the last day of randomized treatment. For participants who utilized the S/R option, samples were taken on S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6, whichever was the last day of S/R treatment. Samples were taken if the participant was symptomatic and continued to be hospitalized on the Post-Treatment +2, +5, +9, +16 and +28 Day assessment. Viral load as measured by PCR.Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles). "99999" indicates that data are not available/analysis was not performed. Data presented is for participants positive at Baseline
    End point type
    Secondary
    End point timeframe
    Baseline, Day 3, Day 5, Day 8, Day 10, Day 11 and/or last day of randomized treatment, if randomized treatment was extended beyond 5 days, and S/R Day 5/6 (up to Day 14) if applicable
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [55]
    162 [56]
    163 [57]
    Units: log10 vp/mL
    median (full range (min-max))
        Day 3 n=126, 127, 129
    -1.5 (-5.4 to 2.2)
    -1.83 (-4.9 to 2)
    -1.75 (-6 to 2.8)
        Day 5 n=110, 114, 114
    -2.51 (-5.8 to 3.2)
    -2.71 (-6.2 to 3.1)
    -2.73 (-6.3 to 2.3)
        Day 8 n=15, 12, 16
    -2.38 (-4.4 to 1)
    -3.16 (-5.5 to -0.3)
    -1.78 (-5.7 to 1.1)
        Day 10 n=13, 6, 8
    -2.75 (-6 to -0.9)
    -3.03 (-3.5 to 1.5)
    -2.63 (-4.6 to 0.9)
        Day 11 n=9,4, 7
    -3.58 (-4.9 to -0.6)
    -2.6 (-3.1 to 1.7)
    -3.29 (-4.9 to -1)
        S/R Day 5 n=0, 1, 1
    99999 (-99999 to 99999)
    -3.8 (-3.8 to -3.8)
    -5.7 (-5.7 to -5.7)
        S/R Day 6 n=1, 1, 2
    -5.2 (-5.2 to -5.2)
    -5.4 (-5.4 to -5.4)
    -3.84 (-4 to -3.7)
    Notes
    [55] - IPP Population
    [56] - IPP Population
    [57] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants with no detectable viral RNA and the absence of cultivable virus in lower respiratory samples (bronchoalveolar lavage sample [BAL], endotracheal aspirate)

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    End point title
    		 Number of participants with no detectable viral RNA and the absence of cultivable virus in lower respiratory samples (bronchoalveolar lavage sample [BAL], endotracheal aspirate)
    End point description
    Lower respiratory samples included BAL and endotracheal aspirates. Endotracheal aspirates were requested in participants (par.) who were intubated. Samples were collected daily from Baseline/Day 1 through Day 5 and Day 6 (if the last day of randomized treatment [trt]). If trt was continued beyond Day 5, additional samples were taken on Trt Day 6, Day 8, Day 10, and/or the day of the last dose of randomized trt, if applicable, and S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6 if the last day of S/R trt. If the par. was symptomatic and hospitalized, samples were taken on the Post-Trt +2, +5, +9, +16 assessment days, and at the Post-Trt [PT]+28 Day assessment. Only those par. available at the specified time points were analyzed (represented by n=X, X, X in the category titles). BAL samples were only collected if the procedure was being carried out for the routine management of the par. Data also presented for par. positive at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [58]
    162 [59]
    163 [60]
    Units: Participants
    number (not applicable)
        Influenza A and B Day 1; n=21, 17, 21
    0
    0
    0
        Influenza A and B Day 2; n=17, 15, 14
    0
    4
    1
        Influenza A and B Day 3; n=16, 10, 15
    1
    2
    0
        Influenza A and B Day 4; n=16,10, 15
    2
    2
    2
        Influenza A and B Day 5; n=15,10, 15
    3
    4
    2
        Influenza A and B Day 6; n= 14, 5, 9
    3
    1
    3
        Influenza A and B Day 8; n=5, 3, 7
    2
    0
    2
        Influenza A and B Day 10; n=4, 3, 3
    0
    0
    0
        Influenza A and B S/R Day 1; n=0, 0, 1
    0
    0
    0
        Influenza A and B S/R Day 3; n=1, 0, 1
    0
    0
    1
        Influenza A and B S/R Day 5; n=1, 0, 0
    0
    0
    0
        Influenza A and B PT + 2 Days; n= 9, 3, 9
    4
    1
    3
        Influenza A and B PT + 5 Days; n= 11, 2, 6
    4
    1
    0
        Influenza A and B PT + 9 Days; n= 5, 2, 4
    4
    1
    3
        Influenza A and B PT + 16 Days; n= 4, 1, 3
    3
    1
    2
        Influenza A and B PT + 28 Days; n= 1, 0, 1
    1
    0
    1
    Notes
    [58] - IPP Population
    [59] - IPP Population
    [60] - IPP Population
    No statistical analyses for this end point

    Secondary: Median time to no detectable viral RNA and the absence of cultivable virus in any obtained sample (upper and lower respiratory samples)

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    End point title
    		 Median time to no detectable viral RNA and the absence of cultivable virus in any obtained sample (upper and lower respiratory samples)
    End point description
    Upper and lower respiratory samples were collected daily from Baseline/Day 1 through Day 5 and Day 6 (if the last day of randomized treatment). If treatment was continued beyond Day 5, additional samples were taken on Treatment Day 6, Day 8, Day 10, and/or the day of the last dose of randomized treatment, if applicable, and S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6 if the last day of S/R treatment. If the participant was symptomatic and hospitalized, samples were taken on the Post-Treatment+2, +5, +9, +16 assessment days, and at the Post-Treatment +28 Day. Assessment of samples was done by quantitative RT-PCR.Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles). Data also presented for participants positive at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [61]
    162 [62]
    163 [63]
    Units: Days
    median (full range (min-max))
        Influenza A and B, n=114, 118, 115
    4 (1 to 34)
    3 (1 to 35)
    4 (1 to 57)
        Positive at baseline; n=102, 104, 102
    4 (2 to 34)
    4 (2 to 35)
    4 (2 to 57)
    Notes
    [61] - IPP Population
    [62] - IPP Population
    [63] - IPP Population
    No statistical analyses for this end point

    Secondary: Resistance-associated mutations events detected in the NA and HA gene of influenza A and B viruses in nasopharyngeal swabs and endotracheal/BAL samples

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    End point title
    		 Resistance-associated mutations events detected in the NA and HA gene of influenza A and B viruses in nasopharyngeal swabs and endotracheal/BAL samples
    End point description
    Nasopharyngeal swabs and endotracheal /BAL samples were collected for viral susceptibility analysis. Susceptibility analyses consisted of phenotyping and genotyping. Resistance mutations were detected by genotyping. Viral susceptibility to zanamivir and oral oseltamivir at Baseline and throughout treatment determined by NA and HA (gene of influenza A and B viruses) sequence analysis and NA enzyme inhibition. Number of participants with viral mutation events are summarized, this includes all resistance mutations (substitutions) i.e. those present at Baseline and those that emerged during treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    163 [64]
    162 [65]
    163 [66]
    Units: Participants
    number (not applicable)
        NA Gene,H3N2: Y155F
    5
    7
    5
        NA Gene,H3N2:S245N
    4
    4
    0
        NA Gene,H3N2:I222V
    0
    1
    2
        NA Gene,H3N2:N294S/N
    2
    0
    0
        NA Gene,H3N2:V149A
    0
    1
    1
        NA Gene,H3N2:D198D/G
    0
    0
    1
        NA Gene,H3N2:G248G/E
    1
    0
    0
        NA Gene,H3N2:N294D/N
    0
    1
    0
        NA Gene,H3N2:R292R/K
    0
    0
    1
        NA Gene,H3N2:T325I
    1
    0
    0
        NA Gene,H3N2:Y155H
    0
    0
    1
        NA Gene,H1N1: H275H/Y
    0
    1
    4
        NA Gene,H1N1:H275Y
    0
    1
    3
        NA Gene,H1N1:Q313R
    1
    0
    2
        NA Gene,H1N1:D199N
    1
    0
    0
        NA Gene,H1N1:E278G/E
    0
    0
    1
        NA Gene,H1N1:I223I/K
    0
    0
    1
        NA Gene,H1N1:Q136Q/R
    0
    0
    1
        NA Gene,H1N1:S247N
    1
    0
    0
        NA Gene,H1N1:S247S/I
    1
    0
    0
        NA Gene,H1N1:S247S/N
    0
    1
    0
        NA Gene,B: E148G
    1
    0
    0
        NA Gene,B: G141E
    0
    0
    1
        NA Gene,B: M403I
    1
    0
    0
        HA Gene, H3N2:R142G
    18
    21
    21
        HA Gene, H3N2:S198A
    13
    8
    11
        HA Gene, H3N2:A138S
    3
    1
    2
        HA Gene, H3N2:R142K
    0
    0
    2
        HA Gene, H3N2:A304A/P
    0
    0
    1
        HA Gene, H3N2:A304D
    0
    1
    0
        HA Gene, H3N2:L194P/L
    1
    0
    0
        HA Gene, H3N2:Q75H
    0
    1
    0
        HA Gene, H3N2:S124G
    0
    0
    1
        HA Gene, H3N2:S262N
    0
    1
    0
        HA Gene, H3N2:H1N1: S183P
    1
    0
    2
        HA Gene, H1N1 :D222D/G
    0
    0
    2
        HA Gene, H1N1 :D222D/N
    0
    2
    0
        HA Gene, H1N1 :D222N
    0
    0
    2
        HA Gene, H1N1 :S162N
    0
    0
    2
        HA Gene, H1N1 :D187E
    0
    1
    0
        HA Gene, H1N1 :D222G
    1
    0
    0
        HA Gene, H1N1 :D222S/D/N/G
    1
    0
    0
        HA Gene, H1N1 :L151P/L
    0
    1
    0
        HA Gene, H1N1 :V152I
    0
    0
    1
    Notes
    [64] - IPP Population
    [65] - IPP Population
    [66] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants with any adverse event (AE) considered to be related to study treatment

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    End point title
    		 Number of participants with any adverse event (AE) considered to be related to study treatment
    End point description
    An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. All AEs were assessed by the Investigator as related or not related to the study treatment. The Safety Population is comprised of all randomized participants who received at least one dose of investigational product and assessed according to their actual treatment received, regardless of the randomization assigned.
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    201 [67]
    209 [68]
    205 [69]
    Units: Participants
        number (not applicable)
    25
    22
    35
    Notes
    [67] - Safety Population
    [68] - Safety Population
    [69] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with any severe or Grade 3/4 AE

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    End point title
    		 Number of participants with any severe or Grade 3/4 AE
    End point description
    An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. AEs that occurred during the study were evaluated by the Investigator and graded according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) table for grading the severity of AEs. Grade 3=severe; Grade 4=potentially life threatening.
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    201 [70]
    209 [71]
    205 [72]
    Units: Participants
        number (not applicable)
    39
    45
    44
    Notes
    [70] - Safety Population
    [71] - Safety Population
    [72] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants who permanently discontinued the study treatment due to an AE

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    End point title
    		 Number of participants who permanently discontinued the study treatment due to an AE
    End point description
    An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse.
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    201 [73]
    209 [74]
    205 [75]
    Units: Participants
        number (not applicable)
    8
    10
    11
    Notes
    [73] - Safety Population
    [74] - Safety Population
    [75] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants who were permanently discontinued from the study due to an AE

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    End point title
    		 Number of participants who were permanently discontinued from the study due to an AE
    End point description
    An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse.
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    201 [76]
    209 [77]
    205 [78]
    Units: Participants
        number (not applicable)
    14
    16
    13
    Notes
    [76] - Safety Population
    [77] - Safety Population
    [78] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with any severe or Grade 3/4 treatment-related AE

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    End point title
    		 Number of participants with any severe or Grade 3/4 treatment-related AE
    End point description
    An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. AEs that occurred during the study were evaluated by the Investigator and graded according to the DAIDS table for grading the severity of adult and pediatric AEs. Grade 3=severe; Grade 4=potentially life threatening. All AEs were assessed by the Investigator as related or not related to the study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    201 [79]
    209 [80]
    205 [81]
    Units: Participants
        number (not applicable)
    5
    3
    7
    Notes
    [79] - Safety Population
    [80] - Safety Population
    [81] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated chemistry laboratory values shifts from Baseline (Day 1) and up to 42 days

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    End point title
    		 Number of participants with the indicated chemistry laboratory values shifts from Baseline (Day 1) and up to 42 days
    End point description
    Samples for laboratory assessments were collected at Baseline (Day 1), Day 3, Day 5/6, Day 8, Day 10/11 (or last day of randomized treatment), switch/rescue (S/R) Day 1, S/R Day 3, and S/R Day 5/6 (last day of S/R treatment for those participants who utilized this option), Post-Treatment +2 (if hospitalized), and Post-Treatment +5, +16, and +28 Days. Clinical chemistry parameters included albumin, alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino tranferase (AST), total bilirubin, calcium, creatine kinase, chloride, carbon dioxide content (CO2), creatinine, potassium, magnesium, sodium. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade (G) 1=mild, G2= moderate, G3=severe and G4=potentially life threatening.The number of participants with values that were G1, G2, G3 and G4 relative to the normal range are summarised.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    201 [82]
    209 [83]
    205 [84]
    Units: Participants
    number (not applicable)
        Albumin G1, n=194,203,202
    12
    18
    15
        Albumin G2, n=194,203,202
    32
    43
    40
        Albumin G3, n=194,203,202
    1
    5
    0
        Albumin G4, n=194,203,202
    0
    0
    0
        ALP G1, n=194,203,202
    10
    15
    9
        ALP G2, n=194,203,202
    0
    4
    1
        ALP G3, n=194,203,202
    0
    2
    0
        ALP G4, n=194,203,202
    0
    0
    0
        ALT G1, n=194,203,202
    13
    10
    12
        ALT G2, n=194,203,202
    2
    1
    1
        ALT G3, n=194,203,202
    0
    0
    0
        ALT G4, n=194,203,202
    0
    0
    1
        AST G1, n=193,202,202
    23
    27
    19
        AST G2, n=193,202,202
    8
    8
    6
        AST G3, n=193,202,202
    2
    0
    2
        AST G4, n=193,202,202
    0
    0
    1
        Total Bilirubin G1, n=194,203,202
    5
    2
    2
        Total Bilirubin G2, n=194,203,202
    3
    2
    3
        Total Bilirubin G3, n=194,203,202
    1
    2
    0
        Total Bilirubin G4, n=194,203,202
    0
    0
    1
        Creatine Kinase G1, n=194,203,202
    10
    11
    6
        Creatine Kinase G2, n=194,203,202
    3
    3
    6
        Creatine Kinase G3, n=194,203,202
    1
    2
    4
        Creatine Kinase G4, n=194,203,202
    1
    1
    2
        CO2 G1, n=193,202,202
    34
    43
    47
        CO2 G2, n=193,202,202
    4
    9
    6
        CO2 G3, n=193,202,202
    0
    0
    0
        CO2 G4, n=193,202,202
    0
    1
    0
        Creatinine G1, n=194,203,202
    6
    5
    4
        Creatinine G2, n=194,203,202
    11
    7
    4
        Creatinine G3, n=194,203,202
    8
    7
    4
        Creatinine G4, n=194,203,202
    0
    0
    1
        Magnesium G1, n=194,203,202
    14
    14
    15
        Magnesium G2, n=194,203,202
    7
    9
    4
        Magnesium G3, n=194,203,202
    0
    0
    0
        Magnesium G4, n=194,203,202
    0
    0
    0
        Hypercalcemia G1, n=193,202,202
    0
    0
    0
        Hypercalcemia G2, n=193,202,202
    0
    0
    0
        Hypercalcemia G3, n=193,202,202
    0
    0
    0
        Hypercalcemia G4, n=193,202,202
    0
    0
    0
        Hyperkalemia G1, n=193,202,202
    0
    1
    1
        Hyperkalemia G2, n=193,202,202
    0
    0
    0
        Hyperkalemia G3, n=193,202,202
    0
    0
    0
        Hyperkalemia G4, n=193,202,202
    1
    0
    1
        Hypernatremia G1, n=194,203,202
    4
    10
    4
        Hypernatremia G2, n=194,203,202
    1
    1
    0
        Hypernatremia G3, n=194,203,202
    0
    1
    1
        Hypernatremia G4, n=194,203,202
    0
    0
    0
        Hypocalcemia G1, n=193,202,202
    43
    48
    40
        Hypocalcemia G2, n=193,202,202
    26
    39
    42
        Hypocalcemia G3, n=193,202,202
    7
    8
    8
        Hypocalcemia G4, n=193,202,202
    0
    1
    0
        Hypokalemia G1, n=193,202,202
    16
    12
    21
        Hypokalemia G2, n=193,202,202
    1
    1
    1
        Hypokalemia G3, n=193,202,202
    1
    0
    0
        Hypokalemia G4, n=193,202,202
    0
    0
    0
        Hyponatremia G1, n=194,203,202
    42
    34
    26
        Hyponatremia G2, n=194,203,202
    2
    2
    4
        Hyponatremia G3, n=194,203,202
    0
    2
    0
        Hyponatremia G4, n=194,203,202
    0
    0
    1
    Notes
    [82] - Safety Population
    [83] - Safety Population
    [84] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated hematology values shifts from Baseline (Day 1) and up to 42 days

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    End point title
    		 Number of participants with the indicated hematology values shifts from Baseline (Day 1) and up to 42 days
    End point description
    Blood samples for laboratory assessments were collected at Baseline (Day 1), Day 3, Day 5/6, Day 8, Day 10/11 (or last day of randomized treatment), S/R Day 1, S/R Day 3, and S/R Day 5/6 (last day of S/R treatment for those participants who utilized this option), Post-Treatment +2 (if hospitalized), and Post-Treatment +5, +16, and +28 Days. Hematology parameters included hemoglobin, lymphocytes , total neutrophils, platelet count, and white blood cell (WBC) count. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade (G) 1=mild, G2= moderate, G3=severe and G4=potentially life threatening.The number of participants with values that were G1, G2, G3 and G4 relative to the normal range for the indicated hematology parameters is summarized. Baseline is defined as the pre-dose value collected on Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    201 [85]
    209 [86]
    205 [87]
    Units: Participants
    number (not applicable)
        Hemoglobin G1, n=194,202,200
    28
    25
    28
        Hemoglobin G2, n=194,202,200
    11
    19
    13
        Hemoglobin G3, n=194,202,200
    14
    10
    8
        Hemoglobin G4, n=194,202,200
    0
    4
    1
        Lymphocytes G1, n=186,199,198
    8
    18
    10
        Lymphocytes G2, n=186,199,198
    11
    15
    11
        Lymphocytes G3, n=186,199,198
    16
    21
    18
        Lymphocytes G4, n=186,199,198
    18
    19
    14
        Neutrophils G1, n=193,202,200
    2
    2
    3
        Neutrophils G2, n=193,202,200
    2
    0
    0
        Neutrophils G3, n=193,202,200
    0
    1
    0
        Neutrophils G4, n=193,202,200
    1
    0
    3
        Platelets G1, n=194,200,198
    8
    22
    21
        Platelets G2, n=194,200,198
    18
    12
    16
        Platelets G3, n=194,200,198
    4
    3
    2
        Platelets G4, n=194,200,198
    2
    1
    2
        Leukocytes G1, n=194,202,200
    3
    2
    1
        Leukocytes G2, n=194,202,200
    3
    5
    3
        Leukocytes G3, n=194,202,200
    0
    1
    0
        Leukocytes G4, n=194,202,200
    1
    0
    2
    Notes
    [85] - Safety Population
    [86] - Safety Population
    [87] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated treatment-emergent (TE) Grade (G) 3/4 clinical chemistry toxicities

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    End point title
    		 Number of participants with the indicated treatment-emergent (TE) Grade (G) 3/4 clinical chemistry toxicities
    End point description
    A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of investigational product). Clinical chemistry parameters included albumin, ALP, ALT, AST, total bilirubin, calcium, creatine kinase, chloride, CO2/bicarbonate, creatinine, potassium, magnesium and sodium. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade 3=severe and Grade 4=potentially life threatening. Baseline is defined as the pre-dose value collected on Study Day 1.Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    201 [88]
    209 [89]
    205 [90]
    Units: Participants
    number (not applicable)
        Albumin, G3; n=194, 203, 202
    6
    3
    4
        Albumin, G4; n=194, 203, 202
    0
    0
    0
        ALP, G3; n=194, 203, 202
    0
    2
    0
        ALP, G4; n=194, 203, 202
    1
    0
    1
        ALT, G3; n=194, 203, 202
    2
    2
    4
        ALT, G4; n=194, 203, 202
    0
    2
    1
        AST, G3; n=193, 202, 202
    2
    4
    5
        AST, G4; n=193, 202, 202
    1
    2
    1
        Total Bilirubin, G3; n=194, 203, 202
    2
    2
    1
        Total Bilirubin, G4; n=194, 203, 202
    0
    0
    0
        Creatine Kinase, G3; n=194, 203, 202
    2
    3
    2
        Creatine Kinase, G4; n=194, 203, 202
    3
    1
    1
        Carbon Dioxide, G3; n=193, 202, 202
    0
    0
    0
        Carbon Dioxide, G4; n=193, 202, 202
    1
    0
    0
        Creatinine, G3; n=194, 203, 202
    3
    6
    1
        Creatinine, G4; n=194, 203, 202
    3
    2
    0
        Magnesium, G3; n=194, 203, 202
    1
    0
    0
        Magnesium, G4; n=194, 203, 202
    0
    0
    1
        Hypercalcemia, G3; n=194, 202, 202
    0
    0
    0
        Hypercalcemia, G4; n=194, 202, 202
    0
    0
    0
        Hyperkalemia, G3; n=193, 202, 202
    2
    0
    1
        Hyperkalemia, G4; n=193, 202, 202
    1
    5
    3
        Hypernatremia, G3; n=194, 203, 202
    0
    1
    5
        Hypernatremia, G4; n=194, 203, 202
    0
    0
    0
        Hypocalcemia, G3; n=193, 202, 202
    10
    7
    8
        Hypocalcemia, G4; n=193, 202, 202
    2
    4
    4
        Hypokalemia, G3; n=193, 202, 202
    0
    0
    0
        Hypokalemia, G4; n=193, 202, 202
    0
    0
    0
        Hyponatremia, G3; n=194, 203, 202
    1
    0
    0
        Hyponatremia G4, n=194,203,202
    0
    0
    0
    Notes
    [88] - Safety Population
    [89] - Safety Population
    [90] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated treatment-emergent (TE) Grade 3/4 hematology toxicities

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    End point title
    		 Number of participants with the indicated treatment-emergent (TE) Grade 3/4 hematology toxicities
    End point description
    A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of investigational product). The hematology parameters included hemoglobin, lymphocytes, total neutrophils, platelet count, and WBC count. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade 3=severe and Grade 4=potentially life threatening. Baseline is defined as the pre-dose value collected on Study Day 1.Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 42 days
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    201 [91]
    209 [92]
    205 [93]
    Units: Participants
    number (not applicable)
        Hemoglobin, G3; n=194, 202, 200
    29
    24
    26
        Hemoglobin, G4; n=194, 202, 200
    2
    5
    8
        Lymphocytes, G3; n=186, 199, 198
    6
    5
    11
        Lymphocytes, G4; n=186, 199, 198
    3
    14
    7
        Total Neutrophils, G3; n=193, 202, 200
    1
    2
    2
        Total Neutrophils, G4; n=193, 202, 200
    4
    4
    3
        Platelet count, G3; n=194, 200, 198
    4
    4
    5
        Platelet count, G4; n=194, 200, 198
    3
    3
    2
        Leukocytes Count, G3; n=194, 202, 200
    1
    1
    0
        Leukocytes Count, G4; n=194, 202, 200
    2
    1
    3
    Notes
    [91] - Safety Population
    [92] - Safety Population
    [93] - Safety Population
    No statistical analyses for this end point

    Secondary: Median quantity of oxygen delivery measured at Baseline (Day 1) and during the study

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    End point title
    		 Median quantity of oxygen delivery measured at Baseline (Day 1) and during the study
    End point description
    The quantity of oxygen delivery were assessed three times daily at Baseline (Day 1) and at Days 2, 3, 4, and 5/6 and once daily during post-treatment +5 days, +16 days, and +28 days. All assessments were to be made at approximately the same time each day (morning, afternoon, and evening) and ideally at least 6 hours apart. The median quantity of oxygen delivery during the study was not summarized since the data was not collected in a way to accurately calculate values. Baseline is defined as the pre-dose value collected on Study Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and during the study
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    0 [94]
    0 [95]
    0 [96]
    Units: Percentage of oxygen level in blood
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    Notes
    [94] - This end point was not analyzed.
    [95] - This end point was not analysed
    [96] - This end point was not analysed
    No statistical analyses for this end point

    Secondary: Number of participants assessed as normal/abnormal (clinically significant [CS] and not clinically significant [NCS]) for 12-lead electrocardiogram (ECG) at Baseline (Day 1) and Day 4

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    End point title
    		 Number of participants assessed as normal/abnormal (clinically significant [CS] and not clinically significant [NCS]) for 12-lead electrocardiogram (ECG) at Baseline (Day 1) and Day 4
    End point description
    On Baseline/Day 1, a 12-lead ECG was obtained within approximately 24 hours prior to dosing. The number of participants with an ECG status of normal and abnormal CS or NCS, as determined by the Investigator, is reported. Normal=all ECG parameters within the accepted normal ranges. Abnormal=ECG findings outside of normal ranges. CS=ECG with a CS abnormality that meets exclusion criteria. NCS=ECG with an abnormality that is not CS nor meets exclusion criteria, per Investigator, based on reasonable standards of clinical judgment. In the original protocol ECGs were also done on Day 4, however amendment 2 removed this requirement and therefore not all participants had Day 4 ECGs. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline/Day 1 and Day 4
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    197 [97]
    208 [98]
    203 [99]
    Units: Participants
    number (not applicable)
        Normal
    100
    121
    99
        Abnormal - Not Clinically Significant
    97
    86
    102
        Abnormal – Clinically Significant
    5
    4
    7
    Notes
    [97] - Safety Population
    [98] - Safety Population
    [99] - Safety Population
    No statistical analyses for this end point

    Secondary: Serum concentration of intravenous (IV) zanamivir

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    End point title
    		 Serum concentration of intravenous (IV) zanamivir
    End point description
    Pharmacokinetic samples were collected at four time points to characterize peak concentration (end of infusion; C[EOI]) after the first dose on Day 1 and on Day 4 to characterize the pre-dose concentration (C[0]), the peak concentration C(EOI), and the trough concentration at 11-12 hours post-dose (C[12]) of zanamavir. The PK Population is comprised of all participants who received IV zanamivir and underwent sparse PK sampling during the study from which one or more serum zanamivir concentrations was determined. Data was summarised by Creatinine clearance (CL) Category.The dose on Day 1 is the initial dose (unadjusted) and the dose on Day 4 is the maintenance dose. "99999" indicates that data are not available/analysis was not performed.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 4
    End point values
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Number of subjects analysed
    180 [100]
    187 [101]
    0 [102]
    Units: microgram/Liter (mcg/L)
    arithmetic mean (standard deviation)
        CL <15, Day 1, 30 min, n=1,3,0
    14454.6 ± 99999
    26410.8 ± 21335.43
    ±
        CL <15, Day 4, pre-dose n=1,2,0
    293.2 ± 99999
    9635.6 ± 8270.67
    ±
        CL <15, Day 4, 30 min n=1,1,0
    1329.4 ± 99999
    19828.9 ± 99999
    ±
        CL <15, Day 4, 11-12 hr n=1,1,0
    605.1 ± 99999
    15459.1 ± 99999
    ±
        CL 15-<30, Day 13, 30 min, n=13,9,0
    20403.3 ± 11623.28
    41102.8 ± 13884.08
    ±
        CL 15-<30, Day 4, pre-dose n=10,6,0
    5906.4 ± 7167.87
    4995.6 ± 1966.72
    ±
        CL 15-<30, Day 4, 30 min n=10,6,0
    13636.4 ± 14029.44
    13378 ± 2581.36
    ±
        CL 15-<30, Day 4, 11-12 hr n=8,5,0
    7600.3 ± 8061.65
    4953.4 ± 2232.16
    ±
        CL 30-<50, Day 1, 30 min, n=28,18,0
    18756.8 ± 12806.43
    42467.3 ± 14574.82
    ±
        CL 30-<50, Day 4, pre-dose n=12,15,0
    2094.8 ± 1300.99
    7637.4 ± 7212.1
    ±
        CL 30-<50, Day 4, 30 min n=12,13,0
    12334.4 ± 12121.18
    159292.1 ± 473267.3
    ±
        CL 30-<50, Day 4, 11-12 hr n=11,13,0
    2932.5 ± 2425.81
    19549.2 ± 40577.76
    ±
        CL 50-<80, Day 1, 30 min, n=36,49,0
    19146.7 ± 8853.11
    49666.1 ± 111785.9
    ±
        CL 50-<80, Day 4, pre-dose n=31,25,0
    2793.3 ± 4694.43
    13107.7 ± 33768.61
    ±
        CL 50-<80, Day 4, 30 min n=32,25,0
    31541.3 ± 93381
    22220.4 ± 10064.83
    ±
        CL 50-<80, Day 4, 11-12 hr n=30,23,0
    1345.9 ± 1122.18
    22623.9 ± 57663.24
    ±
        CL >=80, Day 1, 30 min, n=93,96,0
    18561.7 ± 10332.14
    35139.2 ± 17693.85
    ±
        CL >=80, Day 4, pre-dose n=99,107,0
    2342.6 ± 6672.12
    19379.8 ± 105056.3
    ±
        CL >=80, Day 4, 30 min n=100,106,,0
    21580.7 ± 22062.69
    75255.1 ± 167670.6
    ±
        CL >=80, Day 4, 11-12 hr n=94,99,0
    2036.2 ± 4412.75
    19428.7 ± 142284.7
    ±
        Missing, Day 1, 30 min n=0,2,0
    99999 ± 99999
    41109.7 ± 3831.74
    ±
    Notes
    [100] - PK Population
    [101] - PK Population
    [102] - This end point was not analyzed
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until follow-up (up to 42 days).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    IV zanamivir 300 mg
    Reporting group description
    		 Participants >=16 years of age received intravenous (IV) zanamivir 300 milligrams (mg) twice daily, adjusted for renal function for 5–10 days.

    Reporting group title
    IV zanamivir 600 mg
    Reporting group description
    		 Participants >=16 years of age received IV zanamivir 600 mg twice daily, adjusted for renal function for 5–10 days.

    Reporting group title
    Oral oseltamivir 75 mg
    Reporting group description
    		 Participants >=16 years of age received oral oseltamvir 75 mg twice daily, adjusted for renal function for 5–10 days.

    Serious adverse events
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 201 (18.91%)
    33 / 209 (15.79%)
    38 / 205 (18.54%)
         number of deaths (all causes)
    15
    15
    11
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Distributive shock
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hypotension
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Surgical and medical procedures
    Mechanical ventilation
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    2 / 201 (1.00%)
    2 / 209 (0.96%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anti-neutrophil cytoplasmic antibody positive vasculitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    5 / 201 (2.49%)
    4 / 209 (1.91%)
    5 / 205 (2.44%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    1 / 3
    0 / 2
    Acute respiratory distress syndrome
         subjects affected / exposed
    4 / 201 (1.99%)
    3 / 209 (1.44%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 201 (0.50%)
    2 / 209 (0.96%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bronchospasm
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 209 (0.96%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory disorder
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 209 (0.48%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium febrile
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ECG signs of ventricular hypertrophy
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endotracheal intubation complication
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    2 / 201 (1.00%)
    1 / 209 (0.48%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 209 (0.48%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Neuromyopathy
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Neutropenia
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 201 (1.99%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    IgA nephropathy
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    7 / 201 (3.48%)
    1 / 209 (0.48%)
    4 / 205 (1.95%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    4 / 201 (1.99%)
    1 / 209 (0.48%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
    Sepsis
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 209 (0.48%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Bronchitis
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 209 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 209 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 209 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 IV zanamivir 300 mg IV zanamivir 600 mg Oral oseltamivir 75 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 201 (8.46%)
    26 / 209 (12.44%)
    24 / 205 (11.71%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    10 / 201 (4.98%)
    15 / 209 (7.18%)
    14 / 205 (6.83%)
         occurrences all number
    11
    20
    14
    Constipation
         subjects affected / exposed
    7 / 201 (3.48%)
    13 / 209 (6.22%)
    10 / 205 (4.88%)
         occurrences all number
    8
    16
    10

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jan 2011
    (i) the liver criteria stopping exemption was deleted, (ii) update and clarification to inclusion criteria 1, 2, 4 and 5, and exclusion criteria 5, 7, 13 and 14, and (iii) update to the background information and some minor clarifications within the protocol. The majority of changes detailed in points (i) and (ii) were made in response to requests from regulatory authorities and Ethics Committees.
    01 Jun 2012
    (i) included a contingency study design change to allow for continuation of the study in the event of widespread oseltamivir resistance by temporarily or permanently discontinuing the oseltamivir arm, (ii) removal of exclusion criterion 13 (QTc entry criteria) and removal of Day 4 ECG measurements, and (iii) includes updates and clarifications within the protocol. The major change detailed in point (i) was made in response to comments from regulatory and health agencies to allow the study to be completed in the event of significant oseltamivir resistance developing during the course of the study.
    24 Jan 2014
    (i) changes to the data analysis and statistical considerations section of the protocol, including details of a second interim analysis, (ii) included a few clarifications and updates within the protocol. The major change detailed in point (i) was made following the outcome of the first interim analysis where the IDMC recommended that the study continue with all three treatment arms, resulting in an increase to the sample size from 462 to 600 participants. A second interim analysis was included to inform on whether it was appropriate to continue to recruit 600 participants. The statistical analysis framework was updated to allow for consideration of additional evidence beyond the original primary and secondary endpoints.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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