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    Clinical Trial Results:
    A Phase 2 Randomized, Double-Blind Placebo-Controlled Trial of MHAA4549A, a Monoclonal Antibody in Combination With Oseltamivir Versus Oseltamivir for Treatment of Severe Influenza A Infection

    Summary
    EudraCT number
    		 2014-000461-43
    Trial protocol
    		 IT   GB   HU   DE   CZ   ES   BE   NL   BG   PL   FR  
    Global end of trial date
    23 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 May 2018
    First version publication date
    30 May 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GV29216
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02293863
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124,, Basel,, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, + 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main safety objective of the trial was to evaluate the safety of MHAA4549A in combination with oseltamivir compared with placebo and oseltamivir in subjects with severe influenza A, focusing on serious and non-serious adverse events (AEs) as well as effects on laboratory values, vital signs, electrocardiogram (ECG) parameters and anti-therapeutic antibodies. The main efficacy objective was to determine the time to normalization of respiratory function of subjects dosed with MHAA4549A in combination with oseltamivir compared to subjects dosed with placebo and oseltamivir.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jan 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Bulgaria: 11
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Peru: 1
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Ukraine: 3
    Worldwide total number of subjects
    158
    EEA total number of subjects
    83
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    91
    From 65 to 84 years
    56
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 62 investigational sites in 17 countries.

    Pre-assignment
    Screening details
    		 Subjects with a diagnosis of influenza using a Sponsor-approved influenza test and one of the following markers of severity within 24 hours of admission were included in the study: 1. requirement for oxygen (O2) supplementation to maintain oxygen saturation level (SpO2) greater than (>) 92 %; 2. requirement for Positive Pressure Ventilation (PPV).

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Oseltamivir
    Arm description
    		 Subjects received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single intravenous (IV) dose of placebo matched to MHAA4549A on Day 1.

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Other name
    Tamiflu
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received oseltamivir capsule either 75 mg or 150 mg twice daily (BID) orally for minimum of 5 days. Dosage and administration followed local prescribing information for oseltamivir.

    Arm title
    		 MHAA4549A 3600 mg + Oseltamivir
    Arm description
    		 Subjects received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MHAA4549A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single low (3600 milligrams [mg]) dose of MHAA4549A by IV infusion on Day 1.

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Other name
    Tamiflu
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received oseltamivir capsule either 75 mg or 150 mg twice daily (BID) orally for minimum of 5 days. Dosage and administration followed local prescribing information for oseltamivir.

    Arm title
    		 MHAA4549A 8400 mg + Oseltamivir
    Arm description
    		 Subjects received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Other name
    Tamiflu
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received oseltamivir capsule either 75 mg or 150 mg twice daily (BID) orally for minimum of 5 days. Dosage and administration followed local prescribing information for oseltamivir.

    Investigational medicinal product name
    MHAA4549A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single high (8400 mg) dose of MHAA4549A by IV infusion on Day 1.

    Number of subjects in period 1
    		Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Started
    56
    55
    47
    Completed
    47
    42
    38
    Not completed
    9
    13
    9
         Adverse event, serious fatal
    4
    6
    4
         Consent withdrawn by subject
    3
    3
    1
         Lost to follow-up
    2
    2
    2
         Reason not specified
    -
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Oseltamivir
    Reporting group description
    		 Subjects received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.

    Reporting group title
    MHAA4549A 3600 mg + Oseltamivir
    Reporting group description
    		 Subjects received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.

    Reporting group title
    MHAA4549A 8400 mg + Oseltamivir
    Reporting group description
    		 Subjects received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.

    Reporting group values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir Total
    Number of subjects
    		 56 55 47 158
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.7 ± 17.5 56.5 ± 18.2 59.8 ± 17.9 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 24 25 22 71
        Male
    		 32 30 25 87
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 13 20 8 41
        Not Hispanic or Latino
    		 37 28 34 99
        Not Stated
    		 6 7 5 18
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska native
    		 1 0 1 2
        Asian
    		 4 0 2 6
        Black or African American
    		 1 1 0 2
        White
    		 45 44 39 128
        Multiple
    		 0 1 0 1
        Unknown
    		 5 9 5 19

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Oseltamivir
    Reporting group description
    		 Subjects received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.

    Reporting group title
    MHAA4549A 3600 mg + Oseltamivir
    Reporting group description
    		 Subjects received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.

    Reporting group title
    MHAA4549A 8400 mg + Oseltamivir
    Reporting group description
    		 Subjects received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.

    Primary: Percentage of Subjects With Adverse Events

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    End point title
    		 Percentage of Subjects With Adverse Events [1]
    End point description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Safety population included all randomised subjects who received study drug, with subjects grouped according to the treatment actually received.
    End point type
    Primary
    End point timeframe
    From randomisation up to 60 days
    Notes
    [1] - 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: Only descriptive summary statistics were provided for primary safety outcomes per protocol.
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    56
    55
    47
    Units: percentage of subjects
        number (not applicable)
    80.4
    67.3
    74.5
    No statistical analyses for this end point

    Primary: Number of Subjects With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A

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    End point title
    		 Number of Subjects With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A [2]
    End point description
    Reported are the number of subjects positive for ATAs at baseline, the number of subjects with treatment-induced ATAs and the number of subjects with treatment-enhanced ATAs. Here, "n" indicates the number of subjects analysed for this outcome measure. Safety population included all randomised subjects who received study drug, with subjects grouped according to the treatment actually received.
    End point type
    Primary
    End point timeframe
    From randomisation up to 60 days
    Notes
    [2] - 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: PK results for MHAA4549A are only provided for the arms, which received MHAA4549A.
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    56
    55
    47
    Units: subjects
        Positive for ATAs at baseline (n= 56, 55, 47)
    0
    1
    1
        Treatment-induced ATAs (n= 47, 43, 37)
    0
    0
    0
        Treatment-enhanced ATAs (n= 47, 43, 37)
    0
    0
    0
    No statistical analyses for this end point

    Primary: Time to Normalisation of Respiratory Function

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    End point title
    		 Time to Normalisation of Respiratory Function
    End point description
    The time to normalisation of respiratory function was defined as the time to removal of the subject from oxygen (O2) supplementation in order to maintain a blood oxygen saturation level (SpO2) equal to or greater than 95% as measured by pulse oximetry. Intent-to-treat infected (ITTi) population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Primary
    End point timeframe
    From randomisation up to 60 days
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: days
        median (confidence interval 80%)
    4.28 (3.06 to 6.60)
    2.78 (2.52 to 4.20)
    2.65 (1.58 to 4.52)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.605
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.4
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2028
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.51

    Secondary: Percentage of Subjects by Clinical Status Using a Categorical Ordinal Outcome

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    End point title
    		 Percentage of Subjects by Clinical Status Using a Categorical Ordinal Outcome
    End point description
    The clinical status of subjects was defined by five mutually exclusive categories: 1. Death; 2. In the Intensive Care Unit (ICU); 3. Non-ICU hospitalisation, requiring supplemental oxygen (O2); 4. Non-ICU hospitalisation, not requiring supplemental oxygen (O2); 5. Not hospitalised. ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    Days 1-7, 14 and 30
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: percentage of subjects
    number (not applicable)
        Day 1: Death
    0.0
    0.0
    0.0
        Day 1: In ICU
    42.6
    38.5
    43.2
        Day 1: Non-ICU, requiring supplemental O2
    57.4
    61.5
    52.3
        Day 1: Non-ICU, not requiring supplemental O2
    0.0
    0.0
    4.5
        Day 1: Not hospitalised
    0.0
    0.0
    0.0
        Day 2: Death
    0.0
    0.0
    2.3
        Day 2: In ICU
    42.6
    38.5
    38.6
        Day 2: Non-ICU, requiring supplemental O2
    40.7
    51.9
    31.8
        Day 2: Non-ICU, not requiring supplemental O2
    11.1
    7.7
    20.5
        Day 2: Not hospitalised
    5.6
    1.9
    6.8
        Day 3: Death
    0.0
    0.0
    2.3
        Day 3: In ICU
    37.0
    32.7
    34.1
        Day 3: Non-ICU, requiring supplemental O2
    31.5
    42.3
    27.3
        Day 3: Non-ICU, not requiring supplemental O2
    20.4
    19.2
    25.0
        Day 3: Not hospitalised
    11.1
    5.8
    11.4
        Day 4: Death
    0.0
    0.0
    2.3
        Day 4: In ICU
    35.2
    30.8
    29.5
        Day 4: Non-ICU, requiring supplemental O2
    25.9
    21.2
    18.2
        Day 4: Non-ICU, not requiring supplemental O2
    22.2
    36.5
    29.5
        Day 4: Not hospitalised
    16.7
    11.5
    20.5
        Day 5: Death
    0.0
    0.0
    2.3
        Day 5: In ICU
    27.8
    26.9
    27.3
        Day 5: Non-ICU, requiring supplemental O2
    25.9
    19.2
    18.2
        Day 5: Non-ICU, not requiring supplemental O2
    24.1
    34.6
    27.3
        Day 5: Not hospitalised
    22.2
    19.2
    25.0
        Day 6: Death
    1.9
    1.9
    2.3
        Day 6: In ICU
    22.2
    23.1
    22.7
        Day 6: Non-ICU, requiring supplemental O2
    22.2
    15.4
    15.9
        Day 6: Non-ICU, not requiring supplemental O2
    27.8
    34.6
    25.0
        Day 6: Not hospitalised
    25.9
    25.0
    34.1
        Day 7: Death
    1.9
    1.9
    2.3
        Day 7: In ICU
    18.5
    21.2
    20.5
        Day 7: Non-ICU, requiring supplemental O2
    24.1
    13.5
    15.9
        Day 7: Non-ICU, not requiring supplemental O2
    14.8
    28.8
    25.0
        Day 7: Not hospitalised
    40.7
    34.6
    36.4
        Day 14: Death
    1.9
    3.8
    6.8
        Day 14: In ICU
    5.6
    11.5
    9.1
        Day 14: Non-ICU, requiring supplemental O2
    7.4
    3.8
    6.8
        Day 14: Non-ICU, not requiring supplemental O2
    14.8
    3.8
    4.5
        Day 14: Not hospitalised
    70.4
    76.9
    72.7
        Day 30: Death
    5.6
    7.7
    9.1
        Day 30: In ICU
    1.9
    3.8
    4.5
        Day 30: Non-ICU, requiring supplemental O2
    5.6
    1.9
    4.5
        Day 30: Non-ICU, not requiring supplemental O2
    1.9
    3.8
    0.0
        Day 30: Not hospitalised
    85.2
    82.7
    81.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Failure

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    End point title
    		 Percentage of Subjects With Clinical Failure
    End point description
    Clinical failure after 24 hours post-infusion of study drug was defined as progression to increased O2 requirement defined by an increase in oxygen supplementation from low flow oxygen (i.e., 2−6 liters per minute [L/min]) to high flow oxygen (i.e., > 6 L/min) or from oxygen supplementation alone to any positive pressure ventilation (PPV) or extracorporeal membrane oxygenation (ECMO), progression to ICU, prolonged ventilation or O2 support defined by > 2 weeks, or death. ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    24 hours after end of infusion (infusion duration = approximately 120 minutes) up to Day 60
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: percentage of subjects
        number (confidence interval 80%)
    14.8 (8.82 to 22.95)
    25.0 (17.22 to 34.32)
    22.7 (14.63 to 32.84)
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3168
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    7.91
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -2.64
         upper limit
    		 18.47
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1905
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    10.19
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 20.52

    Secondary: Percentage of Subjects With Clinical Resolution of Abnormal Vital Signs

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    End point title
    		 Percentage of Subjects With Clinical Resolution of Abnormal Vital Signs
    End point description
    Description: Clinical resolution of abnormal vital signs was defined as meeting three out of five of the following criteria: 1. SpO2 ≥ 95% without supplemental O2; 2. Respiratory rate < 24 breaths per minute without supplemental O2; 3. Core temperature < 37.2 Celsius (C) immediately prior to receipt of any antipyretic drug, and at least 6-8 hours from the last dose of antipyretic or core temperature > 36 C in subjects who are initially hypothermic; 4. Heart rate (HR) < 100 beats/minute; 5. Systolic blood pressure (SBP) >90 mmHg. Reported here is the percentage of subjects who had clinical resolution of at least three out of five abnormal vital signs by the end of study. ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    From randomization up to 60 days
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: percentage of subjects
        number (confidence interval 80%)
    81.3 (62.88 to 92.90)
    73.3 (53.60 to 87.82)
    66.7 (44.10 to 84.58)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6043
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    -7.92
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -27.5
         upper limit
    		 11.66
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3865
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    -14.58
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -36.13
         upper limit
    		 6.97

    Secondary: Percentage of Subjects Who Died Due to Any Cause

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    End point title
    		 Percentage of Subjects Who Died Due to Any Cause
    End point description
    ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    Days 14, 30 and 60
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: percentage of subjects
    number (confidence interval 80%)
        Day 14
    1.9 (0.19 to 7.01)
    3.8 (1.03 to 9.91)
    6.8 (2.53 to 14.56)
        Day 30
    5.6 (2.06 to 11.95)
    7.7 (3.40 to 14.79)
    9.1 (4.02 to 17.35)
        Day 60
    7.4 (3.27 to 14.26)
    9.6 (4.75 to 17.11)
    9.1 (4.02 to 17.35)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Day 14
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5379
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    1.99
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -5.57
         upper limit
    		 9.56
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Day 14
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2189
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    4.97
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -3.12
         upper limit
    		 13.05
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Day 30
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6594
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    2.14
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -6.04
         upper limit
    		 10.31
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Day 30
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5013
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    3.54
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -5.24
         upper limit
    		 12.31
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Day 60
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6849
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    2.21
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -6.28
         upper limit
    		 10.69
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Day 60
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7633
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    1.68
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -7.38
         upper limit
    		 10.74

    Secondary: Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus

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    End point title
    		 Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus
    End point description
    Influenza A viral load was measured by quantitative polymerase chain reaction (qPCR) in nasopharyngeal samples at multiple time points during the study. AUEC is the area under the viral load-time curve curve expressed as log10 (viral particles/millilitre x hour) = log10 (vp/mL x hour). ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60)
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    48
    46
    39
    Units: log10 (vp/mL x hour)
        arithmetic mean (standard deviation)
    25.72 ± 15.92
    21.99 ± 16.57
    25.03 ± 13.48
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2407
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.73
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -6.41
         upper limit
    		 -1.06
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8339
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -3.49
         upper limit
    		 2.1

    Secondary: Peak Influenza A Viral Load

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    End point title
    		 Peak Influenza A Viral Load
    End point description
    Influenza A viral load was measured by qPCR in nasopharyngeal samples at multiple time points during the study. Reported here is the peak Influenza A viral load expressed as log10 vp/mL. ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60)
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    48
    46
    39
    Units: log10 vp/mL
        arithmetic mean (standard deviation)
    5.70 ± 1.32
    5.37 ± 1.39
    5.28 ± 1.71
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.279
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.33
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.07
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1909
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.42
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.15

    Secondary: Duration of Viral Shedding

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    End point title
    		 Duration of Viral Shedding
    End point description
    Influenza A viral load was measured by qPCR in nasopharyngeal samples at multiple time points during the study. Reported here is the duration of viral shedding. ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60)
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: days
        median (confidence interval 80%)
    4.00 (3.66 to 5.60)
    4.63 (3.63 to 4.97)
    4.60 (3.57 to 5.53)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7413
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.32
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4763
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.32
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.77

    Secondary: Duration of Hospitalisation

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    End point title
    		 Duration of Hospitalisation
    End point description
    ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    From randomisation up to 60 days
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: days
        median (confidence interval 80%)
    8.95 (5.90 to 10.29)
    7.65 (6.94 to 8.02)
    6.69 (6.00 to 8.86)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8806
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.32
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5447
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.38

    Secondary: Duration of Intensive Care Unit (ICU) Stay

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    End point title
    		 Duration of Intensive Care Unit (ICU) Stay
    End point description
    ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    From randomisation up to 60 days
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: days
        median (confidence interval 80%)
    4.66 (3.91 to 7.10)
    6.60 (4.82 to 10.53)
    5.29 (3.25 to 6.58)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4171
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.03
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8322
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.34

    Secondary: Percentage of Subjects Using Antibiotics for Respiratory Infections

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    End point title
    		 Percentage of Subjects Using Antibiotics for Respiratory Infections
    End point description
    ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    From randomisation up to 60 days
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: percentage of subjects
        number (confidence interval 80%)
    13.0 (7.36 to 20.84)
    11.5 (6.17 to 19.37)
    11.4 (5.63 to 20.06)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.824
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    -1.42
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -10.61
         upper limit
    		 7.76
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8111
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    -1.6
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -11.48
         upper limit
    		 8.28

    Secondary: Percentage of Subjects With Secondary Complications of Influenza

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    End point title
    		 Percentage of Subjects With Secondary Complications of Influenza
    End point description
    The following were considered secondary complications of influenza: pneumonia, including hospital-acquired pneumonia (HAP) and ventilation-acquired pneumonia (VAP), exacerbations of chronic lung disease, myocarditis, acute respiratory distress syndrome (ARDS), otitis media, or other related complications. ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    From randomisation up to 60 days
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: percentage of subjects
        number (confidence interval 80%)
    13.0 (7.36 to 20.84)
    15.4 (9.17 to 23.79)
    13.6 (7.32 to 22.71)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7219
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    2.42
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -6.96
         upper limit
    		 11.8
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9225
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    0.67
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -9.29
         upper limit
    		 10.64

    Secondary: Percentage of Subjects Readmitted to Hospital Due to Any Cause

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    End point title
    		 Percentage of Subjects Readmitted to Hospital Due to Any Cause
    End point description
    ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    Days 30 and 60
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: percentage of subjects
        number (confidence interval 80%)
    1.9 (0.19 to 7.01)
    3.8 (1.03 to 9.91)
    0 (0.00 to 5.10)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5379
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    1.99
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -5.57
         upper limit
    		 9.56
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3667
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in event rates
    Point estimate
    -1.85
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -9.88
         upper limit
    		 6.18

    Secondary: Duration of Ventilation

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    End point title
    		 Duration of Ventilation
    End point description
    ITTi population included all randomised subjects, who were confirmed to be influenza A infected, with subjects grouped according to the treatment assigned at randomisation.
    End point type
    Secondary
    End point timeframe
    From randomisation up to 60 days
    End point values
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    54
    52
    44
    Units: days
        median (confidence interval 80%)
    4.11 (2.72 to 5.32)
    7.05 (1.92 to 13.12)
    5.89 (4.13 to 13.07)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 3600 mg + Oseltamivir
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7827
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.07
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo + Oseltamivir v MHAA4549A 8400 mg + Oseltamivir
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2522
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.96

    Secondary: Area Under Serum Concentration-Time Curve from Time 0 to Infinity (AUC0-inf) of MHAA4549A

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    End point title
    		 Area Under Serum Concentration-Time Curve from Time 0 to Infinity (AUC0-inf) of MHAA4549A [3]
    End point description
    AUC0-inf is reported as day*microgram/millilitre (day*mcg/mL). Pharmacokinetic (PK)−evaluable population included all subjects, who received MHAA4549A and from whom evaluable PK samples were obtained.
    End point type
    Secondary
    End point timeframe
    30 minutes (min) before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK results for MHAA4549A are only provided for the arms, which received MHAA4549A.
    End point values
    		 MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    38
    31
    Units: day*mcg/mL
        arithmetic mean (standard deviation)
    11400 ± 4530
    26700 ± 9810
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration (Cmax) of MHAA4549A

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    End point title
    		 Maximum Serum Concentration (Cmax) of MHAA4549A [4]
    End point description
    PK−evaluable population included all subjects, who received MHAA4549A and from whom evaluable PK samples were obtained.
    End point type
    Secondary
    End point timeframe
    30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK results for MHAA4549A are only provided for the arms, which received MHAA4549A.
    End point values
    		 MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    38
    31
    Units: mcg/mL
        arithmetic mean (standard deviation)
    916 ± 294
    2220 ± 556
    No statistical analyses for this end point

    Secondary: Elimination Half-Life (Terminal t1/2) of MHAA4549A

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    End point title
    		 Elimination Half-Life (Terminal t1/2) of MHAA4549A [5]
    End point description
    PK−evaluable population included all subjects, who received MHAA4549A and from whom evaluable PK samples were obtained.
    End point type
    Secondary
    End point timeframe
    30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK results for MHAA4549A are only provided for the arms, which received MHAA4549A.
    End point values
    		 MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    38
    31
    Units: day
        arithmetic mean (standard deviation)
    19.0 ± 4.91
    17.8 ± 3.88
    No statistical analyses for this end point

    Secondary: Observed Clearance (CL_obs) of MHAA4549A

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    End point title
    		 Observed Clearance (CL_obs) of MHAA4549A [6]
    End point description
    PK−evaluable population included all subjects, who received MHAA4549A and from whom evaluable PK samples were obtained.
    End point type
    Secondary
    End point timeframe
    30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK results for MHAA4549A are only provided for the arms, which received MHAA4549A.
    End point values
    		 MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    38
    31
    Units: mL/day
        arithmetic mean (standard deviation)
    288 ± 158
    350 ± 130
    No statistical analyses for this end point

    Secondary: Observed Steady State Volume of Distribution (Vss_obs) of MHAA4549A

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    End point title
    		 Observed Steady State Volume of Distribution (Vss_obs) of MHAA4549A [7]
    End point description
    PK−evaluable population included all subjects, who received MHAA4549A and from whom evaluable PK samples were obtained.
    End point type
    Secondary
    End point timeframe
    30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK results for MHAA4549A are only provided for the arms, which received MHAA4549A.
    End point values
    		 MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Number of subjects analysed
    38
    31
    Units: mL
        arithmetic mean (standard deviation)
    6410 ± 3170
    7450 ± 2270
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation up to 60 days
    Adverse event reporting additional description
    Safety Population included all randomised subjects, who received study drug, with subjects grouped according to the treatment actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo + Oseltamivir
    Reporting group description
    		 Subjects received a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.

    Reporting group title
    MHAA4549A 3600 mg + Oseltamivir
    Reporting group description
    		 Subjects received a single low intravenous (IV) dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.

    Reporting group title
    MHAA4549A 8400 mg + Oseltamivir
    Reporting group description
    		 Subjects received a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.

    Serious adverse events
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 56 (14.29%)
    11 / 55 (20.00%)
    12 / 47 (25.53%)
         number of deaths (all causes)
    4
    6
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Hypotension
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Surgical and medical procedures
    Extubation
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Ulcer
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 47 (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
    Aspiration
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 47 (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
    Dyspnoea
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 47 (2.13%)
         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 congestion
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Respiratory distress
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 47 (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
    Respiratory failure
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Suture rupture
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 47 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Atrial fibrillation
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 47 (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
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Myocardial ischaemia
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Nervous system disorders
    Intensive care unit acquired weakness
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 47 (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
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 47 (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
    Gastrointestinal disorders
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 55 (5.45%)
    3 / 47 (6.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    Septic shock
         subjects affected / exposed
    2 / 56 (3.57%)
    1 / 55 (1.82%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 47 (2.13%)
         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 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 47 (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
    Tonsillitis
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Placebo + Oseltamivir MHAA4549A 3600 mg + Oseltamivir MHAA4549A 8400 mg + Oseltamivir
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 56 (50.00%)
    26 / 55 (47.27%)
    18 / 47 (38.30%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 56 (12.50%)
    1 / 55 (1.82%)
    4 / 47 (8.51%)
         occurrences all number
    9
    2
    4
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 56 (5.36%)
    4 / 55 (7.27%)
    2 / 47 (4.26%)
         occurrences all number
    3
    8
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 56 (3.57%)
    2 / 55 (3.64%)
    3 / 47 (6.38%)
         occurrences all number
    2
    2
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 56 (3.57%)
    3 / 55 (5.45%)
    2 / 47 (4.26%)
         occurrences all number
    2
    3
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 55 (7.27%)
    2 / 47 (4.26%)
         occurrences all number
    2
    5
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 56 (12.50%)
    3 / 55 (5.45%)
    0 / 47 (0.00%)
         occurrences all number
    7
    3
    0
    Nausea
         subjects affected / exposed
    4 / 56 (7.14%)
    4 / 55 (7.27%)
    1 / 47 (2.13%)
         occurrences all number
    4
    7
    1
    Constipation
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 55 (7.27%)
    2 / 47 (4.26%)
         occurrences all number
    3
    4
    2
    Vomiting
         subjects affected / exposed
    3 / 56 (5.36%)
    2 / 55 (3.64%)
    2 / 47 (4.26%)
         occurrences all number
    3
    4
    2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    4 / 56 (7.14%)
    3 / 55 (5.45%)
    1 / 47 (2.13%)
         occurrences all number
    4
    3
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 56 (5.36%)
    5 / 55 (9.09%)
    0 / 47 (0.00%)
         occurrences all number
    3
    6
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    4 / 56 (7.14%)
    2 / 55 (3.64%)
    4 / 47 (8.51%)
         occurrences all number
    5
    2
    4
    Hypophosphataemia
         subjects affected / exposed
    4 / 56 (7.14%)
    2 / 55 (3.64%)
    2 / 47 (4.26%)
         occurrences all number
    4
    3
    3
    Hyperglycaemia
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 55 (5.45%)
    2 / 47 (4.26%)
         occurrences all number
    1
    7
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 55 (1.82%)
    3 / 47 (6.38%)
         occurrences all number
    1
    1
    3
    Hypoglycaemia
         subjects affected / exposed
    1 / 56 (1.79%)
    3 / 55 (5.45%)
    1 / 47 (2.13%)
         occurrences all number
    1
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2014
    More frequent review of safety data was facilitated by employing an Internal Monitoring Committee (IMC) in combination with a Scientific Oversight Committee (SOC) rather than a single Independent Data Monitoring Committee (iDMC). Allowing the inclusion of subjects diagnosed with influenza A as determined by a Sponsor-supplied rapid influenza test and/or local molecular test (PCR) allowed enrollment flexibility. Subjects on low-flow oxygen were to receive a daily trial off oxygen in the morning. Subjects to be fitted with pulse oximeter,and their SpO2 had to be checked once while on oxygen and then again3-5 minutes after turning off oxygen supplementation. Updated background clinical safety and efficacy data were added to provide investigators with the most current information concerning MHAA4549A.
    20 Mar 2015
    Added a high-dose arm (i.e., 8400 mg MHAA4545A). The addition of the 8400-mg treatment necessitated an adjustment in the infusion rate to 120 minutes for MHAA4549A and placebo. In addition, to mitigate any concerns with safety monitoring, the study design was expanded to include an initial safety assessment by the Internal Monitoring Committee and the Scientific Oversight Committee of a sentinel safety cohort consisting of the first 30 subjects enrolled or those subjects enrolled during the first influenza season, whichever occurs first. The time to normalization end point was adjusted operationally based on investigator feedback to allow greater flexibility to be in line with local standard course of clinical care. The sample size was adjusted to approximately 330 subjects. The MHAA4549A dosing rationale was updated to support the 8400-mg dose. The background clinical safety and efficacy summaries were updated with the most current data concerning MHAA4549A.
    16 May 2016
    Added an additional secondary endpoint to compare the clinical status of subjects using an ordinal outcome with 6 clinical statuses. Revised initial oseltamivir dosing from 8 hours to 12 hours after completion of study drug administration. Clarification to inclusion criteria of “any supplemental O2 to maintain oxygen saturation >92%”. Clarification that subjects with a history of chronic lung disease with a documented SpO2 <95% off oxygen were excluded. Clarification of daily trial off oxygen.

    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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