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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, phase 2a study in healthy volunteers to evaluate the efficacy and safety of MHAA4549A in an Influenza challenge model

    Summary
    EudraCT number
    		 2013-001983-52
    Trial protocol
    		 GB  
    Global end of trial date
    19 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Mar 2016
    First version publication date
    04 Mar 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GV28985
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01980966
    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
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, 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
    18 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the reduction in the area under the curve (AUC) of virus load from the nasopharyngeal mucosa in the MHAA4549A treatment group compared to placebo.
    Protection of trial subjects
    This study was conducted according to Food and Drug Administration (FDA) regulations, the International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), the European Union (EU) Good Clinical Practice Directive (2005/28/EC), and any applicable local, state, and federal laws, as well as other applicable country laws. Participants were followed-up from the time they consented to participate in the study until the end of study. The safety of participants was ensured by monitoring of adverse events throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Oct 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    European Union: 101
    Worldwide total number of subjects
    101
    EEA total number of subjects
    0
    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)
    101
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 1 center in Europe between 14 October 2013 and 19 June 2014.

    Pre-assignment
    Screening details
    		 One hundred participants were planned, 101 participants were randomized and received the challenge virus at Retroscreen, and 100 participants received at least one dose of MHAA4549A.

    Period 1
    Period 1 title
    Overall trial (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
    Arm description
    		 Participants in Cohort 1-5 received matching placebo of MHAA4549A as a single intravenous infusion on Day 1. In addition, participants in Cohort 5 received matching placebo of Tamiflu as an oral capsule from Day 1 to Day 5.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Tamiflu-matching placebo oral / MHAA4549A-matching placebo IV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Solution for infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Participants in Cohort 1-5 received matching placebo of MHAA4549A as a single intravenous infusion on Day 1. In addition, participants in Cohort 5 received twice-daily doses of matching placebo of Tamiflu as an oral capsule from Day 1 to Day 5.

    Arm title
    		 MHAA4549A 400mg
    Arm description
    		 Participants in Cohort 4 and Cohort 5 received MHAA4549A 400 mg as a single intravenous infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MHAA4549A 400 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants in Cohort 4 and Cohort 5 received MHAA4549A 400 mg as a single intravenous infusion on Day 1, 24-36 hours after viral inoculation.

    Arm title
    		 MHAA4549A 1200mg
    Arm description
    		 Participants in Cohort 1 and Cohort 2 received MHAA4549A 1200 mg as a single intravenous infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MHAA4549A 1200 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants in Cohort 1 and Cohort 2 received MHAA4549A 1200 mg as a single intravenous infusion on Day 1, 24-36 hours after viral inoculation.

    Arm title
    		 MHAA4549A 3600mg
    Arm description
    		 Participants in Cohort 3 and Cohort 4 received MHAA4549A 3600 mg as a single intravenous infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MHAA4549A 3600 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants in Cohort 3 and Cohort 4 received MHAA4549A 3600 mg as a single intravenous infusion on Day 1, 24-36 hours after viral inoculation.

    Arm title
    		 Tamiflu
    Arm description
    		 Participants in Cohort 5 received twice-daily doses of 75 mg Tamiflu as an oral capsule from Day 1 to Day 5. Also, participants in all the cohorts received twice-daily doses of Tamiflu from Day 7 to Day 11 to minimize risk of further transmitting the challenge virus.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tamiflu 75 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants in Cohort 5 received twice-daily doses of 75 mg Tamiflu as an oral capsule from Day 1 to Day 5. Also, participants in all the cohorts received twice-daily doses of Tamiflu from Day 7 to Day 11 to minimize risk of further transmitting the challenge virus.

    Number of subjects in period 1
    		Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Started
    32
    20
    20
    21
    8
    Completed
    31
    20
    20
    20
    8
    Not completed
    1
    0
    0
    1
    0
         Physician decision
    1
    -
    -
    -
    -
         AE observed after the challenge virus inoculation
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants in Cohort 1-5 received matching placebo of MHAA4549A as a single intravenous infusion on Day 1. In addition, participants in Cohort 5 received matching placebo of Tamiflu as an oral capsule from Day 1 to Day 5.

    Reporting group title
    MHAA4549A 400mg
    Reporting group description
    		 Participants in Cohort 4 and Cohort 5 received MHAA4549A 400 mg as a single intravenous infusion on Day 1.

    Reporting group title
    MHAA4549A 1200mg
    Reporting group description
    		 Participants in Cohort 1 and Cohort 2 received MHAA4549A 1200 mg as a single intravenous infusion on Day 1.

    Reporting group title
    MHAA4549A 3600mg
    Reporting group description
    		 Participants in Cohort 3 and Cohort 4 received MHAA4549A 3600 mg as a single intravenous infusion on Day 1.

    Reporting group title
    Tamiflu
    Reporting group description
    		 Participants in Cohort 5 received twice-daily doses of 75 mg Tamiflu as an oral capsule from Day 1 to Day 5. Also, participants in all the cohorts received twice-daily doses of Tamiflu from Day 7 to Day 11 to minimize risk of further transmitting the challenge virus.

    Reporting group values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu Total
    Number of subjects
    		 32 20 20 21 8 101
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 29.1 ± 6.2 27.6 ± 5.1 31.3 ± 8.1 28.7 ± 7.7 27 ± 7.7 -
    Gender categorical
    Units: Subjects
        Female
    		 11 10 6 10 2 39
        Male
    		 21 10 14 11 6 62

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants in Cohort 1-5 received matching placebo of MHAA4549A as a single intravenous infusion on Day 1. In addition, participants in Cohort 5 received matching placebo of Tamiflu as an oral capsule from Day 1 to Day 5.

    Reporting group title
    MHAA4549A 400mg
    Reporting group description
    		 Participants in Cohort 4 and Cohort 5 received MHAA4549A 400 mg as a single intravenous infusion on Day 1.

    Reporting group title
    MHAA4549A 1200mg
    Reporting group description
    		 Participants in Cohort 1 and Cohort 2 received MHAA4549A 1200 mg as a single intravenous infusion on Day 1.

    Reporting group title
    MHAA4549A 3600mg
    Reporting group description
    		 Participants in Cohort 3 and Cohort 4 received MHAA4549A 3600 mg as a single intravenous infusion on Day 1.

    Reporting group title
    Tamiflu
    Reporting group description
    		 Participants in Cohort 5 received twice-daily doses of 75 mg Tamiflu as an oral capsule from Day 1 to Day 5. Also, participants in all the cohorts received twice-daily doses of Tamiflu from Day 7 to Day 11 to minimize risk of further transmitting the challenge virus.

    Subject analysis set title
    Intent-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intent-to-treat (ITT) population, included all participants who were randomized and inoculated with the influenza virus, with participants allocated to the treatment arm associated with the regimen to which they were randomized.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population included all participants who were randomized, inoculated with influenza virus, and received at least one dose of study treatment. Participants were allocated to the treatment arm associated with the regimen actually received.

    Subject analysis set title
    Pharmacokinetic population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic (PK) population included all participants who received MHAA4549A or Tamiflu, or both.

    Subject analysis set title
    Intent-to-treat infected population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Intent-to-treat infected (ITTI) population included participants who were inoculated with influenza virus and had laboratory confirmed influenza infection.

    Primary: Median area under the curve of nasopharyngeal viral load by quantitative polymerase chain reaction

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    End point title
    		 Median area under the curve of nasopharyngeal viral load by quantitative polymerase chain reaction
    End point description
    Influenza virus load in the nasopharyngeal samples was determined by quantitative polymerase chain reaction (qPCR assay). The area under the curve (AUC) was calculated by applying the trapezoid rule to the qPCR viral load measurements obtained three times per day for each participant from challenge virus inoculation until the morning of the day of discharge (Day 8). The trapezoidal rule is a numerical method that approximates the value of a definite integral. The ITTI population was the primary analysis population used for the efficacy analyses.
    End point type
    Primary
    End point timeframe
    From the first assessment post dosing to the day of discharge (Day 8)
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    21
    11
    13
    14
    2
    Units: log10 viral copies per milliliter × hour
        median (full range (min-max))
    458.05 (0 to 834.17)
    247.23 (0 to 543.68)
    444.43 (0 to 694.16)
    11.3 (0 to 603.31)
    57.4 (0 to 114.8)
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0455
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -171.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -354.88
         upper limit
    		 -1.75
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 1200mg
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.902
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    15.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -128.92
         upper limit
    		 179.54
    Statistical analysis title
    		 Placebo vs 3600 mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0051
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -323.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -463.75
         upper limit
    		 -116.75
    Statistical analysis title
    		 Placebo vs Tamiflu
    Comparison groups
    Placebo v Tamiflu
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0558
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -374.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -719.38
         upper limit
    		 0

    Secondary: Median area under the curve of nasopharyngeal viral load as measured by cell culture (tissue culture infective dose 50% assay)

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    End point title
    		 Median area under the curve of nasopharyngeal viral load as measured by cell culture (tissue culture infective dose 50% assay)
    End point description
    The AUC of nasopharyngeal viral load, as measured by tissue culture infective dose 50% (TCID50) cell culture assay was calculated by applying the trapezoid rule to the viral load measurements obtained three times per day for participant from challenge virus inoculation until the morning of the day of discharge (Day 8). The ITTI population was the primary analysis population used for the efficacy analyses.
    End point type
    Secondary
    End point timeframe
    From the first assessment post dosing to discharge (Day 8)
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    21
    11
    13
    14
    2
    Units: log10 TCID50 × hour
        median (full range (min-max))
    186.78 (0 to 443.56)
    70.25 (0 to 245.94)
    224.46 (0 to 344.28)
    0 (0 to 327.04)
    28.84 (0 to 57.68)
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0087
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -127.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -203.51
         upper limit
    		 -40.58
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 1200mg
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8742
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -4.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -93.52
         upper limit
    		 75.33
    Statistical analysis title
    		 Placebo vs 3600mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0023
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -149.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -229.11
         upper limit
    		 -68.51
    Statistical analysis title
    		 Placebo vs Tamiflu
    Comparison groups
    Placebo v Tamiflu
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0558
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -170.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -385.88
         upper limit
    		 0

    Secondary: Median peak viral load post dosing to the last day of quarantine (quantitative polymerase chain reaction)

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    End point title
    		 Median peak viral load post dosing to the last day of quarantine (quantitative polymerase chain reaction)
    End point description
    The median peak viral load post dosing to the last day of quarantine was measured by qPCR in ITTI population.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 8
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    21
    11
    13
    14
    2
    Units: log10 viral copies per milliliter
        median (full range (min-max))
    6.38 (0 to 7.76)
    5.08 (0 to 6.39)
    6.36 (0 to 8.01)
    1.45 (0 to 6.89)
    2.3 (0 to 4.6)
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0187
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.37
         upper limit
    		 -0.35
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 1200mg
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 1.12
    Statistical analysis title
    		 Placebo vs 3600mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0024
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -3.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.25
         upper limit
    		 -1.23
    Statistical analysis title
    		 Placebo vs Tamiflu
    Comparison groups
    Placebo v Tamiflu
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0947
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -3.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.37
         upper limit
    		 0.19

    Secondary: Median peak viral load post dosing to the last day of quarantine (cell culture)

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    End point title
    		 Median peak viral load post dosing to the last day of quarantine (cell culture)
    End point description
    The median peak viral load post dosing to the last day of quarantine was measured by cell culture in ITTI population.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 8
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    21
    11
    13
    14
    2
    Units: log10 TCID50
        median (full range (min-max))
    4.25 (0 to 6)
    1.75 (0 to 4.5)
    4 (0 to 5.75)
    0 (0 to 4.75)
    1.25 (0 to 2.5)
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.022
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.75
         upper limit
    		 -0.25
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    MHAA4549A 1200mg v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9578
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.75
         upper limit
    		 1.25
    Statistical analysis title
    		 Placebo vs 3600mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0023
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -3.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.25
         upper limit
    		 -1
    Statistical analysis title
    		 Placebo vs Tamiflu
    Comparison groups
    Placebo v Tamiflu
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.115
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 1.5

    Secondary: Median duration of viral shedding from first positive detection after initiation of dosing until the assessment after the last positive (quantitative polymerase chain reaction)

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    End point title
    		 Median duration of viral shedding from first positive detection after initiation of dosing until the assessment after the last positive (quantitative polymerase chain reaction)
    End point description
    The median duration of viral shedding for participants who had measurable virus by qPCR was computed using Kaplan-Meier methodology in ITTI population. Only participants with detectable event were analyzed.
    End point type
    Secondary
    End point timeframe
    From first positive detection after initiation of dosing until the assessment after the last positive
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    15
    8
    11
    7
    1
    Units: hours
        median (full range (min-max))
    113.7 (0 to 154.1)
    103.8 (0 to 144.1)
    119.9 (0 to 154.2)
    71.7 (0 to 144)
    33.1 (0 to 33.1)
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 5.15
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    MHAA4549A 1200mg v Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 2.78
    Statistical analysis title
    		 Placebo vs 3600mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    3.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.26
         upper limit
    		 8.09
    Statistical analysis title
    		 Placebo vs Tamiflu
    Comparison groups
    Placebo v Tamiflu
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    14.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.54
         upper limit
    		 141.31

    Secondary: Median duration of viral shedding from first positive detection after initiation of dosing until the assessment after the last positive (cell culture)

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    End point title
    		 Median duration of viral shedding from first positive detection after initiation of dosing until the assessment after the last positive (cell culture)
    End point description
    The median duration of viral shedding for participants who had measurable virus by cell culture was computed using Kaplan-Meier methodology in ITTI population. Only participants with detectable event were analyzed.
    End point type
    Secondary
    End point timeframe
    From first positive detection after initiation of dosing until the assessment after the last positive
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    20
    7
    11
    6
    1
    Units: hours
        median (full range (min-max))
    80.5 (0 to 128.8)
    48.2 (0 to 120)
    81.2 (0 to 128.8)
    63.9 (0 to 96)
    33.1 (0 to 33.1)
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 4.85
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 1200mg
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.94
    Statistical analysis title
    		 Placebo vs 3600mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 5.27
    Statistical analysis title
    		 Placebo vs Tamiflu
    Comparison groups
    Placebo v Tamiflu
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    13.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.43
         upper limit
    		 122.47

    Secondary: Median duration of viral shedding from peak viral load (post dosing) until the assessment after the last positive (quantitative polymerase chain reaction)

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    End point title
    		 Median duration of viral shedding from peak viral load (post dosing) until the assessment after the last positive (quantitative polymerase chain reaction)
    End point description
    The median duration of viral shedding by qPCR from the peak viral load was estimated using Kaplan-Meier methodology in the ITTI population. Only participants with detectable event were analyzed.
    End point type
    Secondary
    End point timeframe
    From peak viral load (post dosing) until the assessment after the last positive
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    15
    8
    11
    7
    1
    Units: hours
        median (full range (min-max))
    6.6 (0 to 7.8)
    5.8 (0 to 6.4)
    6.4 (0 to 8)
    4.8 (0 to 6.9)
    4.6 (0 to 4.6)
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    3.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.51
         upper limit
    		 9.8
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 1200mg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 2.3
    Statistical analysis title
    		 Placebo vs 3600mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    3.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 7.76
    Statistical analysis title
    		 Placebo vs Tamiflu
    Comparison groups
    Placebo v Tamiflu
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    8.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 72.12

    Secondary: Median duration of viral shedding from peak viral load (post dosing) until the assessment after the last positive (cell culture)

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    End point title
    		 Median duration of viral shedding from peak viral load (post dosing) until the assessment after the last positive (cell culture)
    End point description
    The median duration of viral shedding by cell culture from the peak viral load was estimated using Kaplan-Meier methodology. Only participants with detectable event were analyzed.
    End point type
    Secondary
    End point timeframe
    From peak viral load (post dosing) until the assessment after the last positive
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    20
    7
    11
    6
    1
    Units: hours
        median (full range (min-max))
    4.3 (0.8 to 6)
    3.5 (0.8 to 4.5)
    4.3 (0.8 to 5.8)
    4 (0.8 to 4.8)
    2.5 (0.8 to 2.5)
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 6.84
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 1200mg
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.93
    Statistical analysis title
    		 Placebo vs 3600mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 5.79
    Statistical analysis title
    		 Placebo vs Tamiflu
    Comparison groups
    Placebo v Tamiflu
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    4.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 35.98

    Secondary: Median duration of Grade 2 or worse symptoms from first assessment after dosing until the assessment after the last positive

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    End point title
    		 Median duration of Grade 2 or worse symptoms from first assessment after dosing until the assessment after the last positive
    End point description
    The median duration of Grade 2 or higher symptoms was estimated using Kaplan-Meier methodology in ITTI population. Only participants with detectable event were analyzed.
    End point type
    Secondary
    End point timeframe
    From first assessment after dosing until the assessment after the last positive
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    11
    3
    4
    6
    0 [1]
    Units: hours
        median (full range (min-max))
    72 (0 to 88)
    48 (0 to 72)
    56 (0 to 96)
    68 (0 to 96)
    ( to )
    Notes
    [1] - No participants had a detectable event which could be analysed in Tamiflu arm
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 7.4
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 1200mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 3.62
    Statistical analysis title
    		 Placebo vs 3600mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 2.47

    Secondary: Median peak composite symptoms from first assessment after dosing to the last day of quarantine

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    End point title
    		 Median peak composite symptoms from first assessment after dosing to the last day of quarantine
    End point description
    The composite symptom score at each time point for a participant was derived by summing the 10 individual symptom scores for that participant at that time point. The individual symptoms were as follows: runny nose, stuffy nose, sneezing, sore throat, earache, malaise (tiredness), cough, shortness of breath, headache, and muscle/joint ache or stiffness. The scores ranged from 0 to 3 and were scored as follows: 0 = absence of symptom; 1 = symptom just noticeable; 2 = symptom bothersome but does not prevent participation in activities, and 3 = symptom bothersome and interferes with activities.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 8
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    21
    11
    13
    14
    2
    Units: Score
        median (full range (min-max))
    4 (0 to 16)
    3 (0 to 11)
    4 (2 to 14)
    2 (0 to 14)
    0.5 (0 to 1)
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2375
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 1
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 1200mg
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.79
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 2
    Statistical analysis title
    		 Placebo vs 3600mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2174
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 1
    Statistical analysis title
    		 Placebo vs Tamiflu
    Comparison groups
    Placebo v Tamiflu
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0664
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 0

    Secondary: Median area under the curve of composite symptoms from the first evaluation after dosing to the last day of quarantine

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    End point title
    		 Median area under the curve of composite symptoms from the first evaluation after dosing to the last day of quarantine
    End point description
    The median AUC for symptom scores over time was calculated from the time of initiating drug administration in the ITTI population.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 8
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    21
    11
    13
    14
    2
    Units: score x hour
        median (full range (min-max))
    207.68 (0 to 783.08)
    87.51 (0 to 458.28)
    192.1 (55.73 to 782.53)
    37.7 (0 to 1214.31)
    8.14 (0 to 16.28)
    Statistical analysis title
    		 Placebo vs 400mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 400mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -91.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -254.22
         upper limit
    		 44.48
    Statistical analysis title
    		 Placebo vs 1200mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 1200mg
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8743
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -14.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -160.58
         upper limit
    		 116.82
    Statistical analysis title
    		 Placebo vs 3600mg MHAA4549A
    Comparison groups
    Placebo v MHAA4549A 3600mg
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2887
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -106.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -238.03
         upper limit
    		 40.79
    Statistical analysis title
    		 Placebo vs Tamiflu
    Comparison groups
    Placebo v Tamiflu
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0855
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -203.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -568.87
         upper limit
    		 8.27

    Secondary: Incidence of treatment emergent adverse events

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    End point title
    		 Incidence of treatment emergent adverse events
    End point description
    An adverse event is any unfavourable and unintended sign, symptom, or disease temporally associated with the use of an IMP or other protocol-imposed intervention, regardless of attribution. All treatment emergent adverse events (TEAEs) (i.e. AEs that occurred during or after dosing) were summarized for each treatment group in safety population.
    End point type
    Secondary
    End point timeframe
    From the time of virus inoculation (one day prior to receiving study drug) until the participant completes (approximately up to 270 days) or discontinues the study
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    32
    20
    20
    20
    8
    Units: Number
    28
    18
    16
    17
    7
    No statistical analyses for this end point

    Secondary: Incidence of Anti−Therapeutic Antibodies to MHAA4549A

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    End point title
    		 Incidence of Anti−Therapeutic Antibodies to MHAA4549A
    End point description
    Serum samples for Anti−Therapeutic Antibodies (ATA) analysis were obtained at Baseline, before dosing, and at multiple time points.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline), Day 29, Day 85 and Day 120
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    31 [2]
    20
    20
    20
    8
    Units: Number
        Positive for ATA
    1
    0
    0
    0
    0
        Negative for ATA
    30
    20
    20
    20
    8
    Notes
    [2] - Only those participants available at the specified time points were analyzed
    No statistical analyses for this end point

    Secondary: Absolute change from Baseline in forced expiratory volume in one second

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    End point title
    		 Absolute change from Baseline in forced expiratory volume in one second
    End point description
    Spirometry was conducted to evaluate lung function. Forced expiratory volume in one second (FEV1) is the amount of air exhaled at 1 second. Change from Baseline in FEV1 on last day of quarantine (Day 8) in safety population was reported. Baseline value was defined as the last value prior to inoculation with challenge virus.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    32
    20
    20
    20
    8
    Units: Litres
        arithmetic mean (standard deviation)
    0 ± 0.16
    0.08 ± 0.24
    -0.1 ± 0.2
    -0.12 ± 0.39
    0.05 ± 0.23
    No statistical analyses for this end point

    Secondary: Absolute change from Baseline in forced vital capacity

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    End point title
    		 Absolute change from Baseline in forced vital capacity
    End point description
    Spirometry was conducted to evaluate lung function. Forced vital capacity (FVC) is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. Change from Baseline in FVC on last day of quarantine (Day 8) in safety population was reported. Baseline value was defined as the last value prior to inoculation with challenge virus.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    32
    20
    20
    20
    8
    Units: Litres
        arithmetic mean (standard deviation)
    0.01 ± 0.33
    0.1 ± 0.34
    -0.21 ± 0.42
    -0.19 ± 0.49
    0.06 ± 0.37
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in forced expiratory volume in one second/forced vital capacity

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    End point title
    		 Absolute change from baseline in forced expiratory volume in one second/forced vital capacity
    End point description
    Spirometry was conducted to evaluate lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second and FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. Change from Baseline in FEV1/FVC on last day of quarantine (Day 8) in safety population was reported. Baseline value was defined as the last value prior to inoculation with challenge virus.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    32
    20
    20
    20
    8
    Units: Percentage
        arithmetic mean (standard deviation)
    -0.03 ± 4.85
    -0.05 ± 3.75
    1.51 ± 5.93
    1 ± 4.58
    0 ± 3.74
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in maximum mid-expiratory flow

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    End point title
    		 Absolute change from baseline in maximum mid-expiratory flow
    End point description
    Spirometry was conducted to evaluate lung function. The maximum midexpiratory flow (MMEF) is the average expiratory flow over the middle half of the FVC. FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8
    End point values
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Number of subjects analysed
    32
    20
    20
    20
    8
    Units: Litres/second
        arithmetic mean (standard deviation)
    0 ± 0.52
    0.07 ± 0.49
    0.03 ± 0.69
    -0.14 ± 0.48
    0.04 ± 0.45
    No statistical analyses for this end point

    Secondary: Area under the curve of MHAA4549A in serum

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    End point title
    		 Area under the curve of MHAA4549A in serum [3]
    End point description
    Blood samples for PK analysis of MHA4459A levels were collected at pre-dose and at 30 minutes and 4 hours post end of infusion on Day 1, 24 hours post end of infusion on Day 2, 72 hours post end of infusion on Day 4, and on Day 8, Day 15, Day 29, Day 57, Day 85 and Day 120. AUC is defined as the area under the MHA4459A concentration-time curve as a measure of drug exposure. AUC (0-inf) is defined as the area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. AUC (0-last) is defined as area under the concentration-time curve from time zero (predose) to the last time of measurable concentration.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose; Study Day 1 is equivalent to PK Day 0) to Day 120 (Study Day 120 is equivalent to PK Day 119)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is applicable only for MHAA4549A arms.
    End point values
    		 MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg
    Number of subjects analysed
    20
    20
    20
    Units: day x microgram/millilitre
    geometric mean (geometric coefficient of variation)
        AUC(0-last)
    1700 ± 21.2
    4940 ± 20.2
    17200 ± 19.5
        AUC(0-infinity)
    1760 ± 22.3
    5130 ± 23.3
    17700 ± 20.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of administration of the study drug until the completion of the study (approximately up to 270 days) or until the participant was discontinued from the study
    Adverse event reporting additional description
    SAEs and non-serious AEs were collected for participants in the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants in Cohort 1-5 received matching placebo of MHAA4549A as a single intravenous infusion on Day 1. In addition, participants in Cohort 5 received matching placebo of Tamiflu as an oral capsule from Day 1 to Day 5.

    Reporting group title
    MHAA4549A 400mg
    Reporting group description
    		 Participants in Cohort 4 and Cohort 5 received MHAA4549A 400 mg as a single intravenous infusion on Day 1.

    Reporting group title
    MHAA4549A 1200mg
    Reporting group description
    		 Participants in Cohort 1 and Cohort 2 received MHAA4549A 1200 mg as a single intravenous infusion on Day 1.

    Reporting group title
    MHAA4549A 3600mg
    Reporting group description
    		 Participants in Cohort 3 and Cohort 4 received MHAA4549A 3600 mg as a single intravenous infusion on Day 1.

    Reporting group title
    Tamiflu
    Reporting group description
    		 Participants in Cohort 5 received twice-daily doses of 75 mg Tamiflu as an oral capsule from Day 1 to Day 5. Also, participants in all the cohorts received twice-daily doses of Tamiflu from Day 7 to Day 11 to minimize risk of further transmitting the challenge virus.

    Serious adverse events
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Postoperative wound infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo MHAA4549A 400mg MHAA4549A 1200mg MHAA4549A 3600mg Tamiflu
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 32 (87.50%)
    18 / 20 (90.00%)
    16 / 20 (80.00%)
    17 / 20 (85.00%)
    7 / 8 (87.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Chest discomfort
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    3 / 20 (15.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    1
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 20 (0.00%)
    2 / 20 (10.00%)
    0 / 20 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    2
    0
    2
    0
    3
    Cough
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    1
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 32 (15.63%)
    5 / 20 (25.00%)
    4 / 20 (20.00%)
    4 / 20 (20.00%)
    2 / 8 (25.00%)
         occurrences all number
    5
    5
    4
    4
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 20 (25.00%)
    3 / 20 (15.00%)
    3 / 20 (15.00%)
    2 / 8 (25.00%)
         occurrences all number
    3
    5
    3
    3
    3
    Amylase increased
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Procedural haemorrhage
         subjects affected / exposed
    8 / 32 (25.00%)
    6 / 20 (30.00%)
    3 / 20 (15.00%)
    6 / 20 (30.00%)
    3 / 8 (37.50%)
         occurrences all number
    8
    6
    4
    7
    3
    Contusion
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 32 (15.63%)
    0 / 20 (0.00%)
    3 / 20 (15.00%)
    2 / 20 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    5
    0
    3
    2
    1
    Presyncope
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Sinus headache
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Ear pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tinnitus
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    3 / 20 (15.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    0
    4
    0
    Diarrhoea
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    0
    2
    0
    Toothache
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    Abdominal pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Vomiting
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Rash erythematous
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    1
    Myalgia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Back pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 32 (18.75%)
    3 / 20 (15.00%)
    2 / 20 (10.00%)
    3 / 20 (15.00%)
    0 / 8 (0.00%)
         occurrences all number
    7
    3
    2
    5
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 20 (15.00%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    3
    1
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Lice infestation
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Postoperative wound infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Tracheitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vaginitis bacterial
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2013
    Substantial amendment was done to change the Principal Investigator.
    28 Jan 2014
    Substantial amendment was done to change the Principal Investigator. In addition, this amendment corrected the instructions for the allocation of a replacement randomization number.

    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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