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    Clinical Trial Results:
    A Double-blind, Randomized, Stratified Multi-center Trial Evaluating Conventional and Double Dose Oseltamivir in the Treatment of Immunocompromised Patients With Influenza

    Summary
    EudraCT number
    		 2006-002468-24
    Trial protocol
    		 GB   ES   FR   BE   HU   LT   CZ   EE   IT   GR   BG   LV   DE  
    Global end of trial date
    02 May 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Feb 2018
    First version publication date
    16 Nov 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    NV20234
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00545532
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000365-PIP08-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This 2-arm study will investigate the safety and tolerability of oseltamivir for the treatment of influenza in immunocompromised subjects and characterize the effects of oseltamivir in immunocompromised subjects on the development of resistant influenza virus.
    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
    04 Feb 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Lithuania: 24
    Country: Number of subjects enrolled
    Latvia: 15
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Ukraine: 2
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    South Africa: 40
    Country: Number of subjects enrolled
    Argentina: 10
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    Guatemala: 2
    Country: Number of subjects enrolled
    Belgium: 30
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Spain: 3
    Worldwide total number of subjects
    215
    EEA total number of subjects
    91
    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)
    9
    Adolescents (12-17 years)
    7
    Adults (18-64 years)
    180
    From 65 to 84 years
    18
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Immunocompromised subjects with primary or secondary immunodeficiency and symptoms suggestive of influenza-like illness were recruited for this study.

    Pre-assignment
    Screening details
    		 Rapid diagnostic test, polymerase chain reaction (PCR), or viral culture had to be positive for influenza in the 96 hours prior to first dose. Subject disposition and baseline characteristics are provided for the safety population.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental: Conventional dose
    Arm description
    		 Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 30 to 75 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 75 mg twice daily for adults/adolescents greater than or equal to (>/=13 years old) or placebo-matched to oseltamivir twice daily over 10 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    oseltamivir
    Investigational medicinal product code
    Other name
    Tamiflu
    Pharmaceutical forms
    Capsule, Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Dose ranging between 30 to 75 milligrams (mg) orally administered as syrup or capsules (depending on participants age and weight) twice daily for 10 days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to oseltamivir administered orally twice daily for 10 days.

    Arm title
    		 Experimental: Double dose
    Arm description
    		 Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 60 to 150 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 150 mg twice daily for adults/adolescents (>/=13 years old) or placebo matched to oseltamivir twice daily over 10 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to oseltamivir administered orally twice daily for 10 days.

    Investigational medicinal product name
    oseltamivir
    Investigational medicinal product code
    Other name
    Tamiflu
    Pharmaceutical forms
    Capsule, Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Dose ranging between 60 to 150 mg orally administered as syrup or capsules (depending on participants age and weight) twice daily for 10 days.

    Number of subjects in period 1
    		Experimental: Conventional dose Experimental: Double dose
    Started
    105
    110
    Completed
    99
    100
    Not completed
    6
    10
         Death
    -
    1
         Withdrawal by Subject
    1
    3
         Lost to follow-up
    5
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental: Conventional dose
    Reporting group description
    		 Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 30 to 75 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 75 mg twice daily for adults/adolescents greater than or equal to (>/=13 years old) or placebo-matched to oseltamivir twice daily over 10 days.

    Reporting group title
    Experimental: Double dose
    Reporting group description
    		 Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 60 to 150 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 150 mg twice daily for adults/adolescents (>/=13 years old) or placebo matched to oseltamivir twice daily over 10 days.

    Reporting group values
    		 Experimental: Conventional dose Experimental: Double dose Total
    Number of subjects
    		 105 110 215
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.0 ( 15.5 ) 43.9 ( 16.5 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 57 62 119
        Male
    		 48 48 96

    End points

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    End points reporting groups
    Reporting group title
    Experimental: Conventional dose
    Reporting group description
    		 Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 30 to 75 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 75 mg twice daily for adults/adolescents greater than or equal to (>/=13 years old) or placebo-matched to oseltamivir twice daily over 10 days.

    Reporting group title
    Experimental: Double dose
    Reporting group description
    		 Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 60 to 150 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 150 mg twice daily for adults/adolescents (>/=13 years old) or placebo matched to oseltamivir twice daily over 10 days.

    Subject analysis set title
    Adults With Pharmacokinetic Evaluation
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set comprises subjects >/= 18 years from both arms in the study who underwent pharmacokinetic evaluation.

    Subject analysis set title
    Adolescents and Children With Pharmacokinetic Evaluation
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set comprises adolescents and children < 18 years from both arms in the study who underwent pharmacokinetic evaluation.

    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 unfavorable 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. The safety population included all subjects who received at least one dose of study drug and had a safety assessment performed post randomisation.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 40
    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: No statistical hypothesis could be defined for this endpoint as the study has no control group.
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    105
    110
    Units: percentage of subjects
    number (not applicable)
        On Treatment
    40.0
    47.3
        Off Treatment
    25.7
    29.1
    No statistical analyses for this end point

    Primary: Percentage of Subjects Who Developed Viral Resistance to Oseltamivir

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    End point title
    		 Percentage of Subjects Who Developed Viral Resistance to Oseltamivir [2]
    End point description
    Resistance was defined as the presence of oseltamivir resistance mutations in viruses isolated from nasopharyngeal swab samples, identified by sequencing of the neuraminidase (NA) and hemagglutinin (HA) genes (genotypic resistance) and/or determination of the oseltamivir concentration at which the response is reduced by half (IC50) in an NA inhibition assay (phenotypic resistance). Modified Intent-to-Treat infected (mITTi) population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. Reported are post-baseline phenotypic and genotypic resistance in adults >/= 18 years and children and adolescents <18 years in the mITTi population. n indicates the number of subjects analysed in the respective study arms.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 40
    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: No statistical hypothesis could be defined for this endpoint as the study has no control group.
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    81
    86
    Units: percentage of subjects
    number (not applicable)
        Post-BL Phenotypic Resist, >/= 18 years (n=73, 78)
    8.2
    1.3
        Post-BL Genotypic Resist, >/= 18 years (n=73, 78)
    9.6
    2.6
        Post-BL Phenotypic Resist, < 18 years (n=8, 8)
    25.0
    0
        Post-BL Genotypic Resist, < 18 years (n=8,8)
    25.0
    12.5
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Tissue Rejection or Graft Versus Host Disease (GvHD)

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    End point title
    		 Percentage of Subjects With Tissue Rejection or Graft Versus Host Disease (GvHD) [3]
    End point description
    The percentage of transplant patients in the safety population who experienced tissue rejection and/or GvHD is reported. The safety population included all subjects who received at least one dose of study drug and had a safety assessment performed post randomisation.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 40
    Notes
    [3] - 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: No statistical hypothesis could be defined for this endpoint as the study has no control group.
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    105 [4]
    110 [5]
    Units: percentage of subjects
        number (not applicable)
    0
    0
    Notes
    [4] - Analyses will be released once data become available.
    [5] - Analyses will be released once data become available.
    No statistical analyses for this end point

    Secondary: Time to Resolution (TTR) of All Clinical Influenza Symptoms

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    End point title
    		 Time to Resolution (TTR) of All Clinical Influenza Symptoms
    End point description
    TTR of all clinical influenza symptoms was defined as the time from treatment initiation to the start of the 24-hour period in which all 7 influenza symptoms had scores </= 1 (mild) and remained </=1 for at least 21.5 hours. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. Reported are TTRs in adults and adolescents >/= 13 years and children <13 years in the mITTi population. n indicates the number of subjects analysed in the respective study arms. 9999=not estimable
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 40
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    82
    86
    Units: hours
    median (confidence interval 95%)
        Adults >/= 18 years (n=71, 75)
    103.3 (69.0 to 112.7)
    103.6 (57.1 to 140.0)
        Adults and adolescents >/= 13 years (n=75, 78)
    103.4 (75.4 to 122.7)
    107.2 (63.9 to 140.0)
        Children < 13 years (n=4, 5)
    32.1 (20.2 to 9999)
    115.9 (45.5 to 495.0)
    No statistical analyses for this end point

    Secondary: Total Symptom Score Area Under the Effect-Time Curve (AUE)

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    End point title
    		 Total Symptom Score Area Under the Effect-Time Curve (AUE)
    End point description
    The overall extent and severity of illness was quantified by the AUE of the total symptom scores over the duration of illness, i.e., from the start of treatment to the time symptoms first alleviated. Total symptom scores were calculated from the sum of seven individual symptom scores. The AUE of these average scores was then calculated for each subject using the trapezoidal rule (the trapezoidal rule calculates the area under any curve by adding up all trapezoids under such a curve). The area of each trapezoid is calculated as the average between consecutive measures. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. Reported are results for adults >/= 18 years in the mITTi population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 40
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    59
    67
    Units: score * hour
        median (full range (min-max))
    774.7 (60.8 to 11435.5)
    811.5 (63.0 to 8648.1)
    No statistical analyses for this end point

    Secondary: Time to Resolution of Fever

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    End point title
    		 Time to Resolution of Fever
    End point description
    Fever was defined as temperature >/= 37.8 degrees Celsius at any time point during the study. TTR of fever was determined in Adults >/= 18 years, Adults and adolescents >/= 13 years and Children < 13 years of the mITTi population. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. n indicates the number of subjects analysed in the respective study arms. 9999 = subject censored for analysis
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 40
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    38
    35
    Units: hours
    median (confidence interval 95%)
        >/= 18 years (n=35, 32)
    11.0 (0.0 to 16.2)
    0.5 (0.0 to 8.8)
        >/= 13 years (n=37, 33)
    11.0 (0.0 to 16.2)
    0.5 (0.0 to 8.8)
        < 13 years (n=1, 2)
    9999 (9999 to 9999)
    26.0 (0.0 to 51.9)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Viral Load Assessed by Culture

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    End point title
    		 Change from Baseline in Viral Load Assessed by Culture
    End point description
    Nasopharyngeal swab samples were cultured in Madin-Darby Canine Kidney cells. Culture supernatants were harvested after 2 weeks, or after a full-blown cytopathic effect was observed. Presence of infectious viruses in the cell culture supernatants (viral titer), expressed as log10 50% Tissue Culture Infectious Dose/millilitre (TCID50/mL), was determined by hemagglutination assay using turkey erythrocytes for H1 and B viruses or by detection of the virus nucleoprotein (NP) using ELISA for H3 viruses. A value of < 0.5 log10 TCID50/mL was interpreted as negative. Data are reported for adults >/= 18 years and adolescents and children < 18 years. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. n = number of subjects analysed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2/3, Day 6, Day 8, Day 11 end of treatment (EOT), follow-up (FU) Day 15 and FU Day 40.
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    81
    86
    Units: TCID50/mL
    median (full range (min-max))
        >/= 18 years, Baseline (BL) (n=70, 76)
    3.38 (0.5 to 6.0)
    3.75 (0.5 to 6.3)
        >/= 18 years, Change from BL on Day 2/3 (n=67, 73)
    -1.50 (-5.3 to 0.8)
    -1.50 (-5.0 to 1.50)
        >/= 18 years, Change from BL on Day 6 (n=65, 71)
    -2.50 (-5.5 to 0.0)
    -3.00 (-5.8 to 1.0)
        >/= 18 years, Change from BL on Day 8 (n=62, 62)
    -2.75 (-5.5 to 0.0)
    -3.25 (-5.8 to 0.0)
        >/= 18 years, Change from BL on Day 11 (n=64, 71)
    -2.88 (-5.5 to 0.0)
    -3.25 (-5.8 to 0.3)
        >/= 18 years, Change from BL on Day 15 (n=62, 65)
    -3.00 (-5.5 to 0.3)
    -3.25 (-5.8 to 0.0)
        >/= 18 years, Change from BL on Day 40 (n=64, 65)
    -3.00 (-5.5 to 0.0)
    -3.25 (-5.8 to 0.0)
        < 18 years, BL (n=8, 8)
    3.13 (0.8 to 6.0)
    4.00 (1.8 to 5.3)
        < 18 years, Change from BL on Day 2/3 (n=7, 8)
    -1.00 (-2.3 to 0.8)
    -2.00 (-3.3 to 0.0)
        < 18 years, Change from BL on Day 6 (n=7, 7)
    -2.00 (-3.3 to -0.3)
    -3.50 (-4.8 to -2.3)
        < 18 years, Change from BL on Day 8 (n=5, 7)
    -2.50 (-3.3 to -0.3)
    -3.50 (-4.8 to -1.3)
        < 18 years, Change from BL on Day 11 (n=7, 7)
    -2.50 (-5.3 to 0.0)
    -3.50 (-4.8 to -2.3)
        < 18 years, Change from BL on Day 15 (n=7, 7)
    -2.50 (-5.3 to 1.0)
    -3.50 (-4.8 to -2.3)
        < 18 years, Change from BL on Day 40 (n=7, 8)
    -2.50 (-5.3 to 0.3)
    -3.50 (-4.8 to -1.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Viral Shedding Assessed by Culture over Time

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    End point title
    		 Percentage of Subjects with Viral Shedding Assessed by Culture over Time
    End point description
    Viral shedding was determined through measurement of the viral titer after viral culture in Madin-Darby Canine Kidney cells by hemagglutination assay (for Flu A/H1N1 and Flu B) and NP-ELISA (for Flu A/H3N2) and expressed in log10 TCID50/mL. Reported is the percentage of subjects with viral shedding over time in adults >/= 18 years and adolescents and children < 18 years. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. n = number of subjects analysed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2/3, Day 6, Day 8, Day 11 end of treatment (EOT), follow-up (FU) Day 15 and FU Day 40.
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    81
    86
    Units: percentage of subjects
    number (not applicable)
        >/= 18 years, Baseline (n=70, 76)
    91.4
    84.2
        >/= 18 years, Day 2/3 (n=67, 73)
    67.2
    58.9
        >/= 18 years, Day 6 (n=65, 71)
    15.4
    18.3
        >/= 18 years, Day 8 (n=63, 62)
    3.2
    4.8
        >/= 18 years, Day 11 (n=65, 71)
    1.5
    4.2
        >/= 18 years, Day 15 (n=63, 65)
    7.9
    1.5
        >/= 18 years, Day 40 (n=65, 65)
    0.0
    0.0
        < 18 years, Baseline (n=8, 8)
    100.0
    100.0
        < 18 years, Day 2/3 (n=7, 8)
    71.4
    75.0
        < 18 years, Day 6 (n=7, 7)
    42.9
    0.0
        < 18 years, Day 8 (n=5, 7)
    0.0
    0.0
        < 18 years, Day 11 (n=7, 7)
    14.3
    0.0
        < 18 years, Day 15 (n=7, 7)
    28.6
    0.0
        < 18 years, Day 40 (n=7, 8)
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Time to Cessation of Viral Shedding by Cell Culture

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    End point title
    		 Time to Cessation of Viral Shedding by Cell Culture
    End point description
    Viral shedding was determined through measurement of the viral titer after viral culture in Madin-Darby Canine Kidney cells by hemagglutination assay (for Flu A/H1N1 and Flu B) and NP-ELISA (for Flu A/H3N2) and expressed in log10 TCID50/mL. Reported is the time to cessation of viral shedding over time in adults >/= 18 years and adolescents and children < 18 years. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. . n = number of subjects analysed.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 40
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    81
    86
    Units: hours
    median (confidence interval 95%)
        >/= 18 years (n=64, 64)
    105.0 (98.3 to 109.2)
    105.4 (83.0 to 107.7)
        < 18 years (n=8, 8)
    150.3 (34.2 to 891.3)
    94.9 (8.6 to 109.4)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Viral Load Assessed by Reverse Transcription Polymerase Chain Reaction (RT-PCR)

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    End point title
    		 Change from Baseline in Viral Load Assessed by Reverse Transcription Polymerase Chain Reaction (RT-PCR)
    End point description
    Nasopharyngeal swab samples were tested for influenza A and B RNA using semi-quantitative RT-PCR specific for influenza A and B matrix gene, respectively, after viral RNA isolation. Cycle threshold (Ct) value was determined for each sample. Conversion of Ct values into viral load, expressed as log10 virus particles/mL (vp/mL), was obtained using external standard curves ran in parallel in all RT-PCR experiments. A value of < 2.6 log10 vp/mL for Flu A strains and < 3.0 log10 vp/mL for Flu B strains was interpreted as a negative result. Data are reported for adults >/= 18 years and adolescents and children < 18 years. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. n = number of subjects analysed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2/3, Day 6, Day 8, Day 11 end of treatment (EOT), follow-up (FU) Day 15 and FU Day 40.
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    81
    86 [6]
    Units: log10 vp/mL
    median (full range (min-max))
        >/= 18 years, Baseline (BL) (n=72, 76)
    6.47 (2.7 to 8.8)
    6.52 (2.8 to 8.5)
        >/= 18 years, Change from BL on Day 2/3 (n=65, 67)
    -1.20 (-6.4 to 1.6)
    -1.35 (-4.6 to 1.1)
        >/= 18 years, Change from BL on Day 6 (n=41, 39)
    -2.36 (-8.0 to 0.1)
    -2.34 (-7.7 to 0.1)
        >/= 18 years, Change from BL on Day 8 (n=28, 20)
    -2.66 (-5.4 to -0.3)
    -2.62 (-7.8 to -0.3)
        >/= 18 years, Change from BL on Day 11 (n=19, 17)
    -3.51 (-7.3 to -2.2)
    -2.96 (-4.5 to 1.3)
        >/= 18 years, Change from BL on Day 15 (n=10, 6)
    -3.63 (-8.0 to -0.9)
    -2.60 (-3.4 to 0.0)
        >/= 18 years, Change from BL on Day 40 (n=3, 1)
    -4.80 (-5.4 to 0.8)
    -7.71 (-7.71 to -7.71)
        < 18 years, BL (n=8, 8)
    5.88 (2.8 to 7.7)
    5.96 (5.5 to 7.3)
        < 18 years, Change from BL on Day 2/3 (n=6, 8)
    -0.66 (-2.7 to 1.4)
    -0.71 (-5.6 to 0.4)
        < 18 years, Change from BL on Day 6 (n=6, 4)
    -1.97 (-2.7 to 0.3)
    -1.73 (-2.7 to -1.2)
        < 18 years, Change from BL on Day 8 (n=1, 3)
    1.56 (1.56 to 1.56)
    -2.26 (-2.9 to -1.5)
        < 18 years, Change from BL on Day 11 (n=2, 1)
    -0.89 (-3.2 to 1.4)
    -2.41 (-2.41 to -2.41)
        < 18 years, Change from BL on Day 15 (n=3, 0)
    1.26 (-2.9 to 1.9)
    9999 (9999 to 9999)
    Notes
    [6] - 9999 = 0 subjects analysed, no data
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Viral Shedding Assessed by RT-PCR over Time

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    End point title
    		 Percentage of Subjects with Viral Shedding Assessed by RT-PCR over Time
    End point description
    Viral shedding was determined by direct viral load measurement from nasopharyngeal swabs by RT-PCR assay and expressed in log10 vp/mL. Reported is the percentage of subjects with viral shedding over time in adults >/= 18 years and adolescents and children < 18 years. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. n = number of subjects analysed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2/3, Day 6, Day 8, Day 11 end of treatment (EOT), follow-up (FU) Day 15 and FU Day 40.
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    81
    86
    Units: percentage of subjects
    number (not applicable)
        >/= 18 years, Baseline (n=72, 78)
    100.0
    97.4
        >/= 18 years, Day 2/3 (n=69, 75)
    92.8
    88.0
        >/= 18 years, Day 6 (n=67, 73)
    56.7
    49.3
        >/= 18 years, Day 8 (n=65, 64)
    41.5
    23.4
        >/= 18 years, Day 11 (n=67, 73)
    25.4
    21.9
        >/= 18 years, Day 15 (n=66, 67)
    10.6
    9.0
        >/= 18 years, Day 40 (n=68, 67)
    1.5
    1.5
        < 18 years, Baseline (n=8, 8)
    100.0
    100.0
        < 18 years, Day 2/3 (n=7, 8)
    85.7
    75.0
        < 18 years, Day 6 (n=7, 7)
    85.7
    57.1
        < 18 years, Day 8 (n=5, 7)
    20.0
    42.9
        < 18 years, Day 11 (n=7, 7)
    28.6
    14.3
        < 18 years, Day 15 (n=7, 7)
    42.9
    0.0
        < 18 years, Day 40 (n=7, 8)
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Time to Cessation of Viral Shedding by RT-PCR

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    End point title
    		 Time to Cessation of Viral Shedding by RT-PCR
    End point description
    Viral shedding was determined by direct viral load measurement from nasopharyngeal swabs by RT-PCR assay and expressed in log10 vp/mL. Reported is the time to cessation of viral shedding over time in adults >/= 18 years and adolescents and children < 18 years. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. n = number of subjects analysed.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 40
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    81
    86
    Units: hours
    median (confidence interval 95%)
        >/= 18 years (n=72, 76)
    178.0 (152.2 to 227.0)
    154.1 (128.5 to 171.0)
        < 18 years (n=8, 8)
    181.0 (106.2 to 943.7)
    180.5 (8.6 to 247.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Persistent Viral Shedding

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    End point title
    		 Percentage of Subjects with Persistent Viral Shedding
    End point description
    Persistent shedding was defined as a viral load reduction <1 log10 vp/mL at end of treatment compared with baseline. Reported is the percentage of subjects with persistent viral shedding at end of treatment in adults >/= 18 years and adolescents and children < 18 years. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 11 (EOT)
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    81
    86
    Units: percentage of subjects
        number (not applicable)
    1.2
    4.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Developed Secondary Illness

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    End point title
    		 Percentage of Subjects Who Developed Secondary Illness
    End point description
    Secondary illness included bronchitis, pneumonia, acute sinusitis, sinusitis, lower respiratory infection or otitis media. Reported is the percentage of subjects with at least one event in adults >/= 18 years and adolescents and children < 18 years. mITTi population: all subjects randomised to a particular treatment, regardless of whether they received that treatment or not, who received at least one dose of study drug and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. n = number of subjects analysed.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 40
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    81
    86
    Units: percentage of subjects
    number (not applicable)
        >/=18 years (n=73, 78)
    8.2
    5.1
        < 18 years (n=8, 8)
    12.5
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Initiated Antibiotic Treatment

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    End point title
    		 Percentage of Subjects Who Initiated Antibiotic Treatment
    End point description
    Secondary illness included bronchitis, pneumonia, acute sinusitis, sinusitis, lower respiratory infection or otitis media. Reported is the percentage of subjects with secondary illness, who initiated antibiotic treatment, in adults >/= 18 years and adolescents and children < 18 years. The safety population included all subjects who received at least one dose of study drug and had a safety assessment performed post randomisation. n = number of subjects analysed.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 40
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    105
    110
    Units: percentage of subjects
    number (not applicable)
        >/= 18 years (n=98, 101)
    8.2
    5.0
        < 18 years (n=7, 9)
    14.3
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Hospitalised

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    End point title
    		 Percentage of Subjects Hospitalised
    End point description
    Reported is the percentage of subjects, who required hospitalisation at any time between treatment initiation and the end of the study period, in adults >/= 18 years and adolescents and children < 18 years. The ITTi population included all subjects randomised and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. n = number of subjects analysed.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 40
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    83
    86
    Units: percentage of subjects
    number (not applicable)
        >/= 18 years (n=74, 78)
    6.8
    7.7
        < 18 years (n=9, 8)
    11.1
    0.0
    No statistical analyses for this end point

    Secondary: Duration of Hospitalisation

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    End point title
    		 Duration of Hospitalisation
    End point description
    Reported is the duration of hospitalizsation at any time between treatment initiation and the end of the study period, in adults >/= 18 years and adolescents and children < 18 years. The ITTi population included all subjects randomised and with central laboratory confirmation of influenza infection, excluding subjects infected with oseltamivir-resistant influenza at baseline. n = number of subjects analysed. 9999 = not estimable as no subject was hospitalised.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 40
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    83
    86
    Units: days
    median (full range (min-max))
        >/= 18 years (n=74, 78)
    7.0 (5.0 to 14.0)
    6.50 (4.0 to 32.0)
        < 18 years (n=9, 8)
    5.0 (5.0 to 5.0)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Oseltamivir in Adults

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    End point title
    		 Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Oseltamivir in Adults
    End point description
    The pharmacokinetic evaluable patient (PKEP) population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    9
    13
    Units: nanograms per millilitre (ng/mL)
        arithmetic mean (standard deviation)
    65.5 ( 26.8 )
    149 ( 80.7 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Trough Plasma Concentration (Ctrough) of Oseltamivir in Adults

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    End point title
    		 Pharmacokinetics: Trough Plasma Concentration (Ctrough) of Oseltamivir in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    9
    13
    Units: ng/mL
        arithmetic mean (standard deviation)
    2.33 ( 0.641 )
    6.98 ( 5.1 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics : Area Under the Concentration-Time Curve from 0 to 12 hours (AUC0-12) at Steady State of Oseltamivir in Adults

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    End point title
    		 Pharmacokinetics : Area Under the Concentration-Time Curve from 0 to 12 hours (AUC0-12) at Steady State of Oseltamivir in Adults
    End point description
    AUC0-12 was reported at steady state as nanograms per hour per millilitre (ng/mL*hr). The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours on Day 6 or any day after the 11th dose
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    9
    13
    Units: ng/mL*hr
        arithmetic mean (standard deviation)
    197 ( 49.7 )
    501 ( 320 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Time to Maximum Concentration (tmax) of Oseltamivir in Adults

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    End point title
    		 Pharmacokinetics: Time to Maximum Concentration (tmax) of Oseltamivir in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    9
    13
    Units: hour
        arithmetic mean (standard deviation)
    1.08 ( 0.484 )
    1.08 ( 0.504 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Elimination Constant (ke) of Oseltamivir in Adults

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    End point title
    		 Pharmacokinetics: Elimination Constant (ke) of Oseltamivir in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adults With Pharmacokinetic Evaluation
    Number of subjects analysed
    22
    Units: 1/hr
        arithmetic mean (standard deviation)
    4.93 ( 1.01 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Apparent Clearance (CL/F) of Oseltamivir in Adults

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    End point title
    		 Pharmacokinetics: Apparent Clearance (CL/F) of Oseltamivir in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adults With Pharmacokinetic Evaluation
    Number of subjects analysed
    22
    Units: litre/hour (L/hr)
        arithmetic mean (standard deviation)
    381 ( 113 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir in Adults

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    End point title
    		 Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adults With Pharmacokinetic Evaluation
    Number of subjects analysed
    22
    Units: litre (L)
        arithmetic mean (standard deviation)
    76.2 ( 15.7 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Cmax of Oseltamivir Carboxylate in Adults

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    End point title
    		 Pharmacokinetics: Cmax of Oseltamivir Carboxylate in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    9
    13
    Units: ng/mL
        arithmetic mean (standard deviation)
    655 ( 276 )
    1420 ( 574 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Ctrough of Oseltamivir Carboxylate in Adults

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    End point title
    		 Pharmacokinetics: Ctrough of Oseltamivir Carboxylate in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    9
    13
    Units: ng/mL
        arithmetic mean (standard deviation)
    363 ( 167 )
    831 ( 358 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics : AUC0-12 at Steady State of Oseltamivir Carboxylate in Adults

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    End point title
    		 Pharmacokinetics : AUC0-12 at Steady State of Oseltamivir Carboxylate in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    9
    13
    Units: ng/mL*hr
        arithmetic mean (standard deviation)
    6240 ( 2710 )
    13800 ( 5670 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Tmax of Oseltamivir Carboxylate in Adults

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    End point title
    		 Pharmacokinetics: Tmax of Oseltamivir Carboxylate in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Experimental: Conventional dose Experimental: Double dose
    Number of subjects analysed
    9
    13
    Units: hour
        arithmetic mean (standard deviation)
    3.83 ( 1.08 )
    3.96 ( 0.841 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Elimination Constant (ke) of Oseltamivir Carboxylate in Adults

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    End point title
    		 Pharmacokinetics: Elimination Constant (ke) of Oseltamivir Carboxylate in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adults With Pharmacokinetic Evaluation
    Number of subjects analysed
    22
    Units: 1/hr
        arithmetic mean (standard deviation)
    1.63 ( 0.81 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Apparent Clearance (CL/F) of Oseltamivir Carboxylate in Adults

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    End point title
    		 Pharmacokinetics: Apparent Clearance (CL/F) of Oseltamivir Carboxylate in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adults With Pharmacokinetic Evaluation
    Number of subjects analysed
    22
    Units: L/hr
        arithmetic mean (standard deviation)
    13.7 ( 6.79 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir Carboxylate in Adults

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    End point title
    		 Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir Carboxylate in Adults
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adults >/= 18 years.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adults With Pharmacokinetic Evaluation
    Number of subjects analysed
    22
    Units: litre (L)
        arithmetic mean (standard deviation)
    8.39 ( 0 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Cmax of Oseltamivir in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Cmax of Oseltamivir in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [7]
    Units: ng/mL
    number (not applicable)
        Conventional Dose: 60 mg
    61.9
        Conventional Dose: 75 mg
    45.9
        Double Dose: 90 mg
    107
        Double Dose: 150 mg
    86.6
    Notes
    [7] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Ctrough of Oseltamivir in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Ctrough of Oseltamivir in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [8]
    Units: ng/mL
    number (not applicable)
        Conventional Dose: 60 mg
    2.84
        Conventional Dose: 75 mg
    3.37
        Double Dose: 90 mg
    6.65
        Double Dose: 150 mg
    3.88
    Notes
    [8] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: AUC0-12 at Steady State of Oseltamivir in Adolescents and Children

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    End point title
    		 Pharmacokinetics: AUC0-12 at Steady State of Oseltamivir in Adolescents and Children
    End point description
    AUC0-12 will be reported at steady state as nanograms per hour per millilitre (ng*h/mL). The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [9]
    Units: ng*h/mL
    number (not applicable)
        Conventional Dose: 60 mg
    229
        Conventional Dose: 75 mg
    171
        Double Dose: 90 mg
    425
        Double Dose: 150 mg
    339
    Notes
    [9] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Tmax of Oseltamivir in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Tmax of Oseltamivir in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [10]
    Units: hour
    number (not applicable)
        Conventional Dose: 60 mg
    1
        Conventional Dose: 75 mg
    1
        Double Dose: 90 mg
    1
        Double Dose: 150 mg
    1.25
    Notes
    [10] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Cmax of Oseltamivir Carboxylate in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Cmax of Oseltamivir Carboxylate in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [11]
    Units: ng/mL
    number (not applicable)
        Conventional Dose: 60 mg
    363
        Conventional Dose: 75 mg
    848
        Double Dose: 90 mg
    770
        Double Dose: 150 mg
    906
    Notes
    [11] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Ctrough of Oseltamivir Carboxylate in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Ctrough of Oseltamivir Carboxylate in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [12]
    Units: ng/mL
    number (not applicable)
        Conventional Dose: 60 mg
    215
        Conventional Dose: 75 mg
    459
        Double Dose: 90 mg
    445
        Double Dose: 150 mg
    464
    Notes
    [12] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: AUC0-12 at Steady State of Oseltamivir Carboxylate in Adolescents and Children

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    End point title
    		 Pharmacokinetics: AUC0-12 at Steady State of Oseltamivir Carboxylate in Adolescents and Children
    End point description
    AUC0-12 will be reported at steady state as nanograms per hour per millilitre (ng*h/mL). The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [13]
    Units: ng*h/mL
    number (not applicable)
        Conventional Dose: 60 mg
    3550
        Conventional Dose: 75 mg
    8010
        Double Dose: 90 mg
    7460
        Double Dose: 150 mg
    8420
    Notes
    [13] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Tmax of Oseltamivir Carboxylate in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Tmax of Oseltamivir Carboxylate in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [14]
    Units: hour
    number (not applicable)
        Conventional Dose: 60 mg
    3.75
        Conventional Dose: 75 mg
    4
        Double Dose: 90 mg
    4
        Double Dose: 150 mg
    4
    Notes
    [14] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Elimination Constant (ke) of Oseltamivir in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Elimination Constant (ke) of Oseltamivir in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [15]
    Units: 1/hr
    number (not applicable)
        Conventional Dose: 60 mg
    4.22
        Conventional Dose: 75 mg
    4.56
        Double Dose: 90 mg
    3.40
        Double Dose: 150 mg
    5.74
    Notes
    [15] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Apparent Clearance (CL/F) of Oseltamivir in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Apparent Clearance (CL/F) of Oseltamivir in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [16]
    Units: L/hr
    number (not applicable)
        Conventional Dose: 60 mg
    263
        Conventional Dose: 75 mg
    439
        Double Dose: 90 mg
    212
        Double Dose: 150 mg
    442
    Notes
    [16] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [17]
    Units: Litre
    number (not applicable)
        Conventional Dose: 60 mg
    62.3
        Conventional Dose: 75 mg
    96.4
        Double Dose: 90 mg
    62.3
        Double Dose: 150 mg
    76.9
    Notes
    [17] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Elimination Constant (ke) of Oseltamivir Carboxylate in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Elimination Constant (ke) of Oseltamivir Carboxylate in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [18]
    Units: 1/hr
    number (not applicable)
        Conventional Dose: 60 mg
    2.01
        Conventional Dose: 75 mg
    1.12
        Double Dose: 90 mg
    1.44
        Double Dose: 150 mg
    2.12
    Notes
    [18] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Apparent Clearance (CL/F), of Oseltamivir Carboxylate in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Apparent Clearance (CL/F), of Oseltamivir Carboxylate in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [19]
    Units: L/hr
    number (not applicable)
        Conventional Dose: 60 mg
    16.9
        Conventional Dose: 75 mg
    9.36
        Double Dose: 90 mg
    12.1
        Double Dose: 150 mg
    17.8
    Notes
    [19] - Data for each subject reported individually.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir Carboxylate in Adolescents and Children

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    End point title
    		 Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir Carboxylate in Adolescents and Children
    End point description
    The PKEP population comprised all subjects in the ITT population who had at least one valid post-dose drug concentration measurement at a scheduled visit time point. Reported here are data for adolescents and children < 18 years. Individual data are provided as subjects received different drug doses. Drug dose is indicated in the row title for each subject.
    End point type
    Secondary
    End point timeframe
    Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose
    End point values
    		 Adolescents and Children With Pharmacokinetic Evaluation
    Number of subjects analysed
    4 [20]
    Units: Litre
    number (not applicable)
        Conventional Dose: 60 mg
    8.39
        Conventional Dose: 75 mg
    8.39
        Double Dose: 90 mg
    8.39
        Double Dose: 150 mg
    8.39
    Notes
    [20] - Data for each subject reported individually.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 40
    Adverse event reporting additional description
    The safety population included all subjects who received at least one treatment with study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Experimental: Double dose
    Reporting group description
    		 Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 60 to 150 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 150 mg twice daily for adults/adolescents (>/=13 years old) or placebo matched to oseltamivir twice daily over 10 days.

    Reporting group title
    Experimental: Conventional dose
    Reporting group description
    		 Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 30 to 75 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 75 mg twice daily for adults/adolescents greater than or equal to (>/=13 years old) or placebo-matched to oseltamivir twice daily over 10 days.

    Serious adverse events
    		 Experimental: Double dose Experimental: Conventional dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 110 (9.09%)
    8 / 105 (7.62%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemia recurrent
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases of meninges
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 110 (0.91%)
    2 / 105 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Experimental: Double dose Experimental: Conventional dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 110 (59.09%)
    53 / 105 (50.48%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 110 (10.91%)
    5 / 105 (4.76%)
         occurrences all number
    14
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 110 (10.00%)
    10 / 105 (9.52%)
         occurrences all number
    15
    11
    Nausea
         subjects affected / exposed
    14 / 110 (12.73%)
    10 / 105 (9.52%)
         occurrences all number
    18
    11
    Vomiting
         subjects affected / exposed
    12 / 110 (10.91%)
    10 / 105 (9.52%)
         occurrences all number
    14
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2008
    In Amendment B, the following significant changes were made: 1) A more timely assessment of baseline nasal and throat swab samples for oseltamivir-resistant virus was added due to the significant increase in oseltamivir-resistant viruses circulating within many countries identified by routine influenza virus surveillance during the 2007/2008 influenza season. Results of real-time PCR-based resistance testing were to be reported promptly to clinical sites to assist in determining the most appropriate treatment options for individual subjects. 2) New criterion was added for premature withdrawal of subjects from study treatment if additional antivirals were added to the patient’s treatment regimen. The protocol was modified to allow replacement of subjects identified as having oseltamivir-resistant influenza virus at baseline by enrolling subjects on a rolling basis. 3) Clarification was made to allow treatment with other antivirals, if in the best interest of the patients and provided study oseltamivir was discontinued. 4) Efficacy data from subjects receiving other antivirals after discontinuing oseltamivir treatment were excluded from efficacy analyses after the date of commencement of other antiviral treatment and these subjects considered as treatment failures. The definition of the ITTi population was revised to exclude subjects with oseltamivir-resistant influenza A H1N1 H274Y virus at baseline.
    28 Mar 2011
    In Amendment C, the following significant changes were made: 1) Because of the need to enroll subjects within 48 hours of the onset of influenza, a number of subjects were ineligible for screening. Inclusion criteria were therefore modified to broaden the time between onset of influenza-like symptoms and first dose of study drug from 48 hours to 96 hours. 2) PCR and culture were added as diagnostic tests at baseline to overcome the high screening failure rate due to low sensitivity of rapid diagnostic tests. 3) The primary objective of the study was revised to become a descriptive characterization of safety, tolerability and resistance. 4) The sample size and number of participating centers were revised to reflect the amended study primary objective. 5) The criteria for withdrawal of subjects with renal failure was stated as subjects with creatinine clearance < 60 mL/min/1.73m^2.
    28 Sep 2012
    In Amendment D, the following significant changes were made: 1) The protocol was amended to include the Southern Hemisphere and allow global enrollment into the trial. Inclusion and exclusion criteria were amended to facilitate enrollment of as much of the immunocompromised population as possible. 2) The protocol was revised to allow self-swabbing at home when there was a home visit planned, thereby allowing shipment of the sample in an expedited manner. 3) The pharmacokinetic component of the study (removed in Amendment B) was reintroduced using a sparse PK sampling schedule not requiring blood a sample collection on multiple days and which was available to subjects who provided additional consent to that of the main study.
    30 Oct 2013
    In Amendment E, the following significant changes were made: 1) The protocol was amended to provide clarity and additional guidance on the inclusion criteria regarding CD4 cell counts for subjects with human immunodeficiency virus (HIV). 2) The criteria for withdrawal of subjects with renal failure was revised to state subjects with creatinine clearance < 45 mL/min/1.73m2. A lower limit of 45 mL/min for creatinine clearance was used to allow for subjects with mild to moderate renal impairment. 3) The statistical methods section was updated to include an overview of the planned pharmacokinetic analysis. 4) Removal of exclusion criterion for subjects who “have evidence of a serious secondary respiratory or disseminated infection that may confound or overlay the diagnosis and/or symptomatology of influenza” to prevent ambiguity around the category of subjects who should not be enrolled.
    18 Jun 2014
    In Amendment F, the following significant change was made: Throughout the protocol, ‘oseltamivir’ was re-introduced to all pharmacokinetic analysis sections, as applicable as both oseltamivir (parent) and oseltamivir carboxylate (metabolite) plasma concentrations were to be determined from blood samples. The term was inadvertently removed in protocol Version E.

    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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