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    Clinical Trial Results:
    An Open-Label, Prospective, Pharmacokinetic/Pharmacodynamic and Safety Evaluation of Intravenous Oseltamivir (Tamiflu®) in the Treatment of Infants Less Than One Year of Age With Influenza Infection

    Summary
    EudraCT number
    		 2016-003003-54
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    28 Jan 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Apr 2017
    First version publication date
    26 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NP25138
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01053663
    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, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F.Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Feb 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jan 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This prospective, open-label, pharmacokinetic (PK)/pharmacodynamic (PD) and safety study was designed to define the PK of oseltamivir and oseltamivir carboxylate and evaluate the safety profile following intravenous (IV) administration of oseltamivir phosphate in infants less than 1 year of age with influenza. The study was also planned to evaluate viral load, viral shedding, and to evaluate all isolates for phenotypic and, where necessary, genotypic resistance.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the ''Declaration of Helsinki" and Good Clinical Practice according to the regulations and procedures described in the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jan 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    9
    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)
    1
    Infants and toddlers (28 days-23 months)
    8
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 2428 participants were prescreened; of which, 2419 failed the prescreening evaluation. The most common reasons for failing the prescreening evaluation included the following: negative influenza diagnosis, not meeting the age criterion, ability to tolerate/absorb oral medication, and inability to comply with the study procedures.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Oseltamivir - All Participants
    Arm description
    		 Participants received oseltamivir (Tamiflu) twice daily (every 12 hours) intravenously (IV) over 5 or 6 days for a total of 10 doses. Oseltamivir doses were based on participant’s age. Participants aged 91 to less than (<) 365 days received 3 milligrams per kilogram (mg/kg); participants aged 31 to 90 days received 2.5 mg/kg; and participants aged 0 to 30 days received 2 mg/kg. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    RO0640796
    Other name
    Tamiflu®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received oseltamivir twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. The oseltamivir doses were based on participant’s age.

    Number of subjects in period 1
    		Oseltamivir - All Participants
    Started
    9
    Completed
    3
    Not completed
    6
         Transferred to Another Hospital
    1
         Death
    2
         Poor IV Access
    1
         Negative Influenza Diagnosis
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oseltamivir - All Participants
    Reporting group description
    		 Participants received oseltamivir (Tamiflu) twice daily (every 12 hours) intravenously (IV) over 5 or 6 days for a total of 10 doses. Oseltamivir doses were based on participant’s age. Participants aged 91 to less than (<) 365 days received 3 milligrams per kilogram (mg/kg); participants aged 31 to 90 days received 2.5 mg/kg; and participants aged 0 to 30 days received 2 mg/kg. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Reporting group values
    		 Oseltamivir - All Participants Total
    Number of subjects
    		 9 9
    Age categorical
    Units: Subjects
    Age continuous
    Here, 99999 represent data not estimable due to single participant analyzed.
    Units: days
        arithmetic mean (standard deviation)
    		 143.2 ( 82.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 7 7
    Subject analysis sets

    Subject analysis set title
    Oseltamivir: Age 91 to <365 Days
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 91 to <365 days received oseltamivir 3 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Subject analysis set title
    Oseltamivir: Age 31 to 90 Days
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 31 to 90 days received oseltamivir 2.5 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Subject analysis set title
    Oseltamivir: Age 0 to 30 Days
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 0 to 30 days received oseltamivir 2 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Subject analysis sets values
    		 Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects
    7
    1
    1
    Age categorical
    Units: Subjects
    Age continuous
    Here, 99999 represent data not estimable due to single participant analyzed.
    Units: days
        arithmetic mean (standard deviation)
    175 ( 62 )
    41 ( 99999 )
    23 ( 99999 )
    Gender categorical
    Units: Subjects
        Female
    2
    0
    0
        Male
    5
    1
    1

    End points

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    End points reporting groups
    Reporting group title
    Oseltamivir - All Participants
    Reporting group description
    		 Participants received oseltamivir (Tamiflu) twice daily (every 12 hours) intravenously (IV) over 5 or 6 days for a total of 10 doses. Oseltamivir doses were based on participant’s age. Participants aged 91 to less than (<) 365 days received 3 milligrams per kilogram (mg/kg); participants aged 31 to 90 days received 2.5 mg/kg; and participants aged 0 to 30 days received 2 mg/kg. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Subject analysis set title
    Oseltamivir: Age 91 to <365 Days
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 91 to <365 days received oseltamivir 3 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Subject analysis set title
    Oseltamivir: Age 31 to 90 Days
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 31 to 90 days received oseltamivir 2.5 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Subject analysis set title
    Oseltamivir: Age 0 to 30 Days
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 0 to 30 days received oseltamivir 2 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Primary: Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Plasma Concentration (AUClast) of Oseltamivir and Oseltamivir Carboxylate on Day 1

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    End point title
    		 Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Plasma Concentration (AUClast) of Oseltamivir and Oseltamivir Carboxylate on Day 1 [1]
    End point description
    Pharmacokinetic (PK) population included all treated participants who had at least one blood sample evaluable for drug concentration level. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
    End point type
    Primary
    End point timeframe
    Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1
    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 analysis was planned for this open-label study.
    End point values
    		 Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    3
    0 [2]
    1
    Units: hour*nanograms/milliliter (h*ng/mL)
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    777 ( 162.8 )
    ( )
    494 ( 99999 )
        Oseltamivir Carboxylate
    5200 ( 87.8 )
    ( )
    7510 ( 99999 )
    Notes
    [2] - No participant was evaluable for this arm.
    No statistical analyses for this end point

    Primary: AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 2

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    End point title
    		 AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 2 [3]
    End point description
    PK population. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
    End point type
    Primary
    End point timeframe
    Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 2
    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 analysis was planned for this open-label study.
    End point values
    		 Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    3
    1
    0 [4]
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    988 ( 57.8 )
    481 ( 99999 )
    ( )
        Oseltamivir Carboxylate
    7270 ( 42.2 )
    5330 ( 99999 )
    ( )
    Notes
    [4] - No participant was evaluable for this arm.
    No statistical analyses for this end point

    Primary: AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 4

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    End point title
    		 AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 4 [5]
    End point description
    PK population. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
    End point type
    Primary
    End point timeframe
    Pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4
    Notes
    [5] - 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 analysis was planned for this open-label study.
    End point values
    		 Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    2
    0 [6]
    1
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    1520 ( 33.9 )
    ( )
    389 ( 99999 )
        Oseltamivir Carboxylate
    3880 ( 98 )
    ( )
    2070 ( 99999 )
    Notes
    [6] - No participant was evaluable for this arm.
    No statistical analyses for this end point

    Primary: Maximum Observed Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate on Day 1

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate on Day 1 [7]
    End point description
    PK population. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
    End point type
    Primary
    End point timeframe
    Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1
    Notes
    [7] - 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 analysis was planned for this open-label study.
    End point values
    		 Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    3
    0 [8]
    1
    Units: nanograms/milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    307 ( 315.7 )
    ( )
    203 ( 99999 )
        Oseltamivir Carboxylate
    736 ( 55.5 )
    ( )
    871 ( 99999 )
    Notes
    [8] - No participant was evaluable for this arm.
    No statistical analyses for this end point

    Primary: Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 2

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    End point title
    		 Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 2 [9]
    End point description
    PK population. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
    End point type
    Primary
    End point timeframe
    Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 2
    Notes
    [9] - 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 analysis was planned for this open-label study.
    End point values
    		 Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    3
    1
    0 [10]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    419 ( 78.4 )
    194 ( 99999 )
    ( )
        Oseltamivir Carboxylate
    1080 ( 43.6 )
    1050 ( 99999 )
    ( )
    Notes
    [10] - No participant was evaluable for this arm.
    No statistical analyses for this end point

    Primary: Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 4

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    End point title
    		 Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 4 [11]
    End point description
    PK population. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
    End point type
    Primary
    End point timeframe
    Pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4
    Notes
    [11] - 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 analysis was planned for this open-label study.
    End point values
    		 Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    2
    0 [12]
    1
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    742 ( 31.1 )
    ( )
    189 ( 99999 )
        Oseltamivir Carboxylate
    1370 ( 89.6 )
    ( )
    727 ( 99999 )
    Notes
    [12] - No participant was evaluable for this arm.
    No statistical analyses for this end point

    Secondary: Time to the Maximum Observed Plasma Concentration (Tmax) of Oseltamivir and Oseltamivir Carboxylate

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    End point title
    		 Time to the Maximum Observed Plasma Concentration (Tmax) of Oseltamivir and Oseltamivir Carboxylate
    End point description
    PK population. Number of subjects analyzed = participants who were evaluable for this outcome, n = number of participants evaluable for specified categories. Here, 9999 represent data not available as no participant was evaluable at specified timepoint and 99999 represent data not estimable due to single participant analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1 and Day 2, pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4
    End point values
    		 Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    3
    1
    1
    Units: hours
    geometric mean (geometric coefficient of variation)
        Day 1: Oseltamivir (n = 3, 0, 1)
    2.51 ( 55.4 )
    9999 ( 9999 )
    2 ( 99999 )
        Day 1: Oseltamivir Carboxylate (n = 3, 0, 1)
    4.57 ( 32.5 )
    9999 ( 9999 )
    5.58 ( 99999 )
        Day 2: Oseltamivir (n = 3, 1, 0)
    2.02 ( 1.4 )
    2.13 ( 99999 )
    9999 ( 9999 )
        Day 2: Oseltamivir Carboxylate (n = 3, 1, 0)
    3.4 ( 47.8 )
    4.3 ( 99999 )
    9999 ( 9999 )
        Day 4: Oseltamivir (n = 2, 0, 1)
    2.02 ( 1.2 )
    9999 ( 9999 )
    1.93 ( 99999 )
        Day 4: Oseltamivir Carboxylate (n = 2, 0, 1)
    3.85 ( 6.7 )
    9999 ( 9999 )
    3.98 ( 99999 )
    No statistical analyses for this end point

    Secondary: Last Measurable Plasma Concentration (Clast) of Oseltamivir and Oseltamivir Carboxylate

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    End point title
    		 Last Measurable Plasma Concentration (Clast) of Oseltamivir and Oseltamivir Carboxylate
    End point description
    PK population. Number of subjects analyzed = participants who were evaluable for this outcome, n = number of participants evaluable for specified categories. Here, 9999 represent data not available as no participant was evaluable at specified timepoint and 99999 represent data not estimable due to single participant analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1 and Day 2, pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4
    End point values
    		 Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    3
    1
    1
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 1: Oseltamivir (n = 3, 0, 1)
    5.58 ( 183 )
    9999 ( 9999 )
    2.76 ( 99999 )
        Day 1: Oseltamivir Carboxylate (n = 3, 0, 1)
    505 ( 82.9 )
    9999 ( 9999 )
    503 ( 99999 )
        Day 2: Oseltamivir (n = 3, 1, 0)
    8.22 ( 183.5 )
    6.84 ( 99999 )
    9999 ( 9999 )
        Day 2: Oseltamivir Carboxylate (n = 3, 1, 0)
    849 ( 67.9 )
    948 ( 99999 )
    9999 ( 9999 )
        Day 4: Oseltamivir (n = 2, 0, 1)
    66.2 ( 28.8 )
    9999 ( 9999 )
    10.7 ( 99999 )
        Day 4: Oseltamivir Carboxylate (n = 2, 0, 1)
    1370 ( 89.6 )
    9999 ( 9999 )
    727 ( 99999 )
    No statistical analyses for this end point

    Secondary: Time of the Last Measurable Plasma Concentration (Tlast) of Oseltamivir and Oseltamivir Carboxylate

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    End point title
    		 Time of the Last Measurable Plasma Concentration (Tlast) of Oseltamivir and Oseltamivir Carboxylate
    End point description
    PK population. Number of subjects analyzed = participants who were evaluable for this outcome, n = number of participants evaluable for specified categories. Here, 9999 represent data not available as no participant was evaluable at specified timepoint and 99999 represent data not estimable due to single participant analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1 and Day 2, pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4
    End point values
    		 Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    3
    1
    1
    Units: hours
    geometric mean (geometric coefficient of variation)
        Day 1: Oseltamivir (n = 3, 0, 1)
    9.62 ( 24.7 )
    9999 ( 9999 )
    10.58 ( 99999 )
        Day 1: Oseltamivir Carboxylate (n = 3, 0, 1)
    9.62 ( 24.7 )
    9999 ( 9999 )
    10.58 ( 99999 )
        Day 2: Oseltamivir (n = 3, 1, 0)
    8.55 ( 51.1 )
    6.47 ( 99999 )
    9999 ( 9999 )
        Day 2: Oseltamivir Carboxylate (n = 3, 1, 0)
    8.55 ( 51.1 )
    6.47 ( 99999 )
    9999 ( 9999 )
        Day 4: Oseltamivir (n = 2, 0, 1)
    3.85 ( 6.7 )
    9999 ( 9999 )
    3.98 ( 99999 )
        Day 4: Oseltamivir Carboxylate (n = 2, 0, 1)
    3.85 ( 6.7 )
    9999 ( 9999 )
    3.98 ( 99999 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Greater Than or Equal to (>/=) 5−Fold Change in Neuraminidase Inhibition (NAI) Assay 50 Percent (%) Inhibitory Concentration (IC50) Values

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    End point title
    		 Number of Participants With Greater Than or Equal to (>/=) 5−Fold Change in Neuraminidase Inhibition (NAI) Assay 50 Percent (%) Inhibitory Concentration (IC50) Values
    End point description
    IC50 was defined as the concentration that causes 50% inhibition of viral activity. IC50 values were calculated using NAI assay. The 5-fold change was calculated as either >/=5 times change in the NAI IC50 visit value from the Reference value at a visit or >/=5 times change in the NAI IC50 Visit value from the Baseline value. Safety population included all participants who received at least one dose of IV study medication and had a safety assessment performed after initiation of treatment. Here, number of subjects analyzed = participants evaluable for this outcome measure, and n = participants evaluable for specified time-point, for each arm, respectively. Here, 9999 represent data not available as no participant was evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 1, 3, 4, 6, 15
    End point values
    		 Oseltamivir - All Participants Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    5
    4
    0 [13]
    1
    Units: participants
        Day 1 (n=5, 4, 0, 1)
    1
    1
    0
        Day 3 (n=1, 0, 0, 1)
    0
    9999
    0
        Day 4 (n=3, 3, 0, 0)
    1
    1
    9999
        Day 6 (n=1, 0, 0, 1)
    0
    9999
    0
        Day 15 (n=1, 1, 0, 0)
    0
    0
    9999
    Notes
    [13] - No participant was evaluable for this arm.
    No statistical analyses for this end point

    Secondary: Number of Participants With Oseltamivir Resistance Mutation

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    End point title
    		 Number of Participants With Oseltamivir Resistance Mutation
    End point description
    Resistance was assessed by neuraminidase (NA) and hemagglutinin (HA) genes sequencing analysis, using Reverse Transcription Polymerase Chain Reaction (RT-PCR). Safety population.
    End point type
    Secondary
    End point timeframe
    Up to Day 30
    End point values
    		 Oseltamivir - All Participants Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Number of subjects analysed
    9
    7
    1
    1
    Units: participants
    1
    1
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 30
    Adverse event reporting additional description
    Safety population
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Oseltamivir - All Participants
    Reporting group description
    		 Participants received oseltamivir (Tamiflu) twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. Oseltamivir doses were based on participant’s age. Participants aged 91 to <365 days received 3 mg/kg; participants aged 31 to 90 days received 2.5 mg/kg; and participants aged 0 to 30 days received 2 mg/kg. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Reporting group title
    Oseltamivir: Age 91 to <365 Days
    Reporting group description
    		 Participants aged 91 to <365 days received oseltamivir 3 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Reporting group title
    Oseltamivir: Age 31 to 90 Days
    Reporting group description
    		 Participants aged 31 to 90 days received oseltamivir 2.5 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Reporting group title
    Oseltamivir: Age 0 to 30 Days
    Reporting group description
    		 Participants aged 0 to 30 days received oseltamivir 2 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.

    Serious adverse events
    		 Oseltamivir - All Participants Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 9 (55.56%)
    5 / 7 (71.43%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    3
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Cerebral Ischaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi−Organ Failure
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory Disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Oseltamivir - All Participants Oseltamivir: Age 91 to <365 Days Oseltamivir: Age 31 to 90 Days Oseltamivir: Age 0 to 30 Days
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 9 (55.56%)
    4 / 7 (57.14%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Cardiac disorders
    Sinus Bradycardia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Nervous system disorders
    Brain Oedema
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    General disorders and administration site conditions
    Application Site Vesicles
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    0
    1
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Hypertension
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2010
    • Modified the requirements for the IV therapy duration and clarified the study population influenza diagnosis and duration of IV therapy • Provided an updated Assessments and Procedures schedule • Specified adverse events grading system
    14 May 2010
    • Decreased the required number of IV doses to at least one and clarified that participants could have switched to oral dosing with oseltamivir after IV therapy was no longer medically necessary • Modified dosing in participants with moderate or severe renal impairment or who required continuous renal replacement therapy • Revised exclusion criteria and increased the flexibility of PK sampling
    19 Sep 2011
    • Clarified the day of treatment completion depending on when dosing was started and whether one or two doses were received on Day 1 • Revised the screening and eligibility text to allow flexibility to include data obtained from standard-of-care procedures prior to obtaining informed consent for study participation • Revised PK sample collection time-points

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    28 Jan 2013
    The study was terminated prematurely after three influenza seasons.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Low number of participants enrolled in the study at the time that the study was terminated limits conclusions that can be derived from the study data.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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