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    Clinical Trial Results:
    An Open Label, Prospective, Pharmacokinetic/Pharmacodynamic and Safety Evaluation of Intravenous Oseltamivir (Tamiflu®) in the Treatment of Children 1 to 12 Years of Age With Influenza Infection

    Summary
    EudraCT number
    		 2016-003004-31
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    13 Dec 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Feb 2017
    First version publication date
    23 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NP25139
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01033734
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Mar 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2012
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study was a prospective, open label, pharmacokinetic (PK)/pharmacodynamic (PD) and safety evaluation of intravenous (IV) oseltamivir therapy in three cohorts of children with influenza infection aged 6-12 years (Cohort I), 3-5 years (Cohort II) and 1-2 years (Cohort III). Children with symptoms of influenza were considered for enrollment into this study.
    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
    19 Dec 2010
    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: 8
    Worldwide total number of subjects
    8
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    1
    Children (2-11 years)
    7
    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 2836 participants were prescreened, of which 2828 failed evaluation. The most common reasons for screen failure included: negative influenza diagnosis, not meeting the age criterion, ability to tolerate/absorb oral medication, and an 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 - overall
    Arm description
    		 Participants received oseltamivir (Tamiflu) 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 body weight. Participants with body weight less than or equal to (<=) 23 kilograms (kg) received 3 milligrams per kilogram (mg/kg); participants with body weight more than (>) 23 kg to 40 kg received 2.5 mg/kg; and participants with body weight >40 kg received 100 milligrams (mg). 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 oral suspension, Powder for solution for infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Participants received oseltamivir twice daily. The oseltamivir doses were based on participant’s age.

    Number of subjects in period 1
    		Oseltamivir - overall
    Started
    8
    Completed
    7
    Not completed
    1
         Withdrawal by Subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oseltamivir - overall
    Reporting group description
    		 Participants received oseltamivir (Tamiflu) 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 body weight. Participants with body weight less than or equal to (<=) 23 kilograms (kg) received 3 milligrams per kilogram (mg/kg); participants with body weight more than (>) 23 kg to 40 kg received 2.5 mg/kg; and participants with body weight >40 kg received 100 milligrams (mg). 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 - overall Total
    Number of subjects
    		 8 8
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 4.8 ( 3.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 6 6

    End points

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    End points reporting groups
    Reporting group title
    Oseltamivir - overall
    Reporting group description
    		 Participants received oseltamivir (Tamiflu) 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 body weight. Participants with body weight less than or equal to (<=) 23 kilograms (kg) received 3 milligrams per kilogram (mg/kg); participants with body weight more than (>) 23 kg to 40 kg received 2.5 mg/kg; and participants with body weight >40 kg received 100 milligrams (mg). 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: 6 to 12 Years
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 6 to 12 years received oseltamivir twice daily IV over 5 or 6 days for a total of 10 doses. The oseltamivir doses were based on participant’s body weight. Participants with body weight <=23 kg received 3 mg/kg; participants with body weight ˃23 kg to 40 kg received 2.5 mg/kg; and participants with body weight >40 kg received 100 mg. 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: 3 to 5 Years
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 3 to 5 years received oseltamivir twice daily IV over 5 or 6 days for a total of 10 doses. The oseltamivir doses were based on participant’s body weight. Participants with body weight <=23 kg received 3 mg/kg; participants with body weight ˃23 kg to 40 kg received 2.5 mg/kg; and participants with body weight ˃40 kg received 100 mg. 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: 1 to 2 Years
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants aged 1 to 2 Years received oseltamivir twice daily IV over 5 or 6 days for a total of 10 doses. The oseltamivir doses were based on participant’s body weight. Participants with body weight <=23 kg received 3 mg/kg; participants with body weight ˃23 kg to 40 kg received 2.5 mg/kg; and participants with body weight ˃40 kg received 100 mg. 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
    PK population included all treated participants who had at least one blood sample evaluable for drug concentration level. Number of participants 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
    Day 1: 15 minutes pre-infusion start, 1, 2, 3, 4, 6, 8, 12 hours post start of infusion
    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: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    1
    3
    0 [2]
    Units: hour*nanogram per milliliter (h*ng/mL)
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    829 ( 99999 )
    1460 ( 46.3 )
    ( )
        Oseltamivir Carboxylate
    1700 ( 99999 )
    4550 ( 61.1 )
    ( )
    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 participants 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
    Day 2: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    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: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    0 [4]
    1
    1
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    ( )
    1070 ( 99999 )
    1920 ( 99999 )
        Oseltamivir Carboxylate
    ( )
    5970 ( 99999 )
    6760 ( 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 3

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    End point title
    		 AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 3 [5]
    End point description
    PK population. Number of participants 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
    Day 3 (with or after fifth dose): 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    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: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    1
    0 [6]
    0 [7]
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    943 ( 99999 )
    ( )
    ( )
        Oseltamivir Carboxylate
    2000 ( 99999 )
    ( )
    ( )
    Notes
    [6] - No participant was evaluable for this arm.
    [7] - 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 [8]
    End point description
    PK population. Number of participants 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
    Day 4: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    Notes
    [8] - 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: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    0 [9]
    1
    0 [10]
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    ( )
    2480 ( 99999 )
    ( )
        Oseltamivir Carboxylate
    ( )
    3800 ( 99999 )
    ( )
    Notes
    [9] - No participant was evaluable for this arm.
    [10] - No participant was evaluable for this arm.
    No statistical analyses for this end point

    Primary: AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 5

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    End point title
    		 AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 5 [11]
    End point description
    PK population. Number of participants 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
    Day 5: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    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: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    1
    0 [12]
    0 [13]
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    1010 ( 99999 )
    ( )
    ( )
        Oseltamivir Carboxylate
    2820 ( 99999 )
    ( )
    ( )
    Notes
    [12] - No participant was evaluable for this arm.
    [13] - 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 [14]
    End point description
    PK population. Number of participants 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
    Day 1: 15 minutes pre-infusion start, 1, 2, 3, 4, 6, 8, 12 hours post start of infusion
    Notes
    [14] - 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: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    1
    3
    0 [15]
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    360 ( 99999 )
    753 ( 36.9 )
    ( )
        Oseltamivir Carboxylate
    311 ( 99999 )
    499 ( 55.1 )
    ( )
    Notes
    [15] - 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 [16]
    End point description
    PK population. Number of participants 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
    Day 2: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    Notes
    [16] - 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: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    0 [17]
    1
    1
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    ( )
    500 ( 99999 )
    1270 ( 99999 )
        Oseltamivir Carboxylate
    ( )
    663 ( 99999 )
    725 ( 99999 )
    Notes
    [17] - No participant was evaluable for this arm.
    No statistical analyses for this end point

    Primary: Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 3

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    End point title
    		 Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 3 [18]
    End point description
    PK population. Number of participants 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
    Day 3 (with or after fifth dose): 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    Notes
    [18] - 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: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    1
    0 [19]
    0 [20]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    404 ( 99999 )
    ( )
    ( )
        Oseltamivir Carboxylate
    237 ( 99999 )
    ( )
    ( )
    Notes
    [19] - No participant was evaluable for this arm.
    [20] - 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 [21]
    End point description
    PK population. Number of participants 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
    Day 4: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    Notes
    [21] - 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: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    0 [22]
    1
    0 [23]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    ( )
    915 ( 99999 )
    ( )
        Oseltamivir Carboxylate
    ( )
    549 ( 99999 )
    ( )
    Notes
    [22] - No participant was evaluable for this arm.
    [23] - No participant was evaluable for this arm.
    No statistical analyses for this end point

    Primary: Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 5

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    End point title
    		 Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 5 [24]
    End point description
    PK population. Number of participants 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
    Day 5: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    Notes
    [24] - 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: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    1
    0 [25]
    0 [26]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    403 ( 99999 )
    ( )
    ( )
        Oseltamivir Carboxylate
    408 ( 99999 )
    ( )
    ( )
    Notes
    [25] - No participant was evaluable for this arm.
    [26] - 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 participants 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 time-point and 99999 represent data not estimable due to single participant analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1: 15 minutes pre-infusion start, 1, 2, 3, 4, 6, 8, 12 hours post start of infusion; Day 2, 3 (with or after fifth dose), 4 or 5: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    End point values
    		 Oseltamivir: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    1
    3
    1
    Units: hours
    geometric mean (geometric coefficient of variation)
        Day 1: Oseltamivir (n = 1, 3, 0)
    2 ( 99999 )
    1.26 ( 41.7 )
    9999 ( 9999 )
        Day 1: Oseltamivir Carboxylate (n = 1, 3, 0)
    4 ( 99999 )
    4.61 ( 53.3 )
    9999 ( 9999 )
        Day 2: Oseltamivir (n = 0, 1, 1)
    9999 ( 9999 )
    2 ( 99999 )
    1 ( 99999 )
        Day 2: Oseltamivir Carboxylate (n = 0, 1, 1)
    9999 ( 9999 )
    4.62 ( 99999 )
    6 ( 99999 )
        Day 3: Oseltamivir (n = 1, 0, 0)
    1.05 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 3: Oseltamivir Carboxylate (n = 1, 0, 0)
    3.05 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 4: Oseltamivir (n = 0, 1, 0)
    9999 ( 9999 )
    2.5 ( 99999 )
    9999 ( 9999 )
        Day 4: Oseltamivir Carboxylate (n = 0, 1, 0)
    9999 ( 9999 )
    8.05 ( 99999 )
    9999 ( 9999 )
        Day 5: Oseltamivir (n = 1, 0, 0)
    2 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 5: Oseltamivir Carboxylate (n = 1, 0, 0)
    4.08 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
    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 participants 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 time-point and 99999 represent data not estimable due to single participant analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1: 15 minutes pre-infusion start, 1, 2, 3, 4, 6, 8, 12 hours post start of infusion; Day 2, 3 (with or after fifth dose), 4 or 5: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    End point values
    		 Oseltamivir: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    1
    3
    1
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 1: Oseltamivir (n = 1, 3, 0)
    4.4 ( 99999 )
    2.41 ( 80.6 )
    9999 ( 9999 )
        Day 1: Oseltamivir Carboxylate (n = 1, 3, 0)
    237 ( 99999 )
    308 ( 74.4 )
    9999 ( 9999 )
        Day 2: Oseltamivir (n = 0, 2, 1)
    9999 ( 9999 )
    25.2 ( 1704911.2 )
    4.76 ( 99999 )
        Day 2: Oseltamivir Carboxylate (n = 0, 2, 1)
    9999 ( 9999 )
    319 ( 0.44 )
    484 ( 99999 )
        Day 3: Oseltamivir (n = 1, 0, 0)
    2.6 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 3: Oseltamivir Carboxylate (n = 1, 0, 0)
    149 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 4: Oseltamivir (n = 0, 1, 0)
    9999 ( 9999 )
    25.1 ( 99999 )
    9999 ( 9999 )
        Day 4: Oseltamivir Carboxylate (n = 0, 1, 0)
    9999 ( 9999 )
    549 ( 99999 )
    9999 ( 9999 )
        Day 5: Oseltamivir (n = 1, 0, 0)
    15.1 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 5: Oseltamivir Carboxylate (n = 1, 0, 0)
    339 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
    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 participants 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 time-point and 99999 represent data not estimable due to single participant analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1: 15 minutes pre-infusion start, 1, 2, 3, 4, 6, 8, 12 hours post start of infusion; Day 2, 3 (with or after fifth dose), 4 or 5: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    End point values
    		 Oseltamivir: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    1
    3
    1
    Units: hours
    geometric mean (geometric coefficient of variation)
        Day 1: Oseltamivir (n = 1, 3, 0)
    7.42 ( 99999 )
    10.5 ( 23.4 )
    9999 ( 9999 )
        Day 1: Oseltamivir Carboxylate (n = 1, 3, 0)
    7.42 ( 99999 )
    11.98 ( 0.2 )
    9999 ( 9999 )
        Day 2: Oseltamivir (n = 0, 2, 1)
    9999 ( 9999 )
    3.5 ( 448.5 )
    12 ( 99999 )
        Day 2: Oseltamivir Carboxylate (n = 0, 2, 1)
    9999 ( 9999 )
    3.5 ( 448.47 )
    12 ( 99999 )
        Day 3: Oseltamivir (n = 1, 0, 0)
    10.13 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 3: Oseltamivir Carboxylate (n = 1, 0, 0)
    10.13 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 4: Oseltamivir (n = 0, 1, 0)
    9999 ( 9999 )
    8.05 ( 99999 )
    9999 ( 9999 )
        Day 4: Oseltamivir Carboxylate (n = 0, 1, 0)
    9999 ( 9999 )
    8.05 ( 99999 )
    9999 ( 9999 )
        Day 5: Oseltamivir (n = 1, 0, 0)
    7.92 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 5: Oseltamivir Carboxylate (n = 1, 0, 0)
    7.92 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Elimination Rate Constant (ke) of Oseltamivir and Oseltamivir Carboxylate

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    End point title
    		 Elimination Rate Constant (ke) of Oseltamivir and Oseltamivir Carboxylate
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1: 15 minutes pre-infusion start, 1, 2, 3, 4, 6, 8, 12 hours post start of infusion; Day 2, 3 (with or after fifth dose), 4 or 5: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    End point values
    		 Oseltamivir - overall
    Number of subjects analysed
    0 [27]
    Units: 1/hour
        geometric mean (geometric coefficient of variation)
    ( )
    Notes
    [27] - Data not available as no participant was evaluable for this endpoint.
    No statistical analyses for this end point

    Secondary: Total Clearance of Drug (CL) of Oseltamivir and Oseltamivir Carboxylate

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    End point title
    		 Total Clearance of Drug (CL) of Oseltamivir and Oseltamivir Carboxylate
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1: 15 minutes pre-infusion start, 1, 2, 3, 4, 6, 8, 12 hours post start of infusion; Day 2, 3 (with or after fifth dose), 4 or 5: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    End point values
    		 Oseltamivir - overall
    Number of subjects analysed
    0 [28]
    Units: liters per hour (L/hour)
        geometric mean (geometric coefficient of variation)
    ( )
    Notes
    [28] - Data not available as no participant was evaluable for this endpoint.
    No statistical analyses for this end point

    Secondary: Volume of Distribution (V) of Oseltamivir and Oseltamivir Carboxylate

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    End point title
    		 Volume of Distribution (V) of Oseltamivir and Oseltamivir Carboxylate
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1: 15 minutes pre-infusion start, 1, 2, 3, 4, 6, 8, 12 hours post start of infusion; Day 2, 3 (with or after fifth dose), 4 or 5: 15 minutes pre-infusion start, 2, 4, 8 hours after start of infusion
    End point values
    		 Oseltamivir - overall
    Number of subjects analysed
    0 [29]
    Units: liters
        geometric mean (geometric coefficient of variation)
    ( )
    Notes
    [29] - Data not collected because of changes in planned analysis, due to early study termination.
    No statistical analyses for this end point

    Secondary: 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
    		 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, >=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 participants 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 time-point.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 1, 6 and 30
    End point values
    		 Oseltamivir - overall Oseltamivir: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Number of subjects analysed
    6
    2
    3
    1
    Units: participants
        Day 1 (n=6, 2, 3, 1)
    1
    0
    1
    0
        Day 6 (n=1, 0, 1, 0)
    1
    9999
    1
    9999
        Day 30 (n=1, 1, 0, 0)
    0
    0
    9999
    9999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Oseltamivir - overall
    Reporting group description
    		 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 body weight. Participants with body weight <=23 kg received 3 mg/kg; participants with body weight >23 kg to 40 kg received 2.5 mg/kg; and participants with body weight >40 kg received 100 mg. 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: 6 to 12 Years
    Reporting group description
    		 Participants aged 6 to 12 years received oseltamivir twice daily IV over 5 or 6 days for a total of 10 doses. The oseltamivir doses were based on participant’s body weight. Participants with body weight <=23 kg received 3 mg/kg; participants with body weight ˃23 kg to 40 kg received 2.5 mg/kg; and participants with body weight >40 kg received 100 mg. 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: 3 to 5 Years
    Reporting group description
    		 Participants aged 3 to 5 years received oseltamivir twice daily IV over 5 or 6 days for a total of 10 doses. The oseltamivir doses were based on participant’s body weight. Participants with body weight <=23 kg received 3 mg/kg; participants with body weight ˃23 kg to 40 kg received 2.5 mg/kg; and participants with body weight ˃40 kg received 100 mg. 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: 1 to 2 Years
    Reporting group description
    		 Participants aged 1 to 2 Years received oseltamivir twice daily IV over 5 or 6 days for a total of 10 doses. The oseltamivir doses were based on participant’s body weight. Participants with body weight <=23 kg received 3 mg/kg; participants with body weight ˃23 kg to 40 kg received 2.5 mg/kg; and participants with body weight ˃40 kg received 100 mg. 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 - overall Oseltamivir: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 2 (50.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 2 (50.00%)
    0 / 5 (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
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Oseltamivir - overall Oseltamivir: 6 to 12 Years Oseltamivir: 3 to 5 Years Oseltamivir: 1 to 2 Years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 8 (62.50%)
    0 / 2 (0.00%)
    4 / 5 (80.00%)
    1 / 1 (100.00%)
    Investigations
    Body Temperature Increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Cardiac disorders
    Left Ventricular Dysfunction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    General disorders and administration site conditions
    Catheter Site Erosion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Device Expulsion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Drug Withdrawal Syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    0
    1
    Infusion Site Erythema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Ingrowing Nail
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pain of Skin
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Mar 2010
    • Provided additional information regarding oseltamivir central nervous system (CNS) distribution • Modified the requirements of IV therapy for a specified number of days and provided clarification on dosing for participants on continuous renal replacement therapy • Removed optional blood pressure monitoring in children <5 years of age and clarified the study population and excluded medication • Provided an updated schedule with amended timepoints • Reduced the maximum concentration of IV oseltamivir to 1 milligrams per milliliter (mg/mL) • Specified that adverse events (AEs) were to be graded based on the Division of Acquired Immune Deficiency Syndrome (AIDS) table for grading the severity of adult and pediatric AEs
    13 May 2010
    • Updated the synopsis to reflect changes in the protocol text • Corrected the exposure data • Modified dosing in participants with moderate renal impairment • Revised Exclusion Criterion 1 to accommodate participants with moderate renal impairment • Specified in the PD assessments section that, for participants who were discharged prior to Study Day 6, it was preferred that the participant returned to the clinic to have the swabs collected on the mornings of Study Day 3 or 4 since PK sampling could occur on Study Day 3 or 4 depending on the time of day (am or pm) initial dose was administered • Corrected the pH value listed for the reconstituted solution of Tamiflu • Increased the flexibility of PK sampling by specifying in the PK assessments section that sample collection (1) could occur on a day other than Study Day 1 due to operational logistics, and (2) could occur on Study Day 3 or 4 depending on the time of day (am or pm) that the initial dose was administered • Added dosing recommendation for participants with renal impairment
    19 Sep 2011
    • Added results from nonclinical studies in juvenile animals • Added clinical experience with the IV formulation text based on results from the previously ongoing adult multiple-dose Study NP25140 • Updated the exposure margins based on data from the multiple-dose IV Study NP25140 • Clarified the day of treatment completion depending on when dosing was started and whether one or two doses were received on Study Day 1 • Changed the upper limit of the range for moderate renal impairment from 50 milliliters per minute (mL/min) to 60 mL/min to reflect the most recent Food and Drug Administration (FDA) Guidance • 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 to allow flexibility in PK sampling and clarification regarding blood collection

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Dec 2012
    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
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