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    Clinical Trial Results:
    An open label, prospective, pharmacokinetic/pharmacodynamic and safety evaluation of oseltamivir (Tamiflu®) in the treatment of infants 0 to less than 12 months of age with confirmed influenza infection.

    Summary
    EudraCT number
    		 2009-014365-12
    Trial protocol
    		 ES   FR   DE   GB   BE   NL   IT  
    Global end of trial date
    04 Jun 2014

    Results information
    Results version number
    		 v1
    This version publication date
    01 Apr 2016
    First version publication date
    01 Apr 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    WP22849
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00988325
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH 4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000365-PIP01-08
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jun 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Apr 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To define the pharmacokinetics of oseltamivir and oseltamivir carboxylate in children with confirmed influenza up to one year of age.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and ICH E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all participants and/or their legally authorized representative. Participants signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jan 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Belgium: 2
    Worldwide total number of subjects
    65
    EEA total number of subjects
    65
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    5
    Infants and toddlers (28 days-23 months)
    60
    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
    		 The study was conducted across 11 centers in Spain, Italy, France, Germany, Belgium, and Poland from 10 January 2011 to 04 April 2012.

    Pre-assignment
    Screening details
    		 A total of 65 participants were enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oseltamivir 3 mg
    Arm description
    		 Participants aged 91 to <365 days received oral suspension of oseltamivir 3 milligram/kilogram (mg/kg) twice a day for 5 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Ro 64-0796
    Other name
    Tamiflu
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The investigational medicinal product (IMP) was provided as 75 mg oseltamivir capsules; however, this was compounded to final concentration of the 10 milligram per milliliter (mg/mL) of oseltamivir in water. It was referred as a bottle of compounded suspension and was used while administering the prescribed dose.

    Arm title
    		 Oseltamivir 2.5 mg
    Arm description
    		 Participants aged 31 to 90 days received oral suspension of oseltamivir 2.5 mg/kg twice a day for 5 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Ro 64-0796
    Other name
    Tamiflu
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The investigational medicinal product (IMP) was provided as 75 mg oseltamivir capsules; however, this was compounded to final concentration of the 10 milligram per milliliter (mg/mL) of oseltamivir in water. It was referred as a bottle of compounded suspension and was used while administering the prescribed dose.

    Arm title
    		 Oseltamivir 2 mg
    Arm description
    		 Participants aged 0 to 30 days received oral suspension of oseltamivir 2 mg/kg twice a day for 5 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Ro 64-0796
    Other name
    Tamiflu
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The investigational medicinal product (IMP) was provided as 75 mg oseltamivir capsules; however, this was compounded to final concentration of the 10 milligram per milliliter (mg/mL) of oseltamivir in water. It was referred as a bottle of compounded suspension and was used while administering the prescribed dose.

    Number of subjects in period 1
    		Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Started
    40
    20
    5
    Completed
    40
    20
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oseltamivir 3 mg
    Reporting group description
    		 Participants aged 91 to <365 days received oral suspension of oseltamivir 3 milligram/kilogram (mg/kg) twice a day for 5 days.

    Reporting group title
    Oseltamivir 2.5 mg
    Reporting group description
    		 Participants aged 31 to 90 days received oral suspension of oseltamivir 2.5 mg/kg twice a day for 5 days.

    Reporting group title
    Oseltamivir 2 mg
    Reporting group description
    		 Participants aged 0 to 30 days received oral suspension of oseltamivir 2 mg/kg twice a day for 5 days.

    Reporting group values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg Total
    Number of subjects
    		 40 20 5 65
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 5 5
        Infants and toddlers (28 days-23 months)
    		 40 20 0 60
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 19 8 2 29
        Male
    		 21 12 3 36

    End points

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    End points reporting groups
    Reporting group title
    Oseltamivir 3 mg
    Reporting group description
    		 Participants aged 91 to <365 days received oral suspension of oseltamivir 3 milligram/kilogram (mg/kg) twice a day for 5 days.

    Reporting group title
    Oseltamivir 2.5 mg
    Reporting group description
    		 Participants aged 31 to 90 days received oral suspension of oseltamivir 2.5 mg/kg twice a day for 5 days.

    Reporting group title
    Oseltamivir 2 mg
    Reporting group description
    		 Participants aged 0 to 30 days received oral suspension of oseltamivir 2 mg/kg twice a day for 5 days.

    Subject analysis set title
    Pharmacokinetic population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic (PK) population included all treated participants with at least one blood sample evaluable for drug concentration level and who adhered to the protocol.

    Subject analysis set title
    Intent to treat infection (ITTI) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITTI population consisted of all infants who had a positive PCR or viral culture at baseline or any time after first dose dministration and was same as pharmacodynamics (PD) population.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Safety population included all treated participants with at least one post-baseline safety assessment (vital sings like temperature, respiratory rate, blood pressure, pulse rate).

    Subject analysis set title
    Reporting group: Genotype A (H1N1)pdm09
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Genotype A (H1N1)pdm09 was present in 21 participants of age group 91 to <365 days, 9 participants of age group 31 to 90 days, and 2 participants of age group less than or equal to (<=) 30 days.

    Subject analysis set title
    Reporting group: Genotype A H3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Genotype Type A H3 was present in 4 participants and 6 participants of age groups 91 to <365 days and 31 to 90 days, respectively.

    Subject analysis set title
    Reporting group: Genotype B
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Genotype B was present in 12, 2, and 2 participants of age groups <365 days, 31 to 90 days, and <=30 days, respectively.

    Primary: Mean steady state area under plasma concentration time curve time zero to 12 hours of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Mean steady state area under plasma concentration time curve time zero to 12 hours of oseltamivir and oseltamivir carboxylate [1]
    End point description
    Oseltamivir carboxylate is an active metabolite of oseltamivir. At steady state, area under curve from time zero to 12 hours (AUC0-12) was estimated for oseltamivir and oseltamivir carboxylate by linear trapezoidal rule. This analysis was performed on PK population. As the EudraCT portal does not accept ‘not estimated’, we have presented an arbitrary value (99999999) for the same.
    End point type
    Primary
    End point timeframe
    15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses were taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose was taken 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 performed for this end point.
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    37 [2]
    17 [3]
    4 [4]
    Units: hour*nanogram/milliliter (h*ng/mL)
    geometric mean (geometric coefficient of variation)
        Oseltamivir, n=37, 17, 4
    277 ( 36.2 )
    194 ( 47.8 )
    142 ( 48.8 )
        Oseltamivir carboxylate, n=18,11, 2
    4990 ( 27.4 )
    4920 ( 35.3 )
    99999999 ( 99999999 )
    Notes
    [2] - Data is presented for the participants available at the time of assessment.
    [3] - Data is presented for the participants available at the time of assessment.
    [4] - Data is presented for the participants available at the time of assessment.
    No statistical analyses for this end point

    Primary: Mean steady-state maximum observed plasma concentration of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Mean steady-state maximum observed plasma concentration of oseltamivir and oseltamivir carboxylate [5]
    End point description
    Oseltamivir carboxylate is an active metabolite of oseltamivir. Maximum observed plasma concentration was estimated for both oseltamivir and oseltamivir carboxylate by non-compartmental analysis. This analysis was performed on PK population.
    End point type
    Primary
    End point timeframe
    15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses were taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose was taken on Day 1
    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 performed for this end point.
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    37 [6]
    17 [7]
    4 [8]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir, n=37, 17, 4
    80.8 ( 47 )
    62.5 ( 69.1 )
    25.2 ( 211.6 )
        Oseltamivir carboxylate, , n=18, 11, 2
    464 ( 37.7 )
    530 ( 33.1 )
    501 ( 22.2 )
    Notes
    [6] - Data is presented for the participants available at the time of assessment.
    [7] - Data is presented for the participants available at the time of assessment.
    [8] - Data is presented for the participants available at the time of assessment.
    No statistical analyses for this end point

    Primary: Mean steady-state minimum observed plasma concentration of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Mean steady-state minimum observed plasma concentration of oseltamivir and oseltamivir carboxylate [9]
    End point description
    Oseltamivir carboxylate is active metabolite of oseltamivir. Minimum observed plasma concentration was estimated for both oseltamivir and oseltamivir carboxylate by non-compartmental analysis. This analysis was performed on PK population.
    End point type
    Primary
    End point timeframe
    15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses were taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose was taken on Day 1
    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 performed for this end point.
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    37 [10]
    17 [11]
    4 [12]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir, n=37, 17, 4
    2.88 ( 65.4 )
    2.09 ( 52.6 )
    2.56 ( 90 )
        Oseltamivir carboxylate, n=18, 11, 2
    238 ( 43.8 )
    248 ( 51.5 )
    169 ( 96.4 )
    Notes
    [10] - Data is presented for the participants available at the time of assessment.
    [11] - Data is presented for the participants available at the time of assessment.
    [12] - Data is presented for the participants available at the time of assessment.
    No statistical analyses for this end point

    Secondary: Median time to the maximum observed plasma concentration of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Median time to the maximum observed plasma concentration of oseltamivir and oseltamivir carboxylate
    End point description
    Oseltamivir carboxylate is an active metabolite of oseltamivir. Time for required to attend maximum plasma concentration was estimated using non-compartmental methods. This analysis was performed on PK population.
    End point type
    Secondary
    End point timeframe
    15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses were taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose was taken on Day 1
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    37 [13]
    17 [14]
    4 [15]
    Units: hour
    median (full range (min-max))
        Oseltamivir, n=37, 17, 4
    1.08 (0.88 to 3.08)
    1.08 (0 to 2.92)
    1.08 (1 to 3)
        Oseltamivir carboxylate, n=18, 11, 2
    5.04 (2.08 to 7)
    2.88 (0 to 6.67)
    5.83 (2.58 to 6.67)
    Notes
    [13] - Data is presented for the participants available at the time of assessment.
    [14] - Data is presented for the participants available at the time of assessment.
    [15] - Data is presented for the participants available at the time of assessment.
    No statistical analyses for this end point

    Secondary: Mean apparent elimination half life of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Mean apparent elimination half life of oseltamivir and oseltamivir carboxylate
    End point description
    Elimination half life is defined as the time required for elimination of a drug to half its plasma concentration and was computed using non-compartmental method. This analysis was performed on PK population. As the EudraCT portal does not accept ‘not estimated’, we have presented an arbitrary value (99999999) for the same.
    End point type
    Secondary
    End point timeframe
    15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses were taken on Day 1 or 15 minutes pre-dose; 1 hour +/-15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose was taken on Day 1
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    37 [16]
    17 [17]
    4 [18]
    Units: hours
    geometric mean (geometric coefficient of variation)
        Oseltamivir, n= 37, 17, 4
    2.02 ( 38.5 )
    2.01 ( 49.3 )
    1.66 ( 41.5 )
        Oseltamivir carboxylate, n=18, 11, 2
    9.45 ( 53.3 )
    11.3 ( 92.7 )
    99999999 ( 99999999 )
    Notes
    [16] - Data is presented for the participants available at the time of assessment.
    [17] - Data is presented for the participants available at the time of assessment.
    [18] - Data is presented for the participants available at the time of assessment.
    No statistical analyses for this end point

    Secondary: Mean apparent first-order elimination rate constant of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Mean apparent first-order elimination rate constant of oseltamivir and oseltamivir carboxylate
    End point description
    Oseltamivir carboxylate is active metabolite of oseltamivir. The apparent first-order elimination rate constant was determined by linear regression analysis of terminal data points. A minimum of 3 data points were used for lambda Z estimation. By reporting tool convention, if n<3, no summary statistics were calculated. This analysis was performed on PK population. As the EudraCT portal does not accept ‘not estimated’, we have presented an arbitrary value (99999999) for the same.
    End point type
    Secondary
    End point timeframe
    15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses were taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose was taken on Day 1
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    37 [19]
    17 [20]
    4 [21]
    Units: 1/hour
    geometric mean (geometric coefficient of variation)
        Oseltamivir, n= 37, 17, 4
    0.349 ( 39.9 )
    0.338 ( 52.9 )
    0.418 ( 41.5 )
        Oseltamivir carboxylate, n=18, 11, 2
    0.0735 ( 55.2 )
    0.0475 ( 110.6 )
    99999999 ( 99999999 )
    Notes
    [19] - Data is presented for the participants available at the time of assessment.
    [20] - Data is presented for the participants available at the time of assessment.
    [21] - Data is presented for the participants available at the time of assessment.
    No statistical analyses for this end point

    Secondary: Mean total plasma clearance as a function of bioavailability and apparent plasma clearance of the metabolite as a function of bioavailability of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Mean total plasma clearance as a function of bioavailability and apparent plasma clearance of the metabolite as a function of bioavailability of oseltamivir and oseltamivir carboxylate
    End point description
    Oseltamivir carboxylate is an active metabolite of oseltamivir. Total plasma clearance as a function of bioavailability was calculated as dose/AUCinf, where AUCinf represents the area under the plasma concentration-time curve of the analyte over the time interval from zero extrapolated to infinity. This analysis was performed on PK population. As the EudraCT portal does not accept ‘not estimated’, we have presented an arbitrary value (99999999) for the same.
    End point type
    Secondary
    End point timeframe
    15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses were taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose was taken on Day 1
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    37 [22]
    17 [23]
    4 [24]
    Units: mL/hour
    arithmetic mean (standard deviation)
        Oseltamivir, n= 37, 17, 4
    80500 ( 42.8 )
    63000 ( 63.7 )
    50600 ( 39.9 )
        Oseltamivir carboxylate, n=18,11, 2
    3940 ( 38.8 )
    2180 ( 54.8 )
    99999999 ( 99999999 )
    Notes
    [22] - Data is presented for the participants available at the time of assessment.
    [23] - Data is presented for the participants available at the time of assessment.
    [24] - Data is presented for the participants available at the time of assessment.
    No statistical analyses for this end point

    Secondary: Mean volume of distribution as a function of bioavailability of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Mean volume of distribution as a function of bioavailability of oseltamivir and oseltamivir carboxylate
    End point description
    Oseltamivir carboxylate is an active metabolite of oseltamivir. The volume of distribution as a function of bioavailability is defined as the theoretical volume in which the total amount of analyte would need to be uniformly distributed to produce the desired blood concentration of a drug. This analysis was performed on PK population. As the EudraCT portal does not accept ‘not estimated’, we have presented an arbitrary value (99999999) for the same.
    End point type
    Secondary
    End point timeframe
    15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses were taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose was taken on Day 1
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    37 [25]
    17 [26]
    4 [27]
    Units: mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir, n= 37, 17, 4
    234000 ( 66.2 )
    183000 ( 87.9 )
    121000 ( 69.8 )
        Oseltamivir carboxylate, n=18,11, 2
    53700 ( 78.1 )
    35400 ( 96.5 )
    99999999 ( 99999999 )
    Notes
    [25] - Data is presented for the participants available at the time of assessment.
    [26] - Data is presented for the participants available at the time of assessment.
    [27] - Data is presented for the participants available at the time of assessment.
    No statistical analyses for this end point

    Secondary: Mean time of the last measurable plasma concentration for oseltamivir and oseltamivir carboxylate

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    End point title
    		 Mean time of the last measurable plasma concentration for oseltamivir and oseltamivir carboxylate
    End point description
    Oseltamivir carboxylate is an active metabolite of oseltamivir. This analysis was performed on PK population.
    End point type
    Secondary
    End point timeframe
    15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses were taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose was taken on Day 1
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    40
    20
    5
    Units: hours
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    9.23 ( 30.1 )
    8.53 ( 32.9 )
    6.93 ( 24.2 )
        Oseltamivir carboxylate
    10.11 ( 21.2 )
    10.64 ( 5.4 )
    10.45 ( 5.3 )
    No statistical analyses for this end point

    Secondary: Number of participants with change from Baseline in neurological assessment scores over time

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    End point title
    		 Number of participants with change from Baseline in neurological assessment scores over time
    End point description
    Neurological assessment was performed to assess the mental state of the participants through two scales: Infant face scale and Glasgow coma scale. Each scale consists of 3 sub-scales: eye opening (ranging 1 to 4), verbal response (ranging 1 to 5), and motor responses (ranging 1 to 6). The final score is the sum of these ranges and is scored between 3 and 15. Three being the worst, and 15 the best. Change from Baseline (Day 1) is change of final score post-baseline minus the final score at Baseline. The final score of the participants at Baseline was reported as 15. This analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) to Day 30
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    40
    20
    5
    Units: Number of participants
        With change in infant face scale measurement
    0
    2
    0
        With change in Glasgow coma scale assessment score
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Median time to cessation of viral shedding in participants with positive culture at Baseline

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    End point title
    		 Median time to cessation of viral shedding in participants with positive culture at Baseline
    End point description
    Median time to cessation of viral shedding was calculated for all participants with positive by culture / by PCR at Baseline using all data points between the start of the treatment and the 1st time point of negative culture without subsequent positive culture results. These time-to-event analyses were only performed for the viral titre. The day when participants stopped shedding the virus and all the participants from respective groups showed negative viral culture on the corresponding days. This time point was equivalent to change from Baseline of 50% tissue culture infective dose [(log10TCID50)]. This analysis was performed using ITTI population.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) to Day 30
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    40
    20
    5
    Units: hour
    median (confidence interval 95%)
        Median time to Cessation of Viral Shedding
    228.5 (118 to 231)
    113 (63 to 230)
    113 (110 to 116)
    No statistical analyses for this end point

    Secondary: Number of participants with virus shedding by virus type over time

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    End point title
    		 Number of participants with virus shedding by virus type over time
    End point description
    The viral titer was measured by culture and reported in log10 (50% tissue culture infective dose [TCID50]). The viral load was analyzed by PCR and reported as log10 particles/mL. It analyzed the number of days required by observed number of participants to completely shed virus from their body reflecting change from Baseline in log10 (TCID50). This analysis was performed using ITTI population.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day3/4, Day 6, Day 11, Day 18, Day 30
    End point values
    		 Reporting group: Genotype A (H1N1)pdm09 Reporting group: Genotype A H3 Reporting group: Genotype B
    Number of subjects analysed
    32 [28]
    10 [29]
    16 [30]
    Units: Number of participants
        Baseline
    32
    10
    14
        Day 3 or 4
    20
    5
    14
        Day 6
    12
    4
    7
        Day 11
    32
    9
    16
        Day 18
    0
    1
    0
        Day 30
    0
    0
    0
    Notes
    [28] - Data is presented for the participants available at the time of assessment.
    [29] - Data is presented for the participants available at the time of assessment.
    [30] - Data is presented for the participants available at the time of assessment.
    No statistical analyses for this end point

    Secondary: Median time to resolution of fever in participants with fever at the Baseline

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    End point title
    		 Median time to resolution of fever in participants with fever at the Baseline
    End point description
    This was performed for all participants who had fever at Baseline. Fever is defined as body temperature > 37.0 degree Celsius. Rectal temperature is converted by subtracting 1 degree Celsius. Time to resolution of fever was defined as the time from the initiation of treatment to first time the afebrile state was reached and maintained for at least 21.5 hours, where afebrile state was defined as axillary temperature <= 37 degree Celsius. This analysis was performed on ITTI population.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) to Day 30
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    37 [31]
    17 [32]
    4 [33]
    Units: hours
    median (full range (min-max))
        Time to Resolution of Fever
    12 (9 to 17)
    20.5 (12 to 36)
    24 (14 to 43)
    Notes
    [31] - Data is presented for the participants available at the time of assessment.
    [32] - Data is presented for the participants available at the time of assessment.
    [33] - Data is presented for the participants available at the time of assessment.
    No statistical analyses for this end point

    Secondary: Percentage of participants with decline of body temperature to the afebrile state over time

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    End point title
    		 Percentage of participants with decline of body temperature to the afebrile state over time
    End point description
    This was performed for all participants who had fever at baseline Fever is defined as body temperature >37.0ºC. Rectal temperature is converted by subtracting 1 ºC. The rate of decline of body temperature was calculated as the slope of body temperature between the baseline temperature and the 1st temperature below 37°C. Participants with decline in body temperature were considered to have no fever; however, participants who did not show any decline in body temperature were considered to have persisting fever. This analysis was performed on ITTI population.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day3/4, Day 6, Day 11, Day 18, Day 30
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    33 [34]
    11 [35]
    4 [36]
    Units: Percentage of participants
        Baseline, n=33, 11, 4, decline
    36
    55
    25
        Baseline, n=33, 11, 4, no decline
    64
    45
    75
        Day 4, n=33, 11, 4, decline
    94
    91
    100
        Day 4, n=33, 11, 4, no decline
    6
    9
    0
        Day 11, n=33, 11, 4, decline
    97
    100
    100
        Day 11, n=33, 11, 4, no decline
    3
    0
    0
        Day 18, n=16, 5, 1, decline
    94
    100
    100
        Day 18, n=16, 5, 1, no decline
    6
    0
    0
        Day 30, n=31, 9, 4, decline
    97
    89
    100
        Day 30, n=31, 9, 4, no decline
    3
    11
    0
    Notes
    [34] - Participants available at a particular time of assessment were included in the analysis.
    [35] - Participants available at a particular time of assessment were included in the analysis.
    [36] - Participants available at a particular time of assessment were included in the analysis.
    No statistical analyses for this end point

    Secondary: Number of participants with adverse events, serious adverse events and secondary illness

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    End point title
    		 Number of participants with adverse events, serious adverse events and secondary illness
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. A serious adverse event (SAE) is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. Secondary illnesses were influenza disease-related events, namely bronchitis, pneumonia, otitis media, and sinusitis that resolved without sequelae. This analysis was performed using safety population.
    End point type
    Secondary
    End point timeframe
    Up to Day 23
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    40
    20
    5
    Units: Number of participants
        Participants with AEs
    17
    13
    2
        Participants with SAEs
    6
    1
    0
        Participants with secondary illness
    2
    1
    0
    No statistical analyses for this end point

    Secondary: Number of participants showing within-participant variability in vital signs

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    End point title
    		 Number of participants showing within-participant variability in vital signs
    End point description
    Systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and heart rate were examined for any consistent within-participant post-baseline changes and none were identified. Due to the small numbers of participants in a cohort and the extent of influenza induced variability, clinically significant changes in vital sign patterns cannot be detected. This analysis was performed on ITTI population.
    End point type
    Secondary
    End point timeframe
    Up to Day 30
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    40
    20
    5
    Units: Number of participants
        Participants with Variability in Vital Signs
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Mean last measurable plasma concentration of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Mean last measurable plasma concentration of oseltamivir and oseltamivir carboxylate
    End point description
    The last measurable plasma concentration of oseltamivir and oseltamivir carboxylate was the last quantifiable concentration of oseltamivir or oseltamivir carboxylate, respectively. This analysis was performed on PK population.
    End point type
    Secondary
    End point timeframe
    15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses were taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose was taken on Day 1
    End point values
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Number of subjects analysed
    40
    20
    5
    Units: h*mg/mL
    geometric mean (geometric coefficient of variation)
        Oseltamivir
    262 ( 39.2 )
    176 ( 58.3 )
    84.3 ( 154.4 )
        Oseltamivir carboxylate
    3800 ( 50.1 )
    4410 ( 34 )
    3940 ( 28.2 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 23 days
    Adverse event reporting additional description
    Serious adverse events (SAEs) and other adverse events (AEs) were reported for the safety population. Safety population included all treated participants with at least one post-baseline safety assessment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Oseltamivir 3 mg
    Reporting group description
    		 Participants aged 91 to <365 days received oral suspension of oseltamivir 3 mg/kg twice a day for 5 days.

    Reporting group title
    Oseltamivir 2.5 mg
    Reporting group description
    		 Participants aged 31 to 90 days received oral suspension of oseltamivir 2.5 mg/Kg twice a day for 5 days.

    Reporting group title
    Oseltamivir 2 mg
    Reporting group description
    		 Participants of age 0 to 30 days received oral suspension of oseltamivir 2 mg/Kg twice a day for 5 days.

    Serious adverse events
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 20 (5.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis orbital
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 20 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 20 (5.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Oseltamivir 3 mg Oseltamivir 2.5 mg Oseltamivir 2 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 40 (32.50%)
    12 / 20 (60.00%)
    2 / 5 (40.00%)
    General disorders and administration site conditions
    Crepitations
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Irritability
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 20 (10.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 20 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 20 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 20 (5.00%)
    0 / 5 (0.00%)
         occurrences all number
    4
    1
    0
    Regurgitation
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 20 (5.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    6
    2
    Vomiting
         subjects affected / exposed
    6 / 40 (15.00%)
    5 / 20 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    10
    11
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Tachypnoea
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 20 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Rash maculo−papular
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    Otitis media
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 20 (5.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Rotavirus infection
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 20 (5.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    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 Sep 2009
    a) Added a third cohort, changing the number of cohorts from two to three, such that the original second cohort (0 to < 3 months) was now Cohort II (1 to < 3 months) and Cohort III (0 to 30 days), allowing infants younger than 1 month to participate. b) Allowed dosing to continue for a further 5 days (an additional 10 doses) if the specimen collected on Day 6 was positive for influenza or the participant had viral infection symptoms.
    01 Oct 2009
    Changed the dosing of oseltamivir such that younger infants received a lower dose of oseltamivir i.e. (2.5 mg/Kg for participants of 1 to < 3 months and 2 mg/Kg for participants of 0 to 30 days), instead of all infants receiving 3 mg/Kg.
    23 Oct 2009
    Changed, at FDA request, study drug preparation such that oseltamivir dry powder was reconstituted to a suspension with a concentration of 11 mg/mL instead of 12 mg/mL.
    30 Nov 2009
    a) For consistency, changed the grading of the intensity of AEs from a 3-point scale to a 4-point scale (mild, moderate, severe, and life threatening). b) Cohorts were defined in terms of infant’s age in days instead of age in months.

    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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