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    Clinical Trial Results:
    A Multicenter, Study of the Safety of Oseltamivir Administered Intravenously for the Treatment of Influenza in Patients Aged >=13 Years

    Summary
    EudraCT number
    		 2010-020083-38
    Trial protocol
    		 HU   DE   LT   DK   FR   IT   ES   PL  
    Global end of trial date
    14 Sep 2012

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NV25118
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01050257
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Sep 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Sep 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Sep 2012
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety of oseltamivir administered by intravenous infusion in the treatment of influenza (seasonal or pandemic [H1N1] 2009 influenza).
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and good clinical practices (GCP) guidelines, or with the laws of the country if these afforded greater protection. Written informed consent for participation in the study was obtained prior to performing any study-specific assessments or procedures. Participants had the right to withdraw from the study at any time for any reason.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jan 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
    Romania: 10
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    United States: 64
    Worldwide total number of subjects
    118
    EEA total number of subjects
    54
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    90
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of the 122 participants screened, 118 were enrolled into the study. Participants were enrolled at 38 active centers in 6 countries.

    Pre-assignment
    Screening details
    		 This study included a 5-day treatment period and an optional extension treatment period. Participants were considered to have completed treatment if they completed the 5-day course of treatment (IV and/or oral).

    Period 1
    Period 1 title
    Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oseltamivir 100 mg IV bid
    Arm description
    		 Participants received 100 mg of oseltamivir administered by controlled IV infusion over 2 hours, twice daily (bid), for 5 days. A minimum of 6 doses (3 days) of IV oseltamivir was required. Thereafter, at the discretion of the investigator, participants had the option of completing the 5-day course with either IV or oral oseltamivir.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oseltamivir (intravenous)
    Investigational medicinal product code
    Ro 64-0796/F09-01
    Other name
    Oseltamivir phosphate
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous oseltamivir was administered by slow infusion over 2 hours, every 12 hours.

    Investigational medicinal product name
    Oseltamivir capsules (75 mg)
    Investigational medicinal product code
    Other name
    Oseltamivir phosphate
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral oseltamivir was administered as 75 mg capsules for the randomized treatment groups. Participants randomized to the 100 mg IV treatment group who switched to oral therapy received one 75 mg capsule twice daily.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo capsule was administered twice daily to participants randomized to the 100 mg IV treatment group who switched to oral therapy.

    Arm title
    		 Oseltamivir 200 mg IV bid
    Arm description
    		 Participants received 200 mg of oseltamivir administered by controlled IV infusion over 2 hours, every 12 hours, for 5 days. A minimum of 6 doses (3 days) of IV oseltamivir was required. Thereafter, at the discretion of the investigator, participants had the option of completing the 5-day course with either IV or oral oseltamivir.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oseltamivir (intravenous)
    Investigational medicinal product code
    Ro 64-0796/F09-01
    Other name
    Oseltamivir phosphate
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous oseltamivir was administered by slow infusion over 2 hours, every 12 hours.

    Investigational medicinal product name
    Oseltamivir capsules (75 mg)
    Investigational medicinal product code
    Other name
    Oseltamivir phosphate
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral oseltamivir was administered as 75 mg capsules for the randomized treatment groups. Participants randomized to the 200 mg IV treatment group who switched to oral therapy received two 75 mg capsules twice daily.

    Arm title
    		 Oseltamivir open-label
    Arm description
    		 Participants with moderate/severe renal impairment or renal failure were offered a 5-day course of treatment with IV oseltamivir at a dosage of 40 mg bid or 40 mg once daily (qd), depending on their creatinine clearance range and whether or not they were on continuous renal replacement therapy (CRRT). For participants with moderate or severe renal impairment who did not receive the full treatment course intravenously, oral oseltamivir was supplied as 30 mg capsules in an open-label fashion. Participants on hemodialysis (HD) received 25 mg IV after every HD session. Participants on continuous ambulatory peritoneal dialysis (CAPD) received a single IV dose of 40 mg. For participants on HD or CAPD who switched to oral dosing during the treatment extension period, oral oseltamivir was supplied as 30 mg capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oseltamivir (intravenous)
    Investigational medicinal product code
    Ro 64-0796/F09-01
    Other name
    Oseltamivir phosphate
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In participants with moderate renal impairment, 40 mg dose was given as a slow IV infusion over 2 hours every 12 hours. In participants with severe renal impairment, 40 mg dose was given as a slow IV infusion over 2 hours every 24 hours.

    Investigational medicinal product name
    Oseltamivir capsules (30 mg)
    Investigational medicinal product code
    Other name
    oseltamivir phosphate
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    For participants with moderate or severe renal impairment who did not receive the full treatment course intravenously, oral oseltamivir was supplied as 30 mg capsules in an open-label fashion. Participants with moderate renal impairment received one 30 mg capsule twice daily, while participants with severe renal impairment received one 30 mg capsule once daily.

    Number of subjects in period 1
    		Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Started
    50
    53
    15
    Completed
    39
    40
    8
    Not completed
    11
    13
    7
         Violation criteria
    -
    1
    -
         Failure to return
    -
    2
    -
         No reason specified
    -
    -
    2
         withdrawal by subject
    -
    3
    -
         Death
    -
    -
    1
         Adverse event
    4
    4
    2
         Refused treatment/did not cooperate
    1
    1
    -
         Admin/other (did not switch to oral)
    6
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oseltamivir 100 mg IV bid
    Reporting group description
    		 Participants received 100 mg of oseltamivir administered by controlled IV infusion over 2 hours, twice daily (bid), for 5 days. A minimum of 6 doses (3 days) of IV oseltamivir was required. Thereafter, at the discretion of the investigator, participants had the option of completing the 5-day course with either IV or oral oseltamivir.

    Reporting group title
    Oseltamivir 200 mg IV bid
    Reporting group description
    		 Participants received 200 mg of oseltamivir administered by controlled IV infusion over 2 hours, every 12 hours, for 5 days. A minimum of 6 doses (3 days) of IV oseltamivir was required. Thereafter, at the discretion of the investigator, participants had the option of completing the 5-day course with either IV or oral oseltamivir.

    Reporting group title
    Oseltamivir open-label
    Reporting group description
    		 Participants with moderate/severe renal impairment or renal failure were offered a 5-day course of treatment with IV oseltamivir at a dosage of 40 mg bid or 40 mg once daily (qd), depending on their creatinine clearance range and whether or not they were on continuous renal replacement therapy (CRRT). For participants with moderate or severe renal impairment who did not receive the full treatment course intravenously, oral oseltamivir was supplied as 30 mg capsules in an open-label fashion. Participants on hemodialysis (HD) received 25 mg IV after every HD session. Participants on continuous ambulatory peritoneal dialysis (CAPD) received a single IV dose of 40 mg. For participants on HD or CAPD who switched to oral dosing during the treatment extension period, oral oseltamivir was supplied as 30 mg capsules.

    Reporting group values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label Total
    Number of subjects
    		 50 53 15 118
    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 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 2 2 0 4
        Adults (18-64 years)
    		 41 43 6 90
        From 65-84 years
    		 7 8 9 24
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.8 ( 16.68 ) 44.3 ( 18.09 ) 66.9 ( 18.28 ) -
    Gender categorical
    Units: Subjects
        Female
    		 25 27 8 60
        Male
    		 25 26 7 58

    End points

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    End points reporting groups
    Reporting group title
    Oseltamivir 100 mg IV bid
    Reporting group description
    		 Participants received 100 mg of oseltamivir administered by controlled IV infusion over 2 hours, twice daily (bid), for 5 days. A minimum of 6 doses (3 days) of IV oseltamivir was required. Thereafter, at the discretion of the investigator, participants had the option of completing the 5-day course with either IV or oral oseltamivir.

    Reporting group title
    Oseltamivir 200 mg IV bid
    Reporting group description
    		 Participants received 200 mg of oseltamivir administered by controlled IV infusion over 2 hours, every 12 hours, for 5 days. A minimum of 6 doses (3 days) of IV oseltamivir was required. Thereafter, at the discretion of the investigator, participants had the option of completing the 5-day course with either IV or oral oseltamivir.

    Reporting group title
    Oseltamivir open-label
    Reporting group description
    		 Participants with moderate/severe renal impairment or renal failure were offered a 5-day course of treatment with IV oseltamivir at a dosage of 40 mg bid or 40 mg once daily (qd), depending on their creatinine clearance range and whether or not they were on continuous renal replacement therapy (CRRT). For participants with moderate or severe renal impairment who did not receive the full treatment course intravenously, oral oseltamivir was supplied as 30 mg capsules in an open-label fashion. Participants on hemodialysis (HD) received 25 mg IV after every HD session. Participants on continuous ambulatory peritoneal dialysis (CAPD) received a single IV dose of 40 mg. For participants on HD or CAPD who switched to oral dosing during the treatment extension period, oral oseltamivir was supplied as 30 mg capsules.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all participants who received at least one dose of study medication (IV or oral) and had a safety assessment performed after initiation of treatment.

    Subject analysis set title
    Intent-to-Treat Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants who received at least one dose of study medication (IV or oral) were included in the intent-to-treat (ITT) population.

    Subject analysis set title
    Intent-to-Treat Influenza Infected (ITTI) Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The subset of participants in the ITT population who had laboratory confirmation of influenza infection (positive viral culture or RT-PCR), excluding participants infected with oseltamivir resistant influenza at baseline (as determined by phenotypic and, where necessary, genotypic testing), were included in the intent-to-treat infected (ITTI) population. The ITTI population was the primary population for the analysis of the efficacy variables.

    Subject analysis set title
    Oseltamivir open-label 40 mg IV bid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with moderate/severe renal impairment not on CRRT with creatinine clearance (CrCL) >30 to 60 millilitre/minute (mL/min), received intravenous oseltamivir at a dose of 40 mg bid. Participants who were on CRRT and who had CRRTCL ± CrCL >30 mL/min also received intravenous oseltamivir at a dose of 40 mg bid.

    Subject analysis set title
    Oseltamivir open-label 40 mg IV qd
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with moderate/severe renal impairment not on CRRT with CrCl 10 to 30 mL/min, received intravenous oseltamivir at a dose of 40 mg daily. Participants who were on CRRT and who had CRRTCL ± CrCL 10 to 30 mL/min also received intravenous oseltamivir at a dose of 40 mg daily.

    Primary: Number of participants with any adverse events or serious adverse events

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    End point title
    		 Number of participants with any adverse events or serious adverse events [1]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is any experience that suggests a significant hazard, contraindication, side effect or precaution that results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. On treatment = AEs that started between the day of first dose and within 2 days after the last dose. Off treatment = AEs that started more than 2 days after the last dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to Day 30
    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: Statistical analysis was not carried out for the primary end point.
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Number of subjects analysed
    48
    51
    14
    Units: Number of participants
        Participants with AEs On treatment (IV dosing)
    24
    27
    11
        Participants with AEs On treatment (oral dosing)
    10
    9
    4
        Participants with AEs Off treatment
    13
    13
    5
        Participants with SAEs On treatment (IV dosing)
    3
    4
    2
        Participants with SAEs On treatment (oral dosing)
    2
    0
    2
        Participants with SAEs Off treatment
    5
    1
    3
    No statistical analyses for this end point

    Secondary: Number of participants with viral shedding by culture

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    End point title
    		 Number of participants with viral shedding by culture
    End point description
    Viral culturing from throat and nasal swabs was used to confirm the occurrence of viral shedding. The presence of viral shedding was determined by means of positive viral culture = log10 TCID50 > 0.5 TCID50 = 50% tissue culture infective dose. Only participants with data available at particular timepoint were analysed. n = the number of participants analysed at the given time point.
    End point type
    Secondary
    End point timeframe
    Days 1, 4, 6, 11, 15, and 30
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Number of subjects analysed
    30
    32
    10
    Units: Number of participants
        Day 1, (n=29, 30, 10)
    22
    24
    9
        Day 4 (n=28, 28, 10)
    4
    8
    3
        Day 6 (n=22, 28, 8)
    1
    0
    0
        Day 11, (n=22, 26, 8)
    0
    1
    0
        Day 15, (n=17, 24, 7)
    0
    1
    1
        Day 30, (n=22, 28, 6)
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Number of participants with viral shedding by reverse transcriptase polymerase chain reaction

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    End point title
    		 Number of participants with viral shedding by reverse transcriptase polymerase chain reaction
    End point description
    Nasal and throat swabs from participants were used to evaluate the occurrence of viral shedding by reverse transcriptase polymerase chain reaction (RT-PCR) (log 10 copies/mL). Only participants with data available at particular time point were analysed. n = the number of participants analysed at the given time point.
    End point type
    Secondary
    End point timeframe
    Days 1, 4, 6, 11, 15, and 30
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Number of subjects analysed
    30
    32
    10
    Units: Number of participants
        Day 1 (n=29, 30, 10)
    25
    28
    9
        Day 4 (n=28, 28, 10)
    18
    20
    6
        Day 6 (n=22, 28, 8)
    9
    10
    5
        Day 11 (n=22, 26, 8)
    2
    3
    1
        Day 15 (n=17, 24, 7)
    0
    1
    0
        Day 30 (n=22, 28, 6)
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Mean change from baseline in influenza titer by culture at Day 4

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    End point title
    		 Mean change from baseline in influenza titer by culture at Day 4
    End point description
    Throat and nasal swabs from participants were used to evaluate viral load (amount of virus present) determined by culture. Positive culture was indicated by a log 10 median TCID50 > 0.5. A negative change from baseline indicated improvement (less virus present). n = the number of participants analysed at the given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Day 4
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Number of subjects analysed
    22
    24
    9
    Units: Log10 (TCID50)
    arithmetic mean (standard deviation)
        Day 4 (n = 4, 8, 3)
    -1.38 ( 1.92 )
    -2.19 ( 1.186 )
    -3 ( 0.75 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline in body temperature until last value

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    End point title
    		 Mean change from baseline in body temperature until last value
    End point description
    Body temperature was recorded twice daily from baseline up to Day 30. Body temperature is presented as the change from baseline until the last value recorded.
    End point type
    Secondary
    End point timeframe
    Baseline, up to Day 30
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Number of subjects analysed
    47
    51
    14
    Units: Centigrade (C)
        arithmetic mean (standard deviation)
    -0.81 ( 1.06 )
    -0.64 ( 0.99 )
    -0.45 ( 1.35 )
    No statistical analyses for this end point

    Secondary: Number of participants who had fever during the study

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    End point title
    		 Number of participants who had fever during the study
    End point description
    Fever is defined as a body temperature >=37.8 degrees Celcius. The number of participants with fever (on a 12-hourly basis) was reported. Only participants with fever at particular time point were analysed. n = the number of participants analysed at the given time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Hours 12, 24, 36, 48, 60, 72, 84, 96 and 108
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Number of subjects analysed
    30
    32
    10
    Units: Number of participants
        Baseline, n = 7, 6, 2
    7
    6
    2
        Hour 12, n = 7, 5, 1
    2
    3
    1
        Hour 24, n = 7, 6, 1
    2
    0
    0
        Hour 36, n = 7, 5, 2
    1
    1
    2
        Hour 48, n = 7, 6, 1
    1
    2
    0
        Hour 60, n = 5, 6, 0
    0
    2
    0
        Hour 72, n = 6, 5, 1
    0
    1
    0
        Hour 84, n = 5, 6, 0
    0
    0
    0
        Hour 96, n = 5, 6, 1
    0
    1
    0
        Hour 108, n = 5, 5, 0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Time to resolution of fever for participants who had a fever at baseline

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    End point title
    		 Time to resolution of fever for participants who had a fever at baseline
    End point description
    Participants who had fever at baseline (based on baseline temperature) were included in the time to resolution of fever (afebrile state) analysis. Fever was defined as a temperature of >= 37.8 degrees Celsius. Resolution of fever was a temperature <=37.2 for at least 21.5 hours.
    End point type
    Secondary
    End point timeframe
    Baseline, Up to Day 30
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Number of subjects analysed
    7
    6
    2 [2]
    Units: hours
        median (confidence interval 95%)
    11.8 (7.8 to 43.5)
    18.6 (8.4 to 66.8)
    47.7 (47.7 to 1000)
    Notes
    [2] - Median could not be calculated due to small number of participants analysed (1 participant censored)
    Statistical analysis title
    		 Oseltamivir 200 mg vs. Oseltamivir 100 mg
    Statistical analysis description
    The time to resolution of fever was compared for the two treatment groups (200 mg oseltamivir and 100 mg oseltamivir). Median time was estimated from the Kaplan-Meier curve. Wilcoxon test was used for testing the homogeneity of the two survival curves.
    Comparison groups
    Oseltamivir 100 mg IV bid v Oseltamivir 200 mg IV bid
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.671
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65
         upper limit
    		 29.7

    Secondary: Number of participants with influenza symptoms

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    End point title
    		 Number of participants with influenza symptoms
    End point description
    Influenza symptoms included nasal congestion, sore throat, cough, aches and pains, fatigue, chills/sweats (feverish), headache, vomiting, and diarrhea. The number of participants with influenza symptoms by study day is reported. Only participants with influenza symptoms at particular time point were analysed. n = the number of participants analysed at the given time point.
    End point type
    Secondary
    End point timeframe
    Days 1, 11, 15, 30
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Number of subjects analysed
    49
    50
    14
    Units: Number of participants
        Day 1, n= 49, 50, 14
    49
    50
    13
        Day 11, n= 41, 41, 11
    31
    32
    11
        Day 15, n=35, 38, 10
    25
    22
    9
        Day 30, n=38, 40, 9
    16
    13
    9
    No statistical analyses for this end point

    Secondary: Number of participants with viral resistance

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    End point title
    		 Number of participants with viral resistance
    End point description
    Nasal and Throat swabs were collected on Days 1, 4, 6, 11, 15 and 30 and were sent to a central laboratory for testing. Viral resistance was determined by phenotypic and genotypic testing.
    End point type
    Secondary
    End point timeframe
    Up to Day 30
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Number of subjects analysed
    30
    32
    10
    Units: Number of participants
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Calculated creatinine clearance

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    End point title
    		 Calculated creatinine clearance [3]
    End point description
    Creatinine Clearance (CrCl) was estimated according to Cockcroft-Gault for participants >=18 years and according to Schwartz equation for participants <18 years. Calculated creatinine clearance measures the rate creatinine (substance formed from metabolism of creatine) is cleared from blood by the kidneys.
    End point type
    Secondary
    End point timeframe
    Screening
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subject analysis sets - Oseltamivir open-label 40 mg IV bid and Oseltamivir open-label 40 mg IV qd contain participants from the Oseltamivir open-label arm reported in the baseline period. Data for the Oseltamivir open-label arm, for this end point, is represented via the Oseltamivir open-label 40 mg IV bid and Oseltamivir open-label 40 mg IV qd subject analysis sets.
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label 40 mg IV bid Oseltamivir open-label 40 mg IV qd
    Number of subjects analysed
    50
    49
    6
    4
    Units: mL/min
    arithmetic mean (standard deviation)
        CrCl
    113 ( 44 )
    122 ( 59 )
    39.2 ( 5.99 )
    23.3 ( 7.37 )
    No statistical analyses for this end point

    Secondary: Area under the curve at steady state of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Area under the curve at steady state of oseltamivir and oseltamivir carboxylate [4]
    End point description
    The area under the plot of plasma concentration of drug against time after drug administration is defined as the area under the curve (AUC). The area under the curve at steady state (AUCss) is the area under the curve during the steady-state period. Participants treated with oseltamivir and who had measurable concentrations of oseltamivir and oseltamivir carboxylate were included in the pharmacokinetic (PK) analysis unless major protocol deviations or unavailability of information occurred which could interfere with PK evaluation.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 5
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subject analysis sets - Oseltamivir open-label 40 mg IV bid and Oseltamivir open-label 40 mg IV qd contain participants from the Oseltamivir open-label arm reported in the baseline period. Data for the Oseltamivir open-label arm, for this end point, is represented via the Oseltamivir open-label 40 mg IV bid and Oseltamivir open-label 40 mg IV qd subject analysis sets.
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label 40 mg IV bid Oseltamivir open-label 40 mg IV qd
    Number of subjects analysed
    50
    49
    6
    4
    Units: nanogram/millilitre*hour
    arithmetic mean (standard deviation)
        AUCss, oseltamivir
    546 ( 120 )
    1120 ( 370 )
    261 ( 22.8 )
    301 ( 38.6 )
        AUCss, oseltamivir carboxylate
    5170 ( 2480 )
    10200 ( 4190 )
    7230 ( 3540 )
    13900 ( 7030 )
    No statistical analyses for this end point

    Secondary: Maximum concentration at steady state and trough concentration at the end of the dosing interval of oseltamivir and oseltamivir carboxylate

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    End point title
    		 Maximum concentration at steady state and trough concentration at the end of the dosing interval of oseltamivir and oseltamivir carboxylate [5]
    End point description
    The Plasma Concentration (Cmax) is defined as the maximum observed drug/analyte concentration. The trough concentration is defined as the plasma level of a drug measured just before the next dose. Trough concentration at the end of the dosing interval (Ctr) values were computed over the 12-hour or 24-hour period depending on the inter-dose interval of each participant. Participants treated with oseltamivir and who had measurable concentrations of oseltamivir and oseltamivir carboxylate were included in the PK analysis unless major protocol deviations or unavailability of information occurred which could interfere with PK evaluation.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 5
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subject analysis sets - Oseltamivir open-label 40 mg IV bid and Oseltamivir open-label 40 mg IV qd contain participants from the Oseltamivir open-label arm reported in the baseline period. Data for the Oseltamivir open-label arm, for this end point, is represented via the Oseltamivir open-label 40 mg IV bid and Oseltamivir open-label 40 mg IV qd subject analysis sets.
    End point values
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label 40 mg IV bid Oseltamivir open-label 40 mg IV qd
    Number of subjects analysed
    50
    49
    6
    4
    Units: nanogram/millilitre
    arithmetic mean (standard deviation)
        Cmax oseltamivir
    230 ( 44.5 )
    468 ( 116 )
    108 ( 8.08 )
    121 ( 11.9 )
        Cmax oseltamivir carboxylate
    555 ( 251 )
    1100 ( 422 )
    721 ( 327 )
    845 ( 403 )
        Ctr oseltamivir
    0.554 ( 0.454 )
    1.5 ( 2.51 )
    0.34 ( 0.0991 )
    0.00344 ( 0.0025 )
        Ctr oseltamivir carboxylate
    292 ( 164 )
    573 ( 270 )
    451 ( 248 )
    302 ( 186 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within 2 days after last dose of treatment
    Adverse event reporting additional description
    An AE can be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. All AEs (related and unrelated) occurring during the treatment period were reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Oseltamivir 100 mg IV bid
    Reporting group description
    		 Participants received 100 mg of oseltamivir administered by controlled IV infusion over 2 hours, every 12 hours, for 5 days. A minimum of 6 doses (3 days) of IV oseltamivir was required. Thereafter, at the discretion of the investigator, participants had the option of completing the 5-day course with either IV or oral oseltamivir.

    Reporting group title
    Oseltamivir 200 mg IV bid
    Reporting group description
    		 Participants received 200 mg of oseltamivir administered by controlled IV infusion over 2 hours, every 12 hours, for 5 days. A minimum of 6 doses (3 days) of IV oseltamivir was required. Thereafter, at the discretion of the investigator, participants had the option of completing the 5-day course with either IV or oral oseltamivir.

    Reporting group title
    Oseltamivir open-label
    Reporting group description
    		 Participants with moderate/severe renal impairment or renal failure were offered a 5-day course of treatment with IV oseltamivir at a dosage of 40 mg bid or 40 mg once daily qd, depending on their creatinine clearance range and whether or not they were on CRRT. For participants with moderate or severe renal impairment who did not receive the full treatment course intravenously, oral oseltamivir was supplied as 30 mg capsules in an open-label fashion. Participants on HD received 25 mg IV after every HD session. Participants on CAPD received a single IV dose of 40 mg. For participants on HD or CAPD who switched to oral dosing during the treatment extension period, oral oseltamivir was supplied as 30 mg capsules.

    Serious adverse events
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 48 (10.42%)
    4 / 51 (7.84%)
    4 / 14 (28.57%)
         number of deaths (all causes)
    1
    1
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 51 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 51 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 51 (1.96%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 51 (1.96%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 51 (1.96%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 51 (0.00%)
    0 / 14 (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 distress
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 51 (1.96%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lung infection pseudomonal
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 51 (1.96%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 51 (0.00%)
    0 / 14 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Oseltamivir 100 mg IV bid Oseltamivir 200 mg IV bid Oseltamivir open-label
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 48 (35.42%)
    18 / 51 (35.29%)
    10 / 14 (71.43%)
    Investigations
    Blood magnesium decreased
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 51 (1.96%)
    1 / 14 (7.14%)
         occurrences all number
    3
    1
    1
    Hypotension
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    Cardiac disorders
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 48 (2.08%)
    4 / 51 (7.84%)
    2 / 14 (14.29%)
         occurrences all number
    1
    4
    2
    Dizziness
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    General disorders and administration site conditions
    Infusion site pain
         subjects affected / exposed
    3 / 48 (6.25%)
    4 / 51 (7.84%)
    0 / 14 (0.00%)
         occurrences all number
    3
    5
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 51 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    0
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 48 (12.50%)
    1 / 51 (1.96%)
    1 / 14 (7.14%)
         occurrences all number
    8
    1
    1
    Vomiting
         subjects affected / exposed
    3 / 48 (6.25%)
    4 / 51 (7.84%)
    0 / 14 (0.00%)
         occurrences all number
    3
    4
    0
    Constipation
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 51 (5.88%)
    1 / 14 (7.14%)
         occurrences all number
    2
    3
    1
    Diarrhoea
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 51 (1.96%)
    0 / 14 (0.00%)
         occurrences all number
    4
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 51 (1.96%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Asthma
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Pneumomediastinum
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 51 (1.96%)
    1 / 14 (7.14%)
         occurrences all number
    4
    1
    1
    Agitation
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    Delirium
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 51 (1.96%)
    2 / 14 (14.29%)
         occurrences all number
    3
    1
    2
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 51 (1.96%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 51 (1.96%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 51 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    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
    20 May 2010
    Enrollment to participants outside of the US was opened. Participants with renal impairment and renal failure were enrolled and treated. New guidelines for the preparation of IV investigational product for the randomized population (change in infusion volume from 50 mL to 100 mL) were provided.
    14 Oct 2011
    Participants undergoing HD and CAPD could be switched from IV to oral dosing. Oral dosing recommendations for participants with renal impairment were updated as a result of the availability of lower dose oseltamivir capsules and the desire to better align oral dosing recommendations with those anticipated for IV oseltamivir. This amendment allowed enrollment of participants up to 144 hours after the onset of first influenza symptoms to allow for the enrollment of participants who may have started on oral oseltamivir and whose condition then necessitated IV oseltamivir. The creatinine clearance cutoff value in moderate renal impairment was corrected from 50 to 60 mL/min to be consistent with available regulatory guidance and prior clinical studies of oseltamivir in participants with renal impairment.

    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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