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    Clinical Trial Results:
    A phase IIIb, open-label, comparative, randomized study on resistance of Influenza A/H1N1 2009 virus to treatment with Oseltamivir at standard dose versus double dose

    Summary
    EudraCT number
    		 2016-001044-18
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    06 Oct 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jan 2017
    First version publication date
    06 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML22789
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00949533
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Oct 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Oct 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This open-label randomized 2 arm study determined the emergence of viral resistance in participants with seasonal influenza A infection treated with oseltamivir. Eligible participants less than or equal to (</=) 5 years of age were randomized to receive oseltamivir at either standard dose (30-75 milligrams [mg] orally twice daily [bid]) or double dose (60-150 mg orally bid) for 5 days.
    Protection of trial subjects
    This protocol and all materials sent to other participating sites or participants were submitted by the investigators to the respective Independent Ethics Committees (IEC) at their research sites. IEC approvals, obtained before the study started, were recorded in opinions, addressed to the Investigators, specifying the date when such documents were analyzed and approved. All modifications effected on the protocol, after the first approval had been granted by the IEC, were submitted by the investigators to their respective IECs, according to local regulatory requirements. The Sponsor was aware that the study protocol (and all subsequent changes), as well as the informed consent procedure, had been reviewed and approved by each site's IEC. These Committees worked in accordance to Federal Regulations in force. The approval document was sent by the investigator to the Sponsor at the beginning of the study and no change was made to the protocol without knowledge of both the Sponsor and the IEC.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Aug 2009
    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
    Brazil: 37
    Worldwide total number of subjects
    37
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    8
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    24
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Out of 199 participants, 162 were considered as screening failures, mainly due to the negative result detected by the quick test for Influenza A Antigen. Therefore, 37 participants included in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard Dose
    Arm description
    		 Oseltamivir capsule was administered orally at a dose of 75 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Other name
    Tamiflu
    Pharmaceutical forms
    Powder for oral suspension, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oseltamivir capsule was administered orally at a dose of 75mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.

    Arm title
    		 Double Dose
    Arm description
    		 Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Other name
    Tamiflu
    Pharmaceutical forms
    Capsule, Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.

    Number of subjects in period 1
    		Standard Dose Double Dose
    Started
    19
    18
    Completed
    19
    17
    Not completed
    0
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard Dose
    Reporting group description
    		 Oseltamivir capsule was administered orally at a dose of 75 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.

    Reporting group title
    Double Dose
    Reporting group description
    		 Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.

    Reporting group values
    		 Standard Dose Double Dose Total
    Number of subjects
    		 19 18 37
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 21.6 ± 11 22 ± 12.7 -
    Gender, Male/Female
    Units: participants
        Female
    		 11 9 20
        Male
    		 8 9 17

    End points

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    End points reporting groups
    Reporting group title
    Standard Dose
    Reporting group description
    		 Oseltamivir capsule was administered orally at a dose of 75 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.

    Reporting group title
    Double Dose
    Reporting group description
    		 Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/mL) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.

    Primary: Percentage of Participants Excreting Resistant Virus

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    End point title
    		 Percentage of Participants Excreting Resistant Virus
    End point description
    Resistant virus included new influenza A virus subtype hemagglutinin type 1 and neuraminidase type 1 (New AH1N1). Intention-to-treat (ITT) population included all enrolled participants who received at least one dose of the study drug.
    End point type
    Primary
    End point timeframe
    Day 5
    End point values
    		 Standard Dose Double Dose
    Number of subjects analysed
    19
    17
    Units: percentage of participants
        number (not applicable)
    26.3
    35.3
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Double Dose v Standard Dose
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.825
    Method
    		 Pearson Chi-Square
    Confidence interval

    Secondary: Percentage of Participants With A Reduction in Viral Load

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    End point title
    		 Percentage of Participants With A Reduction in Viral Load
    End point description
    Viral load is defined as the amount of H1N1 virus in blood As per investigator, a participant was considered as having viral load reduction at Day 5 if the Day 5 viral load was lower than the Baseline viral load. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 5
    End point values
    		 Standard Dose Double Dose
    Number of subjects analysed
    19
    18
    Units: percentage of participants
        number (not applicable)
    100
    100
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Standard Dose v Double Dose
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Number of Participants With Various Clinical Signs and Symptoms

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    End point title
    		 Number of Participants With Various Clinical Signs and Symptoms
    End point description
    Number of participants with various clinical signs and symptoms, as per investigator's discretion, were reported. Same participants were reported in more than 1 category. "Other" in the category included abdominal pain, breathlessness, thoracic pain and tired. ITT population. Here "number of participants analyzed" included evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    Day 5
    End point values
    		 Standard Dose Double Dose
    Number of subjects analysed
    19
    17
    Units: participants
    number (not applicable)
        Cough
    10
    9
        Rhinorrhea
    10
    5
        Sore throat
    2
    2
        Shortness of breath
    2
    1
        Diarrhea
    2
    0
        Headache
    1
    2
        Conjunctivitis
    1
    0
        Vomiting
    1
    0
        Other
    4
    0
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Cough: statistical difference between 2 groups was based on chi-squared test.
    Comparison groups
    Standard Dose v Double Dose
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Rhinorrhea: statistical difference between 2 groups was based on chi-squared test.
    Comparison groups
    Standard Dose v Double Dose
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.284
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Sore throat: statistical difference between 2 groups was based on fisher-exact test.
    Comparison groups
    Standard Dose v Double Dose
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Shortness of breath: statistical difference between 2 groups was based on fisher-exact test.
    Comparison groups
    Standard Dose v Double Dose
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Diarrhea: statistical difference between 2 groups was based on fisher-exact test.
    Comparison groups
    Standard Dose v Double Dose
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.487
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    Conjunctivitis: statistical difference between 2 groups was based on fisher-exact test.
    Comparison groups
    Standard Dose v Double Dose
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical analysis 7
    Statistical analysis description
    Headache: statistical difference between 2 groups was based on fisher-exact test.
    Comparison groups
    Standard Dose v Double Dose
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.593
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical analysis 8
    Statistical analysis description
    Vomiting: statistical difference between 2 groups was based on fisher-exact test.
    Comparison groups
    Standard Dose v Double Dose
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical analysis 9
    Statistical analysis description
    Other: statistical difference between 2 groups was based on fisher-exact test.
    Comparison groups
    Standard Dose v Double Dose
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.106
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Number of Participants With Various Clinical Signs and Symptoms in Whom Resistant Virus Were Detected

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    End point title
    		 Number of Participants With Various Clinical Signs and Symptoms in Whom Resistant Virus Were Detected
    End point description
    Number of participants with various clinical signs and symptoms, as per investigator's discretion, in whom new AH1N1 virus was detected, were reported. Same participants were reported in more than 1 category. ITT population. Here "number of participants analyzed" included evaluable participants for the outcome measure.
    End point type
    Secondary
    End point timeframe
    Day 5
    End point values
    		 Standard Dose Double Dose
    Number of subjects analysed
    5
    6
    Units: participants
    number (not applicable)
        Cough
    3
    4
        Rhinorrhea
    3
    3
        Shortness of breath
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 12 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    0.0
    Reporting groups
    Reporting group title
    Double Dose
    Reporting group description
    		 Oseltamivir capsule was administered orally at a dose of 150 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/ml) based on their body weight with a starting dose of 60 mg BID to a maximum dose of 150 mg BID; for 5 days.

    Reporting group title
    Standard Dose
    Reporting group description
    		 Oseltamivir capsule was administered orally at a dose of 75 mg BID in adult participants and children received oseltamivir powder for oral suspension dose (at 12 mg/ml) based on their body weight with a starting dose of 30 mg BID to a maximum dose of 75 mg BID; for 5 days.

    Serious adverse events
    		 Double Dose Standard Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double Dose Standard Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 18 (38.89%)
    8 / 19 (42.11%)
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Feeling hot
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Tracheobronchitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Dyspepsia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Epigastric discomfort
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Abdominal cramps
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Nausea
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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