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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Pharmacokinetics, Safety, and Antiviral Activity of JNJ-63623872 in Combination With Oseltamivir in Adult and Elderly Hospitalized Patients With Influenza A Infection

    Summary
    EudraCT number
    		 2015-003002-17
    Trial protocol
    		 SE   BE   DE   NL   ES  
    Global end of trial date
    15 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2018
    First version publication date
    31 Mar 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    63623872FLZ2002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International, NV
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, 2340
    Public contact
    Janssen-Cilag International, NV, Clinical Registry group, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Janssen-Cilag International, NV, Clinical Registry group, ClinicalTrialsEU@its.jnj.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
    15 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the pharmacokinetic (PK) parameters of pimodivir in combination with oseltamivir (OST) in elderly subjects (aged 65 to less than or equal to [<=] 85 years) compared to adults (aged 18 to <= 64 years) with influenza A infection.
    Protection of trial subjects
    Safety evaluations included monitoring of adverse events (AEs), clinical laboratory tests (hematology, serum chemistry, and urinalysis), vital signs measurements, physical examinations, electrocardiography (ECGs), pregnancy testing and specific toxicities.
    Background therapy
    		 All subjects received OST
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jan 2016
    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
    Belgium: 3
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Malaysia: 7
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    99
    EEA total number of subjects
    52
    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)
    0
    Adults (18-64 years)
    60
    From 65 to 84 years
    38
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total 194 subjects were screened, 102 were randomized out of which 99 treated.

    Period 1
    Period 1 title
    Overall (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
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid
    Arm description
    		 Subjects received Pimodivir 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily (bid) for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the estimated glomerular filtration rate (eGFR) value.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pimodivir 600 milligram (mg)
    Investigational medicinal product code
    JNJ-63623872
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Pimodivir 600 mg (2*300 mg tablets) orally twice daily for 7 days.

    Investigational medicinal product name
    Oseltamivir 75 mg bid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received oseltamivir 75 mg capsules orally twice daily for 7 days.

    Arm title
    		 Pimodivir placebo bid + Oseltamivir 75 mg bid
    Arm description
    		 Subjects received placebo matched to pimodivir tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the eGFR value.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to Pimodivir tablets orally twice daily for 7 days

    Investigational medicinal product name
    Oseltamivir 75 mg bid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received oseltamivir 75 mg capsules orally twice daily for 7 days.

    Number of subjects in period 1
    		Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Started
    64
    35
    Completed
    55
    30
    Not completed
    9
    5
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    8
    3
         Adverse event, non-fatal
    -
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pimodivir 600 mg bid + Oseltamivir 75 mg bid
    Reporting group description
    		 Subjects received Pimodivir 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily (bid) for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the estimated glomerular filtration rate (eGFR) value.

    Reporting group title
    Pimodivir placebo bid + Oseltamivir 75 mg bid
    Reporting group description
    		 Subjects received placebo matched to pimodivir tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the eGFR value.

    Reporting group values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid Total
    Number of subjects
    		 64 35 99
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 39 21 60
        From 65 to 84 years
    		 24 14 38
        85 years and over
    		 1 0 1
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.1 ( 16.06 ) 57.2 ( 13.71 ) -
    Title for Gender
    Units: subjects
        Female
    		 27 18 45
        Male
    		 37 17 54

    End points

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    End points reporting groups
    Reporting group title
    Pimodivir 600 mg bid + Oseltamivir 75 mg bid
    Reporting group description
    		 Subjects received Pimodivir 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily (bid) for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the estimated glomerular filtration rate (eGFR) value.

    Reporting group title
    Pimodivir placebo bid + Oseltamivir 75 mg bid
    Reporting group description
    		 Subjects received placebo matched to pimodivir tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the eGFR value.

    Subject analysis set title
    Elderly Adults
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received Pimodivir 600 milligram (mg) or matching placebo to Pimodivir tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 to 30 and vice versa during the course of treatment based on the estimated glomerular filtration rate (eGFR) value.

    Subject analysis set title
    Non-elderly Adults
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received Pimodivir 600 milligram (mg) or matching placebo to Pimodivir tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the eGFR value.

    Primary: Maximum Observed Plasma Concentration (Cmax) of Pimodivir

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Pimodivir
    End point description
    Cmax is the maximum observed plasma concentration. Pharmacokinetic (PK) population included all randomized participants who received at least 1 dose of the study drug and with 1 PK blood sample.Here 'n' signifies number of subjects analyzed for under specific age groups for whom Cmax could be determined.
    End point type
    Primary
    End point timeframe
    Pre-dose, 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 3
    End point values
    		 Elderly Adults Non-elderly Adults
    Number of subjects analysed
    15
    20
    Units: nanogram per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    5933 ( 4427 )
    5378 ( 3888 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Elderly Adults v Non-elderly Adults
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    111.71
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 70.7
         upper limit
    		 176.52

    Primary: Minimum Observed Plasma Concentration (Cmin) of Pimodivir

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    End point title
    		 Minimum Observed Plasma Concentration (Cmin) of Pimodivir
    End point description
    Cmin is the minimum observed plasma concentration. PK population included all randomized participants who received at least 1 dose of the study drug and with 1 PK blood sample. Here 'N' signifies number of subjects who were evaluable for this endpoint. Here 'n' signifies number of subjects analyzed for specific arm under specific age groups for whom Cmin could be determined.
    End point type
    Primary
    End point timeframe
    Pre-dose, 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 3
    End point values
    		 Elderly Adults Non-elderly Adults
    Number of subjects analysed
    15
    21
    Units: ng/mL
        arithmetic mean (standard deviation)
    738 ( 892 )
    507 ( 414 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Elderly Adults v Non-elderly Adults
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    104.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 62.14
         upper limit
    		 177.33

    Primary: Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 hours After Dosing (AUC [0-12])

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    End point title
    		 Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 hours After Dosing (AUC [0-12])
    End point description
    The AUC(0-12) was the area under the plasma concentration-time curve from time zero to 12 hours. PK population included all randomized participants who received at least 1 dose of the study drug and with 1 PK blood sample. Here 'n' signifies number of subjects analyzed under specific age groups for whom AUC[0-12] could be determined.
    End point type
    Primary
    End point timeframe
    Pre-dose, 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 3
    End point values
    		 Elderly Adults Non-elderly Adults
    Number of subjects analysed
    15
    20
    Units: nanogram*hour per milliliter (ng*h/mL)
        arithmetic mean (standard deviation)
    27386 ( 25191 )
    20101 ( 11063 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Elderly Adults v Non-elderly Adults
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    116.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 76.49
         upper limit
    		 176.22

    Secondary: Median Time to Influenza Viral Negativity

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    End point title
    		 Median Time to Influenza Viral Negativity
    End point description
    Time to influenza viral negativity was measured based on quantitative reverse transcription polymerase chain reaction (qRT-PCR) and/or viral culture from nasal mid-turbinate (MT) swabs and, if applicable, based on PCR-based rapid molecular testing from nasal MT swabs. Full Analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A.
    End point type
    Secondary
    End point timeframe
    Up to Day 14
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    63
    32
    Units: days
        median (confidence interval 95%)
    9.53 (8.55 to 12.68)
    9.74 (6.67 to 12.99)
    No statistical analyses for this end point

    Secondary: Influenza Viral Load Over Time

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    End point title
    		 Influenza Viral Load Over Time
    End point description
    Viral load over time was measured by qRT-PCR and/or viral culture. Full analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A. Here 'n' signifies number of subjects analyzed for specific time point. 99999 indicates that the data was not estimable due no subject was evaluable.
    End point type
    Secondary
    End point timeframe
    Up to Day 14
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    63
    32
    Units: Log10 viral particles/milliliter (vp/mL)
    median (full range (min-max))
        Baseline (n=58, n=30)
    5.64 (0.0 to 8.4)
    5.83 (3.1 to 9.1)
        Day 1 (n=4, n=1)
    6.57 (5.4 to 7.0)
    4.43 (4.43 to 4.43)
        Day 2 (n=57, n=28)
    4.87 (2.1 to 7.1)
    4.67 (0.0 to 7.3)
        Day 3 (n=45, n=24)
    3.93 (0.0 to 6.8)
    4.10 (0.0 to 6.9)
        Day 4 (n=34, n=15)
    3.31 (0.0 to 5.1)
    3.15 (0.0 to 5.6)
        Day 5 (n=55, n=28)
    2.67 (0.0 to 7.5)
    2.78 (0.0 to 6.5)
        Day 6 (n=14, n=6)
    2.63 (0.0 to 4.0)
    1.66 (0.0 to 5.2)
        Day 7 (n=14, n=5)
    2.12 (0.0 to 4.7)
    3.34 (0.0 to 4.4)
        Day 8 (n=55, n=20)
    2.12 (0.0 to 5.9)
    1.06 (0.0 to 5.1)
        Day 9 (n=7, n=1)
    2.12 (0.0 to 2.12)
    0.0 (0.0 to 0.0)
        Day 10 (n=54, n=23)
    0.0 (0.0 to 5.7)
    0.0 (0.0 to 3.3)
        Day 11 (n=6, n=1)
    0.0 (0.0 to 2.5)
    0.0 (0.0 to 0.0)
        Day 12 (n=2, n=0)
    1.06 (0.0 to 2.1)
    99999 (-99999 to 99999)
        Day 13 (n=2, n=0)
    1.06 (-99999 to 2.1)
    99999 (-99999 to 99999)
        Day 14 (n=51, n=22)
    0.0 (0.0 to 5.3)
    0.0 (0.0 to 2.3)
    No statistical analyses for this end point

    Secondary: Rate of Change in Viral Load

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    End point title
    		 Rate of Change in Viral Load
    End point description
    Rate of change in viral load during treatment as measured by qRT-PCR and/or viral culture. Full analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A. Here 'N' signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to Day 14
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    63
    32
    Units: Log10 vp/mL/day
        median (confidence interval 95%)
    -0.35 (-0.39 to -0.30)
    -0.42 (-0.49 to -0.35)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve (AUC) of Viral Load

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    End point title
    		 Area Under the Plasma Concentration-Time Curve (AUC) of Viral Load
    End point description
    The AUC of viral load as measured by quantitative polymerase chain reaction (qRT-PCR) and/or viral culture. Full analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A.
    End point type
    Secondary
    End point timeframe
    Up to Day 8
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    63
    32
    Units: days*vp/mL
        arithmetic mean (confidence interval 95%)
    22.8 (20.4 to 25.1)
    22.1 (19.0 to 25.2)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Influenza Complications

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    End point title
    		 Percentage of Subjects with Influenza Complications
    End point description
    Disease status and incidence of complications associated with influenza were: bacterial pneumonia (culture confirmed where possible), other bacterial superinfections, respiratory failure, pulmonary disease (example, asthma, chronic obstructive pulmonary disease [COPD]), cardiovascular and cerebrovascular disease (example, myocardial infarction, congestive heart failure [CHF], arrhythmia, stroke). Full analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    63
    32
    Units: Percentage of subjects
    number (not applicable)
        All Complications
    7.9
    15.6
        Bacterial Pneumonia
    0
    0
        Bacterial Superinfections
    1.6
    3.1
        Respiratory Failure
    1.6
    0
        Pulmonary Disease
    3.2
    6.3
        Cardiovascular and Cerebrovascular Disease
    1.6
    0
        Post-baseline ICU Admission
    1.6
    0
        All-cause Mortality
    1.6
    0
        Other
    3.2
    6.3
    No statistical analyses for this end point

    Secondary: Change in Duration and Severity of Clinical Symptoms as Measured by the FLU-PRO through Day 33

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    End point title
    		 Change in Duration and Severity of Clinical Symptoms as Measured by the FLU-PRO through Day 33
    End point description
    Change in duration and severity of clinical symptoms as measured by the influenza patient-reported outcome questionnaire (FLU-PRO). The FLU-PRO total score is computed as a mean score across 32 items contained by the instrument. The total score ranges from 0 (symptom free) to 4 (very severe symptoms). Analysis set is defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A. Here 'n' signifies number of subjects analyzed for specific arm. 99999 indicates that the data was not estimable due to less number of events.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 33
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    63
    32
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 1 (n=20, n=16)
    -0.08 ( 0.247 )
    -0.11 ( 0.349 )
        Day 2 (n=35, n=20)
    -0.48 ( 0.644 )
    -0.33 ( 0.798 )
        Day 3 (n=38, n=22)
    -0.60 ( 0.624 )
    -0.52 ( 0.641 )
        Day 4 (n=35, n=19)
    -0.71 ( 0.702 )
    -0.56 ( 0.625 )
        Day 5 (n=33, n=17)
    -0.76 ( 0.689 )
    -0.67 ( 0.643 )
        Day 6 (n=33, n=17)
    -0.85 ( 0.692 )
    -0.75 ( 0.659 )
        Day 7 (n=33, n=17)
    -0.87 ( 0.738 )
    -0.69 ( 0.623 )
        Day 8 (n=33, n=18)
    -0.89 ( 0.729 )
    -0.80 ( 0.764 )
        Day 9 (n=31, n=20)
    -0.93 ( 0.764 )
    -0.84 ( 0.732 )
        Day 10 (n=32, n=20)
    -0.91 ( 0.723 )
    -0.81 ( 0.743 )
        Day 11 (n=28, n=18)
    -0.87 ( 0.756 )
    -0.76 ( 0.534 )
        Day 12 (n=29, n=18)
    -0.87 ( 0.725 )
    -0.89 ( 0.695 )
        Day 13 (n=28, n=20)
    -0.93 ( 0.702 )
    -0.94 ( 0.650 )
        Day 14 (n=29, n=19)
    -0.85 ( 0.613 )
    -0.92 ( 0.670 )
        Day 15 (n=25, n=15)
    -0.88 ( 0.630 )
    -0.90 ( 0.724 )
        Day 16 (n=23, n=14)
    -0.84 ( 0.588 )
    -0.90 ( 0.762 )
        Day 17 (n=22, n=15)
    -0.98 ( 0.690 )
    -0.97 ( 0.774 )
        Day 18 (n=19, n=15)
    -1.06 ( 0.753 )
    -1.00 ( 0.868 )
        Day 19 (n=21, n=13)
    -1.06 ( 0.749 )
    -1.05 ( 0.880 )
        Day 20 (n=21, n=15)
    -1.03 ( 0.710 )
    -1.03 ( 0.847 )
        Day 21 (n=22, n=16)
    -1.00 ( 0.701 )
    -0.98 ( 0.849 )
        Day 22 (n=18, n=15)
    -1.02 ( 0.789 )
    -0.92 ( 0.690 )
        Day 23 (n=21, n=14)
    -1.11 ( 0.858 )
    -0.96 ( 0.731 )
        Day 24 (n=19, n=11)
    -0.87 ( 0.534 )
    -0.91 ( 0.580 )
        Day 25 (n=17, n=11)
    -0.94 ( 0.659 )
    -0.85 ( 0.661 )
        Day 26 (n=18, n=11)
    -0.86 ( 0.755 )
    -0.87 ( 0.742 )
        Day 27 (n=15, n=8)
    -1.02 ( 0.745 )
    -0.74 ( 0.734 )
        Day 28 (n=12, n=7)
    -0.60 ( 0.505 )
    -0.82 ( 0.675 )
        Day 29 (n=2, n=2)
    -1.13 ( 0.354 )
    -1.63 ( 0.398 )
        Day 30 (n=2, n=0)
    -0.61 ( 0.552 )
    99999 ( 99999 )
        Day 31 (n=1, n=0)
    -0.75 ( 99999 )
    99999 ( 99999 )
        Day 32 (n=2, n=0)
    -0.61 ( 0.420 )
    99999 ( 99999 )
        Day 33 (n=1, n=0)
    -0.94 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Time to Improvement of Vital Signs

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    End point title
    		 Time to Improvement of Vital Signs
    End point description
    The time to improvement of vital signs is defined as the time from first study treatment to when at least 4 of 5 symptoms (temperature, blood oxygen saturation, heart rate, SBP, respiration rate) are recovered, including normalization of temperature and blood oxygen saturation. Full analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A. Here 'N' signifies number of subjects who were evaluable for this endpoint. 99999 indicates that the upper limit of CI was not estimable due to less number of events.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    60
    28
    Units: hour
        median (confidence interval 95%)
    169.92 (46.63 to 99999)
    69.90 (35.83 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Improvement of Respiratory Status

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    End point title
    		 Time to Improvement of Respiratory Status
    End point description
    Time to improvement of respiratory status is defined as normalization of blood oxygen saturation and respiration rate. Full analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A. Here 'N' signifies number of subjects who were evaluable for this endpoint. 99999 indicates that the upper limit of CI was not estimable due to less number of events.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    60
    28
    Units: hour
        median (confidence interval 95%)
    33.53 (21.33 to 241.92)
    40.57 (22.75 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects by Ordinal Scale Category

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    End point title
    		 Percentage of Subjects by Ordinal Scale Category
    End point description
    The ordinal scale will be used to assess participant's status and consists of 6 categories or clinical states that are exhaustive, mutually exclusive, and ordered, where 1- Death, 2- Admitted to Intensive Care Unit (ICU) or mechanically ventilated/ extracorporeal membrane oxygenation (ECMO), 3- Non-ICU plus supplemental oxygen, 4- Non-ICU plus no supplemental oxygen, 5- Not hospitalized (NH), but unable to continue activity, 6- Not hospitalized and continues activities.Full Analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A. Here 'n' signifies number of subjects analyzed for specific category.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    63
    32
    Units: Percentage of subjects
    number (not applicable)
        Baseline (n=63,32) Non-ICU+No Supplemental Oxygen
    49.2
    59.4
        Baseline (n=63,32) Non-ICU+Supplemental Oxygen
    50.8
    40.6
        Day 8 (n=62,31) NH and Continues Activities
    40.3
    29.0
        Day 8 (n=62,31)NH, but Unable to Continue Activity
    27.4
    45.2
        Day 8 (n=62,31) Non-ICU+No Supplemental Oxygen
    14.5
    6.5
        Day 8 (n=62,31) Non-ICU+Supplemental Oxygen
    8.1
    3.2
        Day 8 (n=62,31) Death
    1.6
    0
        Day 8 (n=62,31) Missing
    8.1
    16.1
    No statistical analyses for this end point

    Secondary: Number of Subjects with the Emergence of Drug Resistance Mutations with Oseltamivir (OST) and Pimodivir

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    End point title
    		 Number of Subjects with the Emergence of Drug Resistance Mutations with Oseltamivir (OST) and Pimodivir
    End point description
    The number of subjects with the emergence (from Baseline) of drug resistance mutations was measured. Full Analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 28
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    63
    32
    Units: subjects
    number (not applicable)
        Emergence of Pimodivir Mutation
    0
    0
        Emergence of OST Mutation
    0
    1
    No statistical analyses for this end point

    Secondary: Time to Return to Premorbid Functional Status

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    End point title
    		 Time to Return to Premorbid Functional Status
    End point description
    Time to return to premorbid functional (time to return usual activities) status was evaluated. Full Analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A. Here 'N' signifies number of subjects who were evaluable for this endpoint. 99999 indicates that the data was not estimable due to less number of events.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    60
    32
    Units: hour
        median (confidence interval 95%)
    142.85 (83.27 to 220.15)
    154.83 (74.97 to 386.52)
    No statistical analyses for this end point

    Secondary: Time to Hospital Discharge

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    End point title
    		 Time to Hospital Discharge
    End point description
    Time to hospital discharge in days will be analyzed using an accelerated failure time model (if the data provide an acceptable model fit) or alternatively a Cox proportional hazards model (in case the hazards are proportional). Full analysis set was defined as all randomly assigned subjects who received at least 1 dose of study drug and who have a confirmed infection with influenza A.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    63
    32
    Units: days
        median (confidence interval 95%)
    4.00 (3.00 to 5.00)
    4.00 (3.00 to 4.00)
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects Reporting Treatment-Emergent Adverse Events (TEAEs)
    End point description
    TEAEs are defined as adverse events with onset or worsening on or after date of first dose of study treatment. An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. The Safety Analysis Set included all enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Pimodivir 600 mg bid + Oseltamivir 75 mg bid Pimodivir placebo bid + Oseltamivir 75 mg bid
    Number of subjects analysed
    64
    35
    Units: subjects
    48
    25
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening up to Follow-up (up to Day 28)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Pimodivir 600 mg bid + oseltamivir 75 mg bid
    Reporting group description
    		 Subjects received Pimodivir 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily (bid) for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the estimated glomerular filtration rate (eGFR) value.

    Reporting group title
    Pimodivir placebo bid + oseltamivir 75 mg bid
    Reporting group description
    		 Subjects received matching placebo to Pimodivir tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the eGFR value.

    Serious adverse events
    		 Pimodivir 600 mg bid + oseltamivir 75 mg bid Pimodivir placebo bid + oseltamivir 75 mg bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 64 (17.19%)
    4 / 35 (11.43%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder outlet obstruction
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Pimodivir 600 mg bid + oseltamivir 75 mg bid Pimodivir placebo bid + oseltamivir 75 mg bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 64 (70.31%)
    24 / 35 (68.57%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Chills
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Face oedema
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 35 (2.86%)
         occurrences all number
    4
    1
    Malaise
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 35 (0.00%)
         occurrences all number
    3
    0
    Pyrexia
         subjects affected / exposed
    4 / 64 (6.25%)
    0 / 35 (0.00%)
         occurrences all number
    4
    0
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Bronchospasm
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    4 / 64 (6.25%)
    4 / 35 (11.43%)
         occurrences all number
    4
    4
    Dyspnoea
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Haemothorax
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Increased upper airway secretion
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal discomfort
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Sneezing
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Hallucination
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 35 (0.00%)
         occurrences all number
    3
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    International normalised ratio
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Liver function test increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Troponin increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Post-traumatic pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Dizziness postural
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    7 / 64 (10.94%)
    3 / 35 (8.57%)
         occurrences all number
    7
    4
    Paraesthesia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Restless legs syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Syncope
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Polycythaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Splenomegaly
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Eye disorders
    Amaurosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Eye pruritus
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Eyelid oedema
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Photopsia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Abdominal pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Cheilitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    13 / 64 (20.31%)
    4 / 35 (11.43%)
         occurrences all number
    14
    4
    Dry mouth
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 35 (2.86%)
         occurrences all number
    4
    1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Gingival pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    9 / 64 (14.06%)
    5 / 35 (14.29%)
         occurrences all number
    9
    5
    Oral pain
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    6 / 64 (9.38%)
    2 / 35 (5.71%)
         occurrences all number
    6
    2
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Hepatic steatosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Dyshidrotic eczema
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Prurigo
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Nocturia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Proteinuria
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Urinary hesitation
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Arthritis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Muscle spasms
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Neck pain
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Infections and infestations
    Hepatitis c
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Gout
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2015
    The overall reason for the amendment INT-1 to remove text regarding inclusion of the adolescent population and accordingly, the sample size justification was re-written based on FDA feedback.
    09 Dec 2015
    The overall reason for the amendment INT-2 add a urine pregnancy test (for females of childbearing potential) was added to Day 5 procedures and a hierarchal ordinal scale for clinical outcome was added as a secondary efficacy endpoint based on feedback by Food and Drug Administration (FDA).
    19 Sep 2016
    The overall reason for the amendment INT-3 was to correct exclusion criteria.

    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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