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    Clinical Trial Results:
    A Phase 3, Randomized, Double Blind, Placebo Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Lumacaftor in Combination with Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del CFTR Mutation

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2012-003990-24
    Trial protocol
    BE   DE   AT   GB   ES   DK  
    Global end of trial date
    25 Apr 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    13 Jul 2016
    First version publication date
    07 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Address EudraCT System related issues & verify data

    Trial information

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    Trial identification
    Sponsor protocol code
    VX12-809-104
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01807949
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, MA, United States, 02210-1862
    Public contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
    Scientific contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001582-PIP01-13
    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
    22 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of lumacaftor in combination with ivacaftor at Week 24 in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Apr 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 42
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 36
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Germany: 48
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 335
    Worldwide total number of subjects
    559
    EEA total number of subjects
    168
    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)
    132
    Adults (18-64 years)
    427
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 187, 187, and 189 subjects were randomized in ‘Placebo’, ‘LUM 600 mg qd/IVA 250 mg q12h’, and ‘LUM 400 mg q12h/IVA 250 mg q12h’, respectively; of which 187, 185, and 187 subjects in respective groups received at least 1 dose of the study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to LUM and IVA tablet q12h, up to Week 24.

    Arm title
    LUM 400 mg q12h/IVA 250 mg q12h
    Arm description
    LUM 400 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (FDC) tablets in the morning and in the evening, up to Week 24.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    VX-809+VX-770
    Other name
    LUM+IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 400 mg plus IVA 250 mg supplied as FDC tablet in the morning and in the evening, up to Week 24.

    Arm title
    LUM 600 mg qd/IVA 250 mg q12h
    Arm description
    LUM 600 mg plus IVA 250 mg supplied as FDC tablets in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    VX-809+VX-770
    Other name
    LUM+IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 600 mg plus IVA 250 mg supplied as FDC tablet in the morning up to week 24.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    IVA
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor 250 mg film-coated tablet in the evening up to Week 24.

    Number of subjects in period 1
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Started
    187
    187
    185
    Completed
    185
    180
    180
    Not completed
    2
    7
    5
         Consent withdrawn by subject
    1
    2
    2
         Non-Compliance
    -
    1
    -
         Undefined
    -
    2
    1
         Adverse Events
    1
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24.

    Reporting group title
    LUM 400 mg q12h/IVA 250 mg q12h
    Reporting group description
    LUM 400 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (FDC) tablets in the morning and in the evening, up to Week 24.

    Reporting group title
    LUM 600 mg qd/IVA 250 mg q12h
    Reporting group description
    LUM 600 mg plus IVA 250 mg supplied as FDC tablets in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.

    Reporting group values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h Total
    Number of subjects
    187 187 185 559
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    25.7 ( 10.02 ) 25 ( 9.03 ) 24.3 ( 8.31 ) -
    Gender categorical
    Units: Subjects
        Female
    97 98 96 291
        Male
    90 89 89 268

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24.

    Reporting group title
    LUM 400 mg q12h/IVA 250 mg q12h
    Reporting group description
    LUM 400 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (FDC) tablets in the morning and in the evening, up to Week 24.

    Reporting group title
    LUM 600 mg qd/IVA 250 mg q12h
    Reporting group description
    LUM 600 mg plus IVA 250 mg supplied as FDC tablets in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.

    Primary: Absolute Change from Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24

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    End point title
    Absolute Change from Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24
    End point description
    Absolute change from baseline at week 24 was assessed as the average treatment effect at Week 16 and at Week 24. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 12 to 17 years and for female subjects aged 12 to 15 years. Analysis was performed on Full Analysis Set (FAS) included all randomized subjects who received any amount of study drug. Here, number of subject analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16 and 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    183
    180
    181
    Units: percent predicted of FEV1
        least squares mean (standard error)
    -0.15 ( 0.539 )
    2.85 ( 0.54 )
    2.46 ( 0.54 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using mixed-effects model for repeated measures (MMRM) model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
    Comparison groups
    Placebo v LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    Mixed-Effects Model for Repeated Measure
    Parameter type
    Least Squares (LS) Mean Difference
    Point estimate
    2.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.18
         upper limit
    4.06
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using MMRM model, as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.56
         upper limit
    4.44

    Secondary: Relative Change from Baseline in Percent Predicted FEV1 at Week 24

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    End point title
    Relative Change from Baseline in Percent Predicted FEV1 at Week 24
    End point description
    Assessed as the average treatment effect at Week 16 and at Week 24. FEV1 and percent predicted FEV1 are defined in primary endpoint. Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 and 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    183
    180
    181
    Units: percent change
        least squares mean (standard error)
    0 ( 0.96 )
    5.25 ( 0.961 )
    4.42 ( 0.961 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    4.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.86
         upper limit
    6.98
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using MMRM model, as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    5.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.69
         upper limit
    7.81

    Secondary: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24

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    End point title
    Absolute Change From Baseline in Body Mass Index (BMI) at Week 24
    End point description
    BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2). Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    183
    180
    180
    Units: kilogram per square meter (kg/m^2)
        least squares mean (standard error)
    0.07 ( 0.066 )
    0.43 ( 0.066 )
    0.48 ( 0.066 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline BMI.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    0.59
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using MMRM model, as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.17
         upper limit
    0.54

    Secondary: Absolute Change from Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24

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    End point title
    Absolute Change from Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24
    End point description
    The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    185
    179
    180
    Units: units on a scale
        least squares mean (standard error)
    2.81 ( 1.153 )
    5.66 ( 1.169 )
    5.02 ( 1.166 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline CFQ-R respiratory domain score.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1651
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    2.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.91
         upper limit
    5.33
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using MMRM model, as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0736
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    2.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.27
         upper limit
    5.98

    Secondary: Percentage of Subjects With Response Based on Percent Predicted FEV1

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    End point title
    Percentage of Subjects With Response Based on Percent Predicted FEV1
    End point description
    A subject was considered as a responder if the subject had >=5% increase from baseline in average percent predicted FEV1 at Week 16 and at Week 24 (relative change). FEV1 and percent predicted FEV1 are defined in primary endpoint. A subject with a missing average relative change from baseline in percent predicted FEV1 at Week 16 and at Week 24 was considered as a non-responder. Analysis was performed on FAS
    End point type
    Secondary
    End point timeframe
    Week 16 and 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    187
    187
    185
    Units: percentage of subjects
        number (not applicable)
    22.5
    41.2
    45.9
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Odds Ratio (OR) and 95% confidence intervals (Cis) are Mantel-Haenszel estimates. P values are from a Cochran-Mantel-Haenszel test stratified by sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.9568
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.8829
         upper limit
    4.6431
    Notes
    [1] - This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.3834
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.5234
         upper limit
    3.7286
    Notes
    [2] - This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.

    Secondary: Number of Pulmonary Exacerbation Events

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    End point title
    Number of Pulmonary Exacerbation Events
    End point description
    The total number of days on study is equal to the Week 24 date or the last dose date (whichever occurred last) minus the first dose date plus 1. The total number of years (48 weeks) on study is equal to the number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported. Analysis was performed on FAS.
    End point type
    Secondary
    End point timeframe
    Through Week 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    187
    187
    185
    Units: pulmonary exacerbation events per year
        number (not applicable)
    1.18
    0.67
    0.82
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using regression analysis for a negative binomial distribution with sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70) as covariates with the logarithm of time on study as the offset.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0116 [3]
    Method
    Negative Binomial Regression
    Parameter type
    Event Rate Ratio
    Point estimate
    0.6912
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5187
         upper limit
    0.9209
    Notes
    [3] - This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.0002
    Method
    Negative Binomial Regression
    Parameter type
    Event Rate Ratio
    Point estimate
    0.5659
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4191
         upper limit
    0.7641
    Notes
    [4] - This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.

    Secondary: Absolute Change from Baseline in Weight at Week 24

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    End point title
    Absolute Change from Baseline in Weight at Week 24
    End point description
    Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    183
    180
    180
    Units: kilograms (kg)
        least squares mean (standard error)
    0.44 ( 0.187 )
    1.38 ( 0.187 )
    1.57 ( 0.188 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline weight.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    1.64
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    1.46

    Secondary: Absolute Change from Baseline in BMI-for-age z-score at Week 24

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    End point title
    Absolute Change from Baseline in BMI-for-age z-score at Week 24
    End point description
    Z-Score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is with range from -infinity to +infinity; 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI-for-age z-score was calculated by using Centers for Disease Control and Prevention (CDC) growth charts for the pediatric population. Analysis was performed on FAS. Here, number of subject analyzed signifies subjects who were evaluable for this endpoint. Only subjects who were <20 years of age were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    53
    58
    54
    Units: z-score
        least squares mean (standard error)
    -0.0674 ( 0.04706 )
    0.1544 ( 0.04513 )
    0.164 ( 0.04652 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline BMI z-score.
    Comparison groups
    Placebo v LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.2313
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1037
         upper limit
    0.3589
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.2217
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.0961
         upper limit
    0.3473

    Secondary: Time-to-First Pulmonary Exacerbation

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    End point title
    Time-to-First Pulmonary Exacerbation
    End point description
    Time to first pulmonary exacerbation was assessed using Cox Regression. For subjects who completed 24 weeks of treatment, subjects without a pulmonary exacerbation before treatment completion were considered censored at the time of treatment completion or at the Week 24 Visit (whichever occurred last). For subjects who prematurely discontinued study treatment, subjects without a pulmonary exacerbation through the Week 24 Visit were considered censored at the time of the Week 24 Visit. Analysis was performed on FAS. 99999 indicates median time was not reached as less than 50% of subjects had the event of interest. The number 99999 represents data not available because median time was not reached as less than 50% of subjects had the event of interest.
    End point type
    Secondary
    End point timeframe
    Through Week 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    187
    187
    185
    Units: days
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using Cox proportional hazard regression, time is the time-to-first event or censoring, with adjustment for sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0384
    Method
    Cox Proportional Hazard Regression
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Cox Proportional Hazard Regression
    Confidence interval

    Secondary: Percentage of Subjects With At Least 1 Pulmonary Exacerbation Event

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    End point title
    Percentage of Subjects With At Least 1 Pulmonary Exacerbation Event
    End point description
    Analysis was performed on FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Through Week 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    187
    187
    185
    Units: percentage of subjects
        number (not applicable)
    47.1
    28.9
    36.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    OR and 95% confidence intervals (CIs) are Mantel-Haenszel estimates. P values are from a Cochran-Mantel-Haenszel test stratified by sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0393
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.6373
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.416
         upper limit
    0.9764
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.4429
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2863
         upper limit
    0.6851

    Secondary: Absolute Change from Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24

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    End point title
    Absolute Change from Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24
    End point description
    EQ-5D-3L: subject rated questionnaire to assess health-related quality of life. It consists of EQ-5D descriptive system and EQ-5D Visual Analog Scale (VAS). EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems (1), some problems (2), and extreme problems (3). The 5 dimensional 3-level systems are converted into a single index utility score. Values for theoretically possible health states are calculated using a regression model and weighted according to the social preferences of the Unites States (US) general population. For this population, the possible EQ-5D-3L index scores ranges from -0.11 (that is, 3 for all 5 dimensions) to 1.0 (that is, 1 for all 5 dimensions), where higher scores indicate a better health state. Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    183
    176
    178
    Units: units on a scale
        least squares mean (standard error)
    0.0117 ( 0.00673 )
    0.0108 ( 0.00683 )
    0.009 ( 0.00682 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline EQ-5D-3L index score.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7679
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -0.0028
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0211
         upper limit
    0.0156
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed as described in Statistical Analysis 1.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9214
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -0.0009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0192
         upper limit
    0.0174

    Secondary: Absolute change from Baseline in EQ-5D-3L VAS Score at Week 24

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    End point title
    Absolute change from Baseline in EQ-5D-3L VAS Score at Week 24
    End point description
    The EQ-5D-3L VAS records the subject's self-rated health on a vertical, visual analogue scale where the best state a subject can imagine is marked 100 and the worst state a subject can imagine is marked 0, higher scores indicates a better health state. Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    182
    177
    177
    Units: units on a scale
        least squares mean (standard error)
    3.3 ( 1.07 )
    6.6 ( 1.08 )
    5.7 ( 1.08 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline EQ-5D-3L VAS score.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1034
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    2.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    5.3
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis was performed as described in Statistical Analysis 1.
    Comparison groups
    Placebo v LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0262
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    3.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    6.2

    Secondary: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24

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    End point title
    Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24
    End point description
    The TSQM is a 14-item self-administered questionnaire which measures subject's experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction. Analysis was performed on FAS. Here, “n” signifies subjects who were evaluable for specified category for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    187
    187
    185
    Units: units on a scale
    least squares mean (standard error)
        Effectiveness (n = 159, 161, 161)
    -8.49 ( 1.814 )
    3.12 ( 1.793 )
    0.15 ( 1.807 )
        Side Effects (n = 157, 161, 159)
    2.03 ( 1.144 )
    -2.26 ( 1.121 )
    -1.14 ( 1.137 )
        Convenience (n = 158, 161, 160)
    4.57 ( 1.525 )
    4.88 ( 1.501 )
    4.57 ( 1.523 )
        Global Satisfaction (n= 158, 161, 160)
    -9.62 ( 1.841 )
    -2.46 ( 1.814 )
    -4.98 ( 1.845 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Effectiveness: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM effectiveness score. Actual number of subjects included in analysis were 320.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    8.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.77
         upper limit
    13.51
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Effectiveness: analysis was performed as described in Statistical Analysis 1. Actual number of subjects included in analysis were 320.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    11.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.75
         upper limit
    16.48
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Side Effects: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM side effects score. Actual number of subjects included in analysis were 316.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0403
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -3.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.21
         upper limit
    -0.14
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Side Effects: analysis was performed as described in Statistical Analysis 1. Actual number of subjects included in analysis were 318.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0054
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -4.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.31
         upper limit
    -1.28
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Convenience: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM convenience score. Actual number of subjects included in analysis were 318.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.07
         upper limit
    4.07
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Convenience: analysis was performed as described in Statistical Analysis 1. Actual number of subjects included in analysis were 319.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8777
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.74
         upper limit
    4.37
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Global Satisfaction: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM global satisfaction score. Actual number of subjects included in analysis were 318.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0668
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    4.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.32
         upper limit
    9.61
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    Global Satisfaction: analysis was performed as described in Statistical Analysis 1. Actual number of subjects included in analysis were 319.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0045
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    7.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.23
         upper limit
    12.08

    Secondary: Number of Subjects with Treatment Emergent Adverse Events (AEs) and Treatment Emergent Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects with Treatment Emergent Adverse Events (AEs) and Treatment Emergent Serious Adverse Events (SAEs)
    End point description
    AE: any untoward medical occurrence in a subject during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as Non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Analysis done on Safety Set(SS) included all randomized subjects who received any amount of study drug. Subjects were analyzed as per actual treatment received. Any AE that increased in severity or newly developed at or after the initial dosing of study drug to 28 days after the last dose is TEAE.
    End point type
    Secondary
    End point timeframe
    Up to Week 28
    End point values
    Placebo LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    186
    187
    185 [5]
    Units: subjects
    number (not applicable)
        Subjects With Treatment-Emergent AEs
    181
    177
    181
        Subjects With Treatment-Emergent SAEs
    57
    31
    51
    Notes
    [5] - Actual Number of Subjects Analyzed as per Actual Treatment Received = 186
    No statistical analyses for this end point

    Secondary: Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,avg)

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    End point title
    Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,avg) [6]
    End point description
    Ctrough, Ctrough,avg, C3-6h, and C3-6h,avg for lumacaftor, M28 lumacaftor (lumacaftor metabolite), ivacaftor, M1 ivacaftor (ivacaftor metabolite), and M6 ivacaftor (ivacaftor metabolite) were calculated. C3-6h,ave is average of individual 3 to 6 hours post-dose observed concentrations across Day 15, and Weeks 4 and 8 and Ctrough,ave is average of individual pre-dose observed concentrations across Weeks 4, 8, and 16. This endpoint was not planned to be assessed in Placebo arm. Analysis was performed on Pharmacokinetic (PK) population included all randomized subjects who received at least one dose of study drug and had a PK assessment. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint and “n” signifies subjects evaluable for specified category for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    For C3-6h: 3 to 6 hours after morning dose on Day 1 and 15, Week 4 and 8; For C3-6h,avg 3 to 6 hours after morning dose on Day 15, Week 4 and 8; For Ctrough and Ctrough,avg: before morning dose on Week 4, 8, and 16
    Notes
    [6] - 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: Pharmacokinetic (PK) analysis was not performed in subjects receiving placebo.
    End point values
    LUM 400 mg q12h/IVA 250 mg q12h LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects analysed
    182
    182
    Units: microgram per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        LUM, Day 1: C3-6h (n = 180, 181)
    20.2 ( 8.33 )
    30.8 ( 12.6 )
        LUM, Day 15: C3-6h (n = 176, 174)
    23.9 ( 8.87 )
    30.4 ( 11.2 )
        LUM, Week 4: Ctrough (n = 179, 174)
    13.2 ( 6.28 )
    8.11 ( 5.21 )
        LUM, Week 4: C3-6h (n = 168, 164)
    24.5 ( 8.75 )
    29.2 ( 12.1 )
        LUM, Week 8: Ctrough (n = 177, 177)
    12.4 ( 6.87 )
    7.87 ( 5.71 )
        LUM, Week 8: C3-6h (n = 170, 174)
    24.9 ( 9.79 )
    30.4 ( 11.6 )
        LUM, Week 16: Ctrough (n = 173, 171)
    12.2 ( 6.87 )
    7.53 ( 6.05 )
        M-28 LUM, Day 1: C3-6h (n = 180, 181)
    0.181 ( 0.079 )
    0.226 ( 0.103 )
        M-28 LUM, Day 15: C3-6h (n = 176, 174)
    1.39 ( 0.606 )
    1.43 ( 0.588 )
        M-28 LUM, Week 4: Ctrough (n = 179, 174)
    1.42 ( 0.661 )
    1.32 ( 0.68 )
        M-28 LUM, Week 4: C3-6h (n = 168, 164)
    1.45 ( 0.675 )
    1.39 ( 0.657 )
        M-28 LUM, Week 8: Ctrough (n = 177, 177)
    1.44 ( 0.722 )
    1.34 ( 0.714 )
        M-28 LUM, Week 8: C3-6h (n = 170, 174)
    1.48 ( 0.711 )
    1.41 ( 0.702 )
        M-28 LUM, Week 16: Ctrough (n = 173, 171)
    1.43 ( 0.775 )
    1.27 ( 0.763 )
        IVA, Day 1: C3-6h (n = 180, 181)
    1.36 ( 0.647 )
    1.34 ( 0.643 )
        IVA, Day 15: C3-6h (n = 176, 174)
    0.469 ( 0.282 )
    0.647 ( 0.492 )
        IVA, Week 4: Ctrough (n = 179, 174)
    0.108 ( 0.112 )
    0.164 ( 0.207 )
        IVA, Week 4: C3-6h (n = 168, 164)
    0.473 ( 0.239 )
    0.636 ( 0.38 )
        IVA, Week 8: Ctrough (n = 177, 177)
    0.102 ( 0.13 )
    0.182 ( 0.293 )
        IVA, Week 8: C3-6h (n = 170, 174)
    0.513 ( 0.277 )
    0.71 ( 0.567 )
        IVA, Week 16: Ctrough (n = 173, 171)
    0.113 ( 0.218 )
    0.163 ( 0.237 )
        M-1 IVA, Day 1: C3-6h (n = 180, 181)
    2.65 ( 1.29 )
    2.51 ( 1.3 )
        M-1 IVA, Day 15: C3-6h (n = 176, 174)
    1.85 ( 0.86 )
    2.21 ( 1.08 )
        M-1 IVA, Week 4: Ctrough (n = 179, 174)
    0.501 ( 0.455 )
    0.676 ( 0.612 )
        M-1 IVA, Week 4: C3-6h (n = 168, 164)
    1.88 ( 0.953 )
    2.11 ( 1.12 )
        M-1 IVA, Week 8: Ctrough (n = 177, 177)
    0.463 ( 0.495 )
    0.672 ( 0.704 )
        M-1 IVA, Week 8: C3-6h (n = 170, 174)
    1.91 ( 0.91 )
    2.15 ( 1.19 )
        M-1 IVA, Week 16: Ctrough (n = 173, 171)
    0.465 ( 0.449 )
    0.643 ( 0.594 )
        M-6 IVA, Day 1: C3-6h (n = 180, 181)
    0.996 ( 0.797 )
    0.993 ( 0.82 )
        M-6 IVA, Day 15: C3-6h (n = 176, 174)
    2.99 ( 1.68 )
    3.62 ( 2.18 )
        M-6 IVA, Week 4: Ctrough (n = 179, 174)
    1.64 ( 1.2 )
    1.73 ( 1.34 )
        M-6 IVA, Week 4: C3-6h (n = 168, 164)
    2.64 ( 1.45 )
    3.07 ( 1.84 )
        M-6 IVA, Week 8: Ctrough (n = 177, 177)
    1.47 ( 1.17 )
    1.6 ( 1.22 )
        M-6 IVA, Week 8: C3-6h (n = 170, 174)
    2.56 ( 1.48 )
    3 ( 2.01 )
        M-6 IVA, Week 16: Ctrough (n = 173, 171)
    1.42 ( 1.05 )
    1.51 ( 1.29 )
        LUM: Ctrough,ave (n = 182, 179)
    12.7 ( 5.6 )
    7.81 ( 4.26 )
        LUM: C3-6h,ave (n = 181, 182)
    24.3 ( 7.72 )
    29.9 ( 9.19 )
        M-28 LUM: Ctrough,ave (n = 182, 179)
    1.42 ( 0.676 )
    1.31 ( 0.672 )
        M-28 LUM: C3-6h,ave (n = 181, 182)
    1.43 ( 0.64 )
    1.41 ( 0.62 )
        IVA: Ctrough,ave (n = 182, 179)
    0.11 ( 0.124 )
    0.17 ( 0.196 )
        IVA: C3-6h,ave (n = 181, 182)
    0.484 ( 0.21 )
    0.668 ( 0.392 )
        M1-IVA: Ctrough,ave (n = 182, 179)
    0.484 ( 0.391 )
    0.66 ( 0.504 )
        M1-IVA: C3-6h,ave (n = 181, 182)
    1.87 ( 0.71 )
    2.14 ( 0.951 )
        M6-IVA: Ctrough,ave (n = 182, 179)
    1.5 ( 0.897 )
    1.6 ( 1.08 )
        M6-IVA: C3-6h,ave (n = 181, 182)
    2.7 ( 1.23 )
    3.18 ( 1.65 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 28
    Adverse event reporting additional description
    Subjects were analyzed as per actual treatment received. Other adverse events includes only non-serious AEs.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo matched to LUM and IVA tablet q12h, up to Week 24.

    Reporting group title
    LUM 600 mg qd/IVA 250 mg q12h
    Reporting group description
    LUM 600 mg plus IVA 250 mg supplied as FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.

    Reporting group title
    LUM 400 mg q12h/IVA 250 mg q12h
    Reporting group description
    LUM 400 mg plus IVA 250 mg supplied as FDC tablet in the morning and in the evening, up to Week 24.

    Serious adverse events
    Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Total subjects affected by serious adverse events
         subjects affected / exposed
    57 / 186 (30.65%)
    51 / 186 (27.42%)
    31 / 187 (16.58%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Axillary vein thrombosis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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
    Hypertension
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Deep vein thrombosis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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
    General disorders and administration site conditions
    Medical device complication
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Bronchospasm
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Haemoptysis
         subjects affected / exposed
    1 / 186 (0.54%)
    4 / 186 (2.15%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary cavitation
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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
    Suicidal ideation
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    2 / 187 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial test positive
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Injury, poisoning and procedural complications
    Suture related complication
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Post procedural haematoma
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    3 / 186 (1.61%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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
    Colitis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Ileus
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Hepatitis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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
    Proteinuria
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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
    Nephrolithiasis
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    48 / 186 (25.81%)
    36 / 186 (19.35%)
    24 / 187 (12.83%)
         occurrences causally related to treatment / all
    6 / 60
    0 / 39
    1 / 27
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Lung infection pseudomonal
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Influenza
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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 tract infection fungal
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (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
    Viraemia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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
    Viral infection
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (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
    Pneumonia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    181 / 186 (97.31%)
    179 / 186 (96.24%)
    175 / 187 (93.58%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    1
    2
    0
    Hot flush
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    2 / 187 (1.07%)
         occurrences all number
    0
    0
    2
    Orthostatic hypotension
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Peripheral coldness
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Phlebitis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    22 / 186 (11.83%)
    22 / 186 (11.83%)
    16 / 187 (8.56%)
         occurrences all number
    27
    25
    20
    Fatigue
         subjects affected / exposed
    10 / 186 (5.38%)
    13 / 186 (6.99%)
    17 / 187 (9.09%)
         occurrences all number
    11
    14
    20
    Chest discomfort
         subjects affected / exposed
    4 / 186 (2.15%)
    4 / 186 (2.15%)
    4 / 187 (2.14%)
         occurrences all number
    4
    4
    4
    Pain
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    5 / 187 (2.67%)
         occurrences all number
    2
    1
    5
    Malaise
         subjects affected / exposed
    1 / 186 (0.54%)
    4 / 186 (2.15%)
    2 / 187 (1.07%)
         occurrences all number
    1
    6
    2
    Chills
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    3 / 187 (1.60%)
         occurrences all number
    2
    1
    3
    Chest pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    3 / 187 (1.60%)
         occurrences all number
    1
    0
    3
    Medical device pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    2 / 187 (1.07%)
         occurrences all number
    1
    0
    2
    Influenza like illness
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    2
    0
    1
    Thirst
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    2 / 187 (1.07%)
         occurrences all number
    0
    2
    2
    Application site pruritus
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Sensation of foreign body
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    1
    2
    0
    Application site rash
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Asthenia
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    1
    1
    0
    Device occlusion
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Energy increased
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    2
    0
    0
    Infusion site pain
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    2
    0
    0
    Feeling jittery
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Local swelling
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    2
    0
    0
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Application site irritation
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Adverse drug reaction
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Application site reaction
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Discomfort
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Device leakage
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Device malfunction
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Infusion site bruising
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Injection site erythema
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site warmth
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Medical device complication
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Thrombosis in device
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Vessel puncture site pain
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Drug hypersensitivity
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Food allergy
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    3 / 187 (1.60%)
         occurrences all number
    0
    2
    3
    Metrorrhagia
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    1 / 187 (0.53%)
         occurrences all number
    4
    2
    1
    Polymenorrhoea
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    0
    1
    2
    Menstruation irregular
         subjects affected / exposed
    0 / 186 (0.00%)
    3 / 186 (1.61%)
    3 / 187 (1.60%)
         occurrences all number
    0
    3
    4
    Menorrhagia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    0
    1
    2
    Amenorrhoea
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Endometriosis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Breast tenderness
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Uterine spasm
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Oligomenorrhoea
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Vulvovaginal pain
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    82 / 186 (44.09%)
    69 / 186 (37.10%)
    56 / 187 (29.95%)
         occurrences all number
    116
    89
    85
    Sputum increased
         subjects affected / exposed
    47 / 186 (25.27%)
    40 / 186 (21.51%)
    29 / 187 (15.51%)
         occurrences all number
    51
    45
    36
    Dyspnoea
         subjects affected / exposed
    15 / 186 (8.06%)
    32 / 186 (17.20%)
    31 / 187 (16.58%)
         occurrences all number
    19
    35
    35
    Nasal congestion
         subjects affected / exposed
    19 / 186 (10.22%)
    24 / 186 (12.90%)
    13 / 187 (6.95%)
         occurrences all number
    21
    27
    18
    Haemoptysis
         subjects affected / exposed
    26 / 186 (13.98%)
    28 / 186 (15.05%)
    20 / 187 (10.70%)
         occurrences all number
    32
    48
    22
    Oropharyngeal pain
         subjects affected / exposed
    20 / 186 (10.75%)
    20 / 186 (10.75%)
    13 / 187 (6.95%)
         occurrences all number
    23
    20
    13
    Rhinorrhoea
         subjects affected / exposed
    10 / 186 (5.38%)
    11 / 186 (5.91%)
    11 / 187 (5.88%)
         occurrences all number
    11
    12
    13
    Respiration abnormal
         subjects affected / exposed
    13 / 186 (6.99%)
    14 / 186 (7.53%)
    18 / 187 (9.63%)
         occurrences all number
    16
    18
    21
    Productive cough
         subjects affected / exposed
    14 / 186 (7.53%)
    11 / 186 (5.91%)
    5 / 187 (2.67%)
         occurrences all number
    15
    13
    9
    Sinus congestion
         subjects affected / exposed
    11 / 186 (5.91%)
    8 / 186 (4.30%)
    8 / 187 (4.28%)
         occurrences all number
    11
    10
    9
    Wheezing
         subjects affected / exposed
    9 / 186 (4.84%)
    7 / 186 (3.76%)
    6 / 187 (3.21%)
         occurrences all number
    10
    9
    6
    Respiratory tract congestion
         subjects affected / exposed
    6 / 186 (3.23%)
    8 / 186 (4.30%)
    9 / 187 (4.81%)
         occurrences all number
    6
    10
    9
    Sputum discoloured
         subjects affected / exposed
    6 / 186 (3.23%)
    3 / 186 (1.61%)
    3 / 187 (1.60%)
         occurrences all number
    6
    4
    3
    Dysphonia
         subjects affected / exposed
    4 / 186 (2.15%)
    3 / 186 (1.61%)
    7 / 187 (3.74%)
         occurrences all number
    4
    3
    8
    Paranasal sinus hypersecretion
         subjects affected / exposed
    5 / 186 (2.69%)
    8 / 186 (4.30%)
    6 / 187 (3.21%)
         occurrences all number
    5
    8
    7
    Rales
         subjects affected / exposed
    6 / 186 (3.23%)
    2 / 186 (1.08%)
    2 / 187 (1.07%)
         occurrences all number
    7
    2
    2
    Asthma
         subjects affected / exposed
    2 / 186 (1.08%)
    4 / 186 (2.15%)
    2 / 187 (1.07%)
         occurrences all number
    2
    6
    2
    Epistaxis
         subjects affected / exposed
    2 / 186 (1.08%)
    5 / 186 (2.69%)
    1 / 187 (0.53%)
         occurrences all number
    2
    5
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 186 (1.08%)
    3 / 187 (1.60%)
         occurrences all number
    2
    2
    3
    Bronchial obstruction
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    2
    1
    2
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    3 / 186 (1.61%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    4
    0
    0
    Painful respiration
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    3 / 187 (1.60%)
         occurrences all number
    1
    0
    4
    Throat irritation
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    1
    2
    0
    Nasal discharge discolouration
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    0
    2
    2
    Sneezing
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    0
    1
    2
    Pleuritic pain
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    1
    1
    1
    Rhinitis allergic
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    2
    1
    0
    Bronchospasm
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Nasal polyps
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    2
    0
    0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Sputum decreased
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Hiccups
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Bronchial secretion retention
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperventilation
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Increased bronchial secretion
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Lung disorder
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal discomfort
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Lung hyperinflation
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngeal exudate
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngeal erythema
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Pleurisy
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngeal oedema
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Respiratory disorder
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory gas exchange disorder
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus disorder
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Pulmonary pain
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory tract irritation
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Rhonchi
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract inflammation
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 186 (3.76%)
    5 / 186 (2.69%)
    2 / 187 (1.07%)
         occurrences all number
    7
    5
    2
    Depression
         subjects affected / exposed
    3 / 186 (1.61%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    3
    1
    1
    Anxiety
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 186 (1.08%)
    2 / 187 (1.07%)
         occurrences all number
    2
    2
    2
    Libido decreased
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Mental disorder
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Mood altered
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Nervousness
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Nightmare
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 186 (2.69%)
    3 / 186 (1.61%)
    5 / 187 (2.67%)
         occurrences all number
    5
    3
    5
    Blood creatine phosphokinase increased
         subjects affected / exposed
    10 / 186 (5.38%)
    4 / 186 (2.15%)
    12 / 187 (6.42%)
         occurrences all number
    11
    4
    17
    Pulmonary function test decreased
         subjects affected / exposed
    14 / 186 (7.53%)
    5 / 186 (2.69%)
    3 / 187 (1.60%)
         occurrences all number
    16
    5
    3
    Bacterial test positive
         subjects affected / exposed
    1 / 186 (0.54%)
    4 / 186 (2.15%)
    7 / 187 (3.74%)
         occurrences all number
    1
    4
    7
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 186 (2.15%)
    2 / 186 (1.08%)
    4 / 187 (2.14%)
         occurrences all number
    4
    2
    4
    Forced expiratory volume decreased
         subjects affected / exposed
    4 / 186 (2.15%)
    0 / 186 (0.00%)
    2 / 187 (1.07%)
         occurrences all number
    4
    0
    2
    Weight decreased
         subjects affected / exposed
    2 / 186 (1.08%)
    3 / 186 (1.61%)
    2 / 187 (1.07%)
         occurrences all number
    2
    3
    3
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 186 (0.00%)
    4 / 186 (2.15%)
    2 / 187 (1.07%)
         occurrences all number
    0
    4
    3
    Sputum abnormal
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    2 / 187 (1.07%)
         occurrences all number
    2
    0
    2
    Blood glucose increased
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 186 (1.61%)
    1 / 187 (0.53%)
         occurrences all number
    1
    3
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    1
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    2
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    1
    1
    1
    Body temperature increased
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    1 / 187 (0.53%)
         occurrences all number
    0
    3
    1
    Blood glucose decreased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    0
    1
    3
    Eosinophil count increased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    1
    1
    0
    Atypical mycobacterium test positive
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Fungal test positive
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Blood immunoglobulin E increased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Blood iron decreased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Blood calcium increased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Blood sodium decreased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Breath sounds abnormal
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Blood urine present
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Blood sodium increased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Coagulation test abnormal
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Crystal urine present
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Electrocardiogram PR shortened
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Haemophilus test positive
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    2
    Liver function test abnormal
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Mean cell volume increased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Mean cell haemoglobin decreased
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    2
    Red blood cell count decreased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Serum ferritin decreased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Vitamin D decreased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    2 / 186 (1.08%)
    3 / 186 (1.61%)
    3 / 187 (1.60%)
         occurrences all number
    2
    3
    3
    Muscle strain
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    3 / 187 (1.60%)
         occurrences all number
    2
    1
    3
    Procedural pain
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    1
    1
    2
    Laceration
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 186 (1.61%)
    1 / 187 (0.53%)
         occurrences all number
    1
    3
    1
    Joint injury
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    1
    1
    1
    Arthropod bite
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Sunburn
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    1
    1
    1
    Concussion
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Alcohol poisoning
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Vaccination complication
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    2
    0
    1
    Arthropod sting
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Animal bite
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Ankle fracture
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Iliotibial band syndrome
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Foreign body
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Ligament injury
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Joint dislocation
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Splinter
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Stoma site irritation
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Traumatic haematoma
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Thermal burn
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Congenital, familial and genetic disorders
    Cystic fibrosis related diabetes
         subjects affected / exposed
    5 / 186 (2.69%)
    0 / 186 (0.00%)
    2 / 187 (1.07%)
         occurrences all number
    5
    0
    2
    Talipes
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    1
    1
    1
    Tachycardia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus arrhythmia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Cyanosis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Sinus headache
         subjects affected / exposed
    7 / 186 (3.76%)
    15 / 186 (8.06%)
    7 / 187 (3.74%)
         occurrences all number
    8
    16
    11
    Headache
         subjects affected / exposed
    33 / 186 (17.74%)
    30 / 186 (16.13%)
    29 / 187 (15.51%)
         occurrences all number
    37
    39
    36
    Dizziness
         subjects affected / exposed
    5 / 186 (2.69%)
    7 / 186 (3.76%)
    3 / 187 (1.60%)
         occurrences all number
    5
    7
    3
    Lethargy
         subjects affected / exposed
    3 / 186 (1.61%)
    3 / 186 (1.61%)
    2 / 187 (1.07%)
         occurrences all number
    3
    3
    2
    Dysgeusia
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    1
    2
    0
    Migraine
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    2
    1
    1
    Amnesia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    1
    1
    1
    Tremor
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    1
    1
    1
    Paraesthesia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Intercostal neuralgia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Parosmia
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    1
    1
    0
    Convulsion
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Cervicogenic headache
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Ageusia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Coordination abnormal
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Disturbance in attention
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperaesthesia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Epilepsy
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertonia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Hyposmia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Nerve compression
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle contractions involuntary
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Loss of consciousness
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Increased tendency to bruise
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    3
    0
    0
    Leukopenia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Eosinophilia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    3 / 187 (1.60%)
         occurrences all number
    1
    1
    3
    Ear pain
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    3 / 187 (1.60%)
         occurrences all number
    0
    1
    3
    Tympanic membrane disorder
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Ear discomfort
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    1
    1
    1
    Vertigo
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Vertigo positional
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Middle ear effusion
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    2 / 187 (1.07%)
         occurrences all number
    0
    0
    2
    Vision blurred
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    0
    1
    2
    Blindness transient
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Eye pruritus
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    1
    1
    0
    Eye irritation
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Eye pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Eye swelling
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Periorbital oedema
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Photopsia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    19 / 186 (10.22%)
    15 / 186 (8.06%)
    10 / 187 (5.35%)
         occurrences all number
    21
    24
    12
    Diarrhoea
         subjects affected / exposed
    18 / 186 (9.68%)
    20 / 186 (10.75%)
    21 / 187 (11.23%)
         occurrences all number
    19
    28
    24
    Nausea
         subjects affected / exposed
    17 / 186 (9.14%)
    20 / 186 (10.75%)
    32 / 187 (17.11%)
         occurrences all number
    18
    22
    39
    Flatulence
         subjects affected / exposed
    10 / 186 (5.38%)
    11 / 186 (5.91%)
    13 / 187 (6.95%)
         occurrences all number
    10
    13
    13
    Abdominal pain upper
         subjects affected / exposed
    8 / 186 (4.30%)
    15 / 186 (8.06%)
    7 / 187 (3.74%)
         occurrences all number
    8
    16
    7
    Vomiting
         subjects affected / exposed
    9 / 186 (4.84%)
    12 / 186 (6.45%)
    9 / 187 (4.81%)
         occurrences all number
    9
    14
    9
    Abdominal distension
         subjects affected / exposed
    2 / 186 (1.08%)
    6 / 186 (3.23%)
    5 / 187 (2.67%)
         occurrences all number
    2
    6
    6
    Constipation
         subjects affected / exposed
    8 / 186 (4.30%)
    5 / 186 (2.69%)
    6 / 187 (3.21%)
         occurrences all number
    8
    5
    6
    Dyspepsia
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 186 (1.61%)
    5 / 187 (2.67%)
         occurrences all number
    1
    3
    5
    Frequent bowel movements
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    7 / 187 (3.74%)
         occurrences all number
    2
    1
    7
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    6 / 187 (3.21%)
         occurrences all number
    1
    1
    6
    Abdominal discomfort
         subjects affected / exposed
    0 / 186 (0.00%)
    3 / 186 (1.61%)
    3 / 187 (1.60%)
         occurrences all number
    0
    4
    3
    Steatorrhoea
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 186 (1.08%)
    1 / 187 (0.53%)
         occurrences all number
    2
    2
    2
    Eructation
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    1
    1
    3
    Mouth ulceration
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    1
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Post-tussive vomiting
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    1
    1
    0
    Abdominal tenderness
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Abnormal faeces
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Aerophagia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Epigastric discomfort
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Faecaloma
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Faeces discoloured
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Faeces soft
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Food poisoning
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Gastritis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal sounds abnormal
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Gastrointestinal tract irritation
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Haematochezia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Lip pain
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Lip ulceration
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Retching
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Odynophagia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Oral pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Oesophageal pain
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Tongue discolouration
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Tongue disorder
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Tooth development disorder
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Umbilical hernia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth impacted
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Hepatic pain
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Cholecystitis acute
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 186 (2.69%)
    8 / 186 (4.30%)
    18 / 187 (9.63%)
         occurrences all number
    5
    8
    19
    Acne
         subjects affected / exposed
    4 / 186 (2.15%)
    8 / 186 (4.30%)
    1 / 187 (0.53%)
         occurrences all number
    4
    8
    1
    Hyperhidrosis
         subjects affected / exposed
    2 / 186 (1.08%)
    5 / 186 (2.69%)
    3 / 187 (1.60%)
         occurrences all number
    2
    5
    3
    Pruritus
         subjects affected / exposed
    3 / 186 (1.61%)
    2 / 186 (1.08%)
    2 / 187 (1.07%)
         occurrences all number
    3
    2
    2
    Alopecia
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    3 / 187 (1.60%)
         occurrences all number
    1
    1
    3
    Night sweats
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    1
    1
    2
    Urticaria
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    2
    2
    0
    Eczema
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    2
    2
    0
    Erythema
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    1
    1
    0
    Onychoclasis
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    2
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Red man syndrome
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    2
    0
    0
    Skin odour abnormal
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Rash pruritic
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Cutaneous lupus erythematosus
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Blister
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Hair texture abnormal
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Drug eruption
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Lividity
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Ingrowing nail
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Papule
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus allergic
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Rash erythematous
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Pruritus generalised
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Rash papular
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Swelling face
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    1 / 187 (0.53%)
         occurrences all number
    1
    2
    1
    Calculus ureteric
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Proteinuria
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    1
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Renal colic
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Urine odour abnormal
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Early menarche
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 186 (3.23%)
    5 / 186 (2.69%)
    9 / 187 (4.81%)
         occurrences all number
    7
    6
    10
    Myalgia
         subjects affected / exposed
    8 / 186 (4.30%)
    6 / 186 (3.23%)
    3 / 187 (1.60%)
         occurrences all number
    8
    6
    4
    Arthralgia
         subjects affected / exposed
    7 / 186 (3.76%)
    2 / 186 (1.08%)
    6 / 187 (3.21%)
         occurrences all number
    8
    3
    6
    Flank pain
         subjects affected / exposed
    2 / 186 (1.08%)
    3 / 186 (1.61%)
    3 / 187 (1.60%)
         occurrences all number
    2
    4
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 186 (0.54%)
    8 / 186 (4.30%)
    1 / 187 (0.53%)
         occurrences all number
    1
    8
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    3 / 187 (1.60%)
         occurrences all number
    1
    2
    3
    Pain in extremity
         subjects affected / exposed
    2 / 186 (1.08%)
    3 / 186 (1.61%)
    2 / 187 (1.07%)
         occurrences all number
    2
    3
    2
    Neck pain
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    0
    1
    2
    Muscle spasms
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    2
    1
    0
    Muscle twitching
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    0
    1
    2
    Muscle tightness
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    0
    2
    0
    Tendonitis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Joint swelling
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    2
    0
    0
    Arthropathy
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    2
    Arthritis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Bone cyst
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Foot deformity
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Hypermobility syndrome
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Chondritis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle contracture
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Pubic pain
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Tendon pain
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    74 / 186 (39.78%)
    58 / 186 (31.18%)
    50 / 187 (26.74%)
         occurrences all number
    101
    77
    65
    Viral upper respiratory tract infection
         subjects affected / exposed
    13 / 186 (6.99%)
    13 / 186 (6.99%)
    10 / 187 (5.35%)
         occurrences all number
    15
    15
    11
    Nasopharyngitis
         subjects affected / exposed
    20 / 186 (10.75%)
    14 / 186 (7.53%)
    22 / 187 (11.76%)
         occurrences all number
    23
    15
    26
    Sinusitis
         subjects affected / exposed
    7 / 186 (3.76%)
    17 / 186 (9.14%)
    11 / 187 (5.88%)
         occurrences all number
    8
    19
    12
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 186 (5.38%)
    8 / 186 (4.30%)
    20 / 187 (10.70%)
         occurrences all number
    12
    9
    26
    Rhinitis
         subjects affected / exposed
    6 / 186 (3.23%)
    14 / 186 (7.53%)
    8 / 187 (4.28%)
         occurrences all number
    8
    21
    11
    Pharyngitis
         subjects affected / exposed
    4 / 186 (2.15%)
    3 / 186 (1.61%)
    3 / 187 (1.60%)
         occurrences all number
    4
    3
    3
    Influenza
         subjects affected / exposed
    3 / 186 (1.61%)
    6 / 186 (3.23%)
    11 / 187 (5.88%)
         occurrences all number
    3
    6
    11
    Gastroenteritis
         subjects affected / exposed
    5 / 186 (2.69%)
    4 / 186 (2.15%)
    4 / 187 (2.14%)
         occurrences all number
    5
    4
    4
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 186 (1.61%)
    2 / 187 (1.07%)
         occurrences all number
    1
    4
    2
    Viral infection
         subjects affected / exposed
    4 / 186 (2.15%)
    4 / 186 (2.15%)
    0 / 187 (0.00%)
         occurrences all number
    5
    4
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 186 (0.00%)
    5 / 186 (2.69%)
    3 / 187 (1.60%)
         occurrences all number
    0
    6
    3
    Bronchitis
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    2 / 187 (1.07%)
         occurrences all number
    1
    2
    3
    Ear infection
         subjects affected / exposed
    3 / 186 (1.61%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    3
    1
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    2 / 187 (1.07%)
         occurrences all number
    1
    2
    2
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    3 / 187 (1.60%)
         occurrences all number
    0
    2
    3
    Gastroenteritis viral
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    2 / 187 (1.07%)
         occurrences all number
    1
    1
    2
    Respiratory tract infection
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 186 (1.08%)
    1 / 187 (0.53%)
         occurrences all number
    2
    2
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    1 / 187 (0.53%)
         occurrences all number
    1
    2
    1
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 186 (0.00%)
    3 / 186 (1.61%)
    1 / 187 (0.53%)
         occurrences all number
    0
    6
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    2
    1
    3
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    1
    2
    0
    Acute sinusitis
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    3
    0
    2
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    0 / 187 (0.00%)
         occurrences all number
    1
    2
    0
    Laryngitis
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 186 (1.08%)
    1 / 187 (0.53%)
         occurrences all number
    0
    2
    1
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    1
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Clostridium difficile infection
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    2 / 187 (1.07%)
         occurrences all number
    0
    0
    4
    Conjunctivitis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)
         occurrences all number
    0
    1
    1
    Oral fungal infection
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    1
    1
    0
    Infectious mononucleosis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Rash pustular
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    1
    0
    1
    Otitis externa
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    2
    0
    0
    Acarodermatitis
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Asymptomatic bacteriuria
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Chronic sinusitis
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Bacterial disease carrier
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchitis viral
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Device related infection
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Cystitis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Eye infection
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Eyelid infection
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Epididymitis
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Gynaecological chlamydia infection
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Fungal infection
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Genital herpes
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Herpes simplex
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Hordeolum
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Infected bites
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Infusion site infection
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Localised infection
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Nipple infection
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Pharyngitis bacterial
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Pseudomonas bronchitis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Tooth abscess
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 186 (0.00%)
    0 / 187 (0.00%)
         occurrences all number
    1
    0
    0
    Tinea versicolour
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Vaginitis bacterial
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 186 (0.00%)
    1 / 187 (0.53%)
         occurrences all number
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    0 / 187 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    5 / 186 (2.69%)
    4 / 186 (2.15%)
    2 / 187 (1.07%)
         occurrences all number
    5
    4
    2
    Decreased appetite
         subjects affected / exposed
    5 / 186 (2.69%)
    7 / 186 (3.76%)
    12 / 187 (6.42%)
         occurrences all number
    5
    8
    13
    Hyperglycaemia
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 186 (1.08%)
    3 / 187 (1.60%)
         occurrences all number
    1
    2
    3
    Dehydration
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 186 (0.54%)
    1 / 187 (0.53%)