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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

    Summary
    EudraCT number
    2012-003989-40
    Trial protocol
    SE   IT   CZ   DE   IE   GB   NL  
    Global end of trial date
    29 Apr 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Jul 2016
    First version publication date
    07 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX12-809-103
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01807923
    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
    29 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 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 aged 12 years and older 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
    28 May 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
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    United States: 261
    Country: Number of subjects enrolled
    Australia: 49
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    France: 44
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Ireland: 13
    Country: Number of subjects enrolled
    Italy: 54
    Country: Number of subjects enrolled
    Netherlands: 18
    Worldwide total number of subjects
    549
    EEA total number of subjects
    211
    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)
    158
    Adults (18-64 years)
    391
    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, 185, and 187 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 184, 183, and 182 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 600 mg qd/IVA 250 mg q12h
    Arm description
    LUM 600 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (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.

    Arm title
    LUM 400 mg q12h/IVA 250 mg q12h
    Arm description
    LUM 400 mg plus IVA 250 mg supplied as 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.

    Number of subjects in period 1
    Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Started
    184
    183
    182
    Completed
    182
    179
    176
    Not completed
    2
    4
    6
         Withdrawal of Consent (not due to AE)
    -
    3
    2
         Physician decision
    -
    -
    1
         Not Eligible (Genotype)
    -
    -
    1
         Adverse Event
    2
    1
    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 600 mg qd/IVA 250 mg q12h
    Reporting group description
    LUM 600 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (FDC) tablets 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 tablets in the morning and in the evening, up to Week 24.

    Reporting group values
    Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h Total
    Number of subjects
    184 183 182 549
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    25 ± 10.8 24.7 ± 9.71 25.5 ± 10.09 -
    Gender categorical
    Units: Subjects
        Female
    84 86 84 254
        Male
    100 97 98 295

    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 600 mg qd/IVA 250 mg q12h
    Reporting group description
    LUM 600 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (FDC) tablets 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 tablets in the morning and 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 subjects 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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    180
    176
    172
    Units: percent predicted of FEV1
        least squares mean (standard error)
    -0.44 ± 0.524
    3.59 ± 0.525
    2.16 ± 0.53
    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 ( less than (<)18 versus greater than equal to (>=) 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
    356
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    Least Squares (LS) Mean Difference
    Point estimate
    4.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.62
         upper limit
    5.44
    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
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    2.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.18
         upper limit
    4.01

    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
    Relative change from baseline at week 24 was 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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    180
    176
    172
    Units: percent change
        least squares mean (standard error)
    -0.34 ± 0.913
    6.39 ± 0.914
    3.99 ± 0.923
    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
    356
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    6.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.27
         upper limit
    9.19
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.0006
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    4.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.86
         upper limit
    6.8
    Notes
    [1] - Analysis was performed using MMRM model, as described in Statistical Analysis 1.

    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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    184
    178
    176
    Units: kilogram per square meter (kg/m^2)
        least squares mean (standard error)
    0.19 ± 0.07
    0.35 ± 0.07
    0.32 ± 0.071
    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
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1122
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.04
         upper limit
    0.35
    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
    360
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1938
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    0.32

    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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    184
    176
    172
    Units: units on a scale
        least squares mean (standard error)
    1.1 ± 1.161
    4.98 ± 1.178
    2.6 ± 1.192
    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
    360
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0168 [2]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    3.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    7.05
    Notes
    [2] - 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 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
    356
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3569
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.69
         upper limit
    4.69

    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. Analysis was performed on FAS. 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.
    End point type
    Secondary
    End point timeframe
    Week 16 and 24
    End point values
    Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    184
    183
    182
    Units: percentage of subjects
        number (not applicable)
    22.3
    46.4
    36.8
    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
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.9378
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.8786
         upper limit
    4.5941
    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
    Placebo v LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0023 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.0592
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.292
         upper limit
    3.2819
    Notes
    [4] - 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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    184
    183
    182
    Units: pulmonary exacerbation events per year
        number (not applicable)
    1.07
    0.77
    0.71
    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
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0491
    Method
    Negative Binomial Regression
    Parameter type
    Event Rate Ratio
    Point estimate
    0.7186
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.517
         upper limit
    0.9987
    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
    366
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0169 [5]
    Method
    Negative Binomial Regression
    Parameter type
    Event Rate Ratio
    Point estimate
    0.6643
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4749
         upper limit
    0.9291
    Notes
    [5] - 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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    184
    178
    176
    Units: kilograms (kg)
        least squares mean (standard error)
    0.93 ± 0.202
    1.34 ± 0.205
    1.23 ± 0.205
    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
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1565
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.16
         upper limit
    0.96
    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
    360
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2992
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.26
         upper limit
    0.86

    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 subjects 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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    69
    65
    58
    Units: z-score
        least squares mean (standard error)
    0.0153 ± 0.04886
    0.1132 ± 0.05081
    0.0933 ± 0.05431
    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
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1539
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.098
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.037
         upper limit
    0.233
    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
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2713
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.0781
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0615
         upper limit
    0.2176

    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. 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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    184
    183
    182
    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
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0396
    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
    366
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0385
    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.
    End point type
    Secondary
    End point timeframe
    through Week 24
    End point values
    Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    184
    183
    182
    Units: percentage of subjects
        number (not applicable)
    39.7
    30.1
    30.2
    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-Mante-lHaenszel 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
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0552
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.6565
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4266
         upper limit
    1.0103
    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
    366
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0512
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.6438
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4142
         upper limit
    1.0005

    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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    179
    175
    170
    Units: units on a scale
        least squares mean (standard error)
    0.0006 ± 0.00739
    0.0066 ± 0.00746
    0.01 ± 0.00757
    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 EQ5D3L index score.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5604
    Method
    MMRM
    Parameter type
    LS Mean Difference]
    Point estimate
    0.006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0142
         upper limit
    0.0262
    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
    349
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3613
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.0095
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0109
         upper limit
    0.0298

    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 subjects 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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    180
    173
    171
    Units: units on a scale
        least squares mean (standard error)
    1.4 ± 1.03
    3.5 ± 1.04
    2.8 ± 1.04
    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
    Placebo v LUM 600 mg qd/IVA 250 mg q12h
    Number of subjects included in analysis
    353
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1342
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    4.9
    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
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3071
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    4.2

    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 subjects 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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    184
    183
    182
    Units: units on a scale
    least squares mean (standard error)
        Effectiveness (n = 163, 156, 144)
    -5.3 ± 1.643
    0.19 ± 1.666
    0.5 ± 1.726
        Side Effects (n = 162, 154, 143)
    2.23 ± 1.119
    -1.94 ± 1.141
    -2.51 ± 1.179
        Convenience (n = 163, 154, 144)
    4.37 ± 1.504
    4.98 ± 1.54
    7.45 ± 1.579
        Global Satisfaction (n= 163, 154, 144)
    -10.49 ± 1.863
    -5 ± 1.906
    -3.77 ± 1.956
    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 319.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.016
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    5.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    9.96
    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 307.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0126
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    5.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.25
         upper limit
    10.35
    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
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0074
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -4.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.23
         upper limit
    -1.13
    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 305.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0029
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -4.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.85
         upper limit
    -1.63
    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 317.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7721
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.5
         upper limit
    4.71
    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 307.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1472
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    3.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.09
         upper limit
    7.25
    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 317.
    Comparison groups
    LUM 600 mg qd/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0345
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    5.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    10.58
    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 307.
    Comparison groups
    LUM 400 mg q12h/IVA 250 mg q12h v Placebo
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0109
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    6.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.55
         upper limit
    11.89

    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. Any AE that increased in severity or that was newly developed at or after the initial dosing of study drug to 28 days after the last dose of study drug is considered treatment-emergent. Safety Set (SS) included all randomized subjects who received any amount of study drug.
    End point type
    Secondary
    End point timeframe
    up to Week 28
    End point values
    Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    184
    183
    182
    Units: subjects
    number (not applicable)
        Subjects With Treatment-Emergent AEs
    174
    175
    174
        Subjects With Treatment-Emergent SAEs
    49
    33
    33
    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 outcome was not planned to be assessed in Placebo arm. 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 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/IVA 250 mg q12h
    Number of subjects analysed
    180
    181
    Units: microgram per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        LUM, Day 1: C3-6h (n = 180, 175)
    27.5 ± 12.5
    18.4 ± 8.55
        LUM, Day 15: Ctrough (n = 172, 175)
    7.56 ± 5.33
    14.1 ± 6.99
        LUM, Day 15: C3-6 (n = 167, 171)
    26.1 ± 11.5
    23.6 ± 8.54
        LUM, Week 4: Ctrough (n = 172, 178)
    7.75 ± 5.05
    13.4 ± 6.7
        LUM, Week 4: C3-6 (n = 170, 171)
    28.4 ± 11.2
    24.2 ± 8.66
        LUM, Week 8: Ctrough (n = 173, 174)
    7.43 ± 5.6
    13.4 ± 6.68
        LUM, Week 8: C3-6 (n = 165, 171)
    28.2 ± 11.2
    24.4 ± 8.8
        LUM, Week 16: Ctrough (n = 165, 164)
    6.95 ± 4.99
    13.5 ± 7.49
        M-28 LUM, Day 1: C3-6h (n = 180, 175)
    0.22 ± 0.107
    0.179 ± 0.0811
        M-28 LUM, Day 15: Ctrough (n = 172, 175)
    1.25 ± 0.614
    1.48 ± 0.59
        M-28 LUM, Day 15: C3-6 (n = 167, 171)
    1.37 ± 0.606
    1.49 ± 0.576
        M-28 LUM, Week 4: Ctrough (n = 172, 178)
    1.31 ± 0.646
    1.48 ± 0.642
        M-28 LUM, Week 4: C3-6 (n = 170, 171)
    1.39 ± 0.635
    1.49 ± 0.615
        M-28 LUM, Week 8: Ctrough (n = 173, 174)
    1.32 ± 0.684
    1.53 ± 0.674
        M-28 LUM, Week 8: C3-6 (n = 165, 171)
    1.42 ± 0.658
    1.56 ± 0.669
        M-28 LUM, Week 16: Ctrough (n = 165, 164)
    1.3 ± 0.769
    1.57 ± 0.757
        IVA, Day 1: C3-6h (n = 180, 175)
    1.29 ± 0.624
    1.24 ± 0.63
        IVA, Day 15: Ctrough (n = 172, 176)
    0.151 ± 0.123
    0.115 ± 0.123
        IVA, Day 15: C3-6 (n = 167, 171)
    0.557 ± 0.311
    0.413 ± 0.199
        IVA, Week 4: Ctrough (n = 172, 178)
    0.142 ± 0.107
    0.105 ± 0.083
        IVA, Week 4: C3-6 (n = 170, 171)
    0.638 ± 0.325
    0.456 ± 0.235
        IVA, Week 8: Ctrough (n = 173, 174)
    0.13 ± 0.101
    0.0894 ± 0.0726
        IVA, Week 8: C3-6 (n = 165, 171)
    0.648 ± 0.364
    0.47 ± 0.295
        IVA, Week 16: Ctrough (n = 165, 164)
    0.133 ± 0.131
    0.0834 ± 0.0622
        M-1 IVA, Day 1: C3-6h (n = 180, 175)
    2.46 ± 1.29
    2.41 ± 1.35
        M-1 IVA, Day 15: Ctrough (n = 172, 176)
    0.665 ± 0.578
    0.511 ± 0.53
        M-1 IVA, Day 15: C3-6 (n = 167, 171)
    1.94 ± 0.981
    1.71 ± 0.867
        M-1 IVA, Week 4: Ctrough (n = 172, 178)
    0.628 ± 0.492
    0.45 ± 0.345
        M-1 IVA, Week 4: C3-6 (n = 170, 171)
    2.21 ± 1.01
    1.76 ± 0.932
        M-1 IVA, Week 8: Ctrough (n = 173, 174)
    0.584 ± 0.451
    0.404 ± 0.381
        M-1 IVA, Week 8: C3-6 (n = 165, 171)
    2.17 ± 1.06
    1.78 ± 0.975
        M-1 IVA, Week 16: Ctrough (n = 165, 164)
    0.589 ± 0.519
    0.396 ± 0.319
        M-6 IVA, Day 1: C3-6h (n = 180, 175)
    0.976 ± 0.877
    0.927 ± 0.875
        M-6 IVA, Day 15: Ctrough (n = 172, 176)
    1.68 ± 1.31
    1.67 ± 1.4
        M-6 IVA, Day 15: C3-6 (n = 167, 171)
    3.03 ± 1.96
    2.87 ± 1.81
        M-6 IVA, Week 4: Ctrough (n = 172, 178)
    1.66 ± 1.36
    1.46 ± 0.938
        M-6 IVA, Week 4: C3-6 (n = 170, 171)
    3.07 ± 1.92
    2.49 ± 1.53
        M-6 IVA, Week 8: Ctrough (n = 173, 174)
    1.52 ± 1.12
    1.31 ± 0.946
        M-6 IVA, Week 8: C3-6 (n = 165, 171)
    2.96 ± 1.86
    2.36 ± 1.57
        M-6 IVA, Week 16: Ctrough (n = 165, 164)
    1.4 ± 1.11
    1.33 ± 1.02
        LUM: Ctrough,ave (n = 179, 181)
    7.49 ± 3.93
    13.5 ± 5.52
        LUM: C3-6h, ave (n = 179, 181)
    27.7 ± 8.63
    24 ± 7.29
        M-28 LUM: Ctrough,ave (n = 179, 181)
    1.31 ± 0.628
    1.51 ± 0.614
        M-28 LUM: C3-6h, ave (n = 179, 181)
    1.39 ± 0.596
    1.51 ± 0.585
        IVA: Ctrough,ave (n = 179, 181)
    0.137 ± 0.0773
    0.0989 ± 0.0644
        IVA: C3-6h, ave (n = 179, 181)
    0.614 ± 0.271
    0.445 ± 0.193
        M1-IVA: Ctrough,ave (n = 179, 181)
    0.606 ± 0.35
    0.441 ± 0.293
        M1-IVA: C3-6h, ave (n = 179, 181)
    2.11 ± 0.817
    1.74 ± 0.726
        M6-IVA: Ctrough,ave (n = 179, 181)
    1.57 ± 0.992
    1.44 ± 0.861
        M6-IVA: C3-6h, ave (n = 179, 181)
    3.04 ± 1.55
    2.57 ± 1.34
    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 nonserious AEs.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    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 600 mg qd/IVA 250 mg q12h
    Reporting group description
    LUM 600 mg plus IVA 250 mg supplied as fixed-dose combination (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
    49 / 184 (26.63%)
    33 / 183 (18.03%)
    33 / 182 (18.13%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer metastatic
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (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
    Renal cancer
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (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
    Seminoma
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Implant site thrombosis
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    0 / 182 (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
    Device dislocation
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Post procedural haematoma
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (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
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Haemoptysis
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    5 / 182 (2.75%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Dyspnoea
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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 disorder
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    2 / 184 (1.09%)
    2 / 183 (1.09%)
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Dysphagia
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Vomiting
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Hepatobiliary disorders
    Hepatitis cholestatic
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Nephrolithiasis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (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
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    41 / 184 (22.28%)
    19 / 183 (10.38%)
    17 / 182 (9.34%)
         occurrences causally related to treatment / all
    1 / 51
    0 / 22
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (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
    Bronchopneumonia
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (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
    Catheter site cellulitis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Clostridium difficile infection
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (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
    Kidney infection
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (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 mycoplasmal
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         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
    173 / 184 (94.02%)
    175 / 183 (95.63%)
    172 / 182 (94.51%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    2 / 182 (1.10%)
         occurrences all number
    0
    2
    2
    Flushing
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Hot flush
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    0
    0
    2
    Deep vein thrombosis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Poor venous access
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Seasonal allergy
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Anaphylactic reaction
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Hypersensitivity
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Milk allergy
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    19 / 184 (10.33%)
    17 / 183 (9.29%)
    17 / 182 (9.34%)
         occurrences all number
    20
    17
    18
    Pyrexia
         subjects affected / exposed
    12 / 184 (6.52%)
    12 / 183 (6.56%)
    17 / 182 (9.34%)
         occurrences all number
    14
    14
    19
    Asthenia
         subjects affected / exposed
    3 / 184 (1.63%)
    5 / 183 (2.73%)
    3 / 182 (1.65%)
         occurrences all number
    3
    5
    3
    Pain
         subjects affected / exposed
    2 / 184 (1.09%)
    4 / 183 (2.19%)
    3 / 182 (1.65%)
         occurrences all number
    2
    4
    3
    Chest discomfort
         subjects affected / exposed
    1 / 184 (0.54%)
    3 / 183 (1.64%)
    3 / 182 (1.65%)
         occurrences all number
    1
    4
    3
    Malaise
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    3 / 182 (1.65%)
         occurrences all number
    1
    4
    3
    Chills
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    1
    0
    2
    Drug intolerance
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    3 / 182 (1.65%)
         occurrences all number
    0
    0
    3
    Chest pain
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    2
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Drug interaction
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    2
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Feeling abnormal
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Feeling cold
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Feeling hot
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Hyperthermia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Implant site thrombosis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Local swelling
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Medical device pain
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 184 (3.26%)
    2 / 183 (1.09%)
    3 / 182 (1.65%)
         occurrences all number
    8
    2
    3
    Anxiety
         subjects affected / exposed
    2 / 184 (1.09%)
    2 / 183 (1.09%)
    2 / 182 (1.10%)
         occurrences all number
    2
    2
    2
    Depression
         subjects affected / exposed
    4 / 184 (2.17%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    4
    1
    1
    Depressed mood
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    3 / 182 (1.65%)
         occurrences all number
    0
    0
    3
    Irritability
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Bradyphrenia
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Depressive symptom
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Disorientation
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Disturbance in social behaviour
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Emotional disorder
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Libido decreased
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Middle insomnia
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Suicidal ideation
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 184 (1.09%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    2
    3
    3
    Metrorrhagia
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    3 / 182 (1.65%)
         occurrences all number
    0
    3
    3
    Amenorrhoea
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    3 / 182 (1.65%)
         occurrences all number
    0
    0
    4
    Menorrhagia
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences all number
    0
    2
    1
    Menstruation irregular
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences all number
    0
    3
    1
    Polymenorrhoea
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Erectile dysfunction
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Gynaecomastia
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Penile erythema
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Testicular pain
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    2
    Injury, poisoning and procedural complications
    Muscle strain
         subjects affected / exposed
    0 / 184 (0.00%)
    3 / 183 (1.64%)
    2 / 182 (1.10%)
         occurrences all number
    0
    4
    2
    Joint injury
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    1
    1
    2
    Ligament sprain
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    0
    1
    2
    Procedural pain
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    1
    0
    2
    Concussion
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    0
    0
    2
    Excoriation
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    3
    0
    0
    Facial bones fracture
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    2
    0
    0
    Stoma site pain
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    0
    3
    0
    Sunburn
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Arthropod bite
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Back injury
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Foreign body in eye
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Meniscus injury
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle rupture
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Post procedural complication
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Radius fracture
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Respiratory fume inhalation disorder
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Skeletal injury
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Stoma site erythema
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Vaccination complication
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Vascular procedure complication
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    10 / 184 (5.43%)
    10 / 183 (5.46%)
    13 / 182 (7.14%)
         occurrences all number
    11
    12
    14
    Bacterial test positive
         subjects affected / exposed
    9 / 184 (4.89%)
    4 / 183 (2.19%)
    7 / 182 (3.85%)
         occurrences all number
    13
    6
    9
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 184 (2.72%)
    4 / 183 (2.19%)
    3 / 182 (1.65%)
         occurrences all number
    5
    4
    4
    Forced expiratory volume decreased
         subjects affected / exposed
    7 / 184 (3.80%)
    3 / 183 (1.64%)
    1 / 182 (0.55%)
         occurrences all number
    7
    3
    1
    Weight decreased
         subjects affected / exposed
    5 / 184 (2.72%)
    2 / 183 (1.09%)
    4 / 182 (2.20%)
         occurrences all number
    5
    2
    4
    Liver function test abnormal
         subjects affected / exposed
    6 / 184 (3.26%)
    3 / 183 (1.64%)
    1 / 182 (0.55%)
         occurrences all number
    7
    3
    1
    Pulmonary function test decreased
         subjects affected / exposed
    6 / 184 (3.26%)
    4 / 183 (2.19%)
    0 / 182 (0.00%)
         occurrences all number
    7
    4
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 184 (1.63%)
    3 / 183 (1.64%)
    3 / 182 (1.65%)
         occurrences all number
    3
    3
    4
    Blood creatinine increased
         subjects affected / exposed
    4 / 184 (2.17%)
    3 / 183 (1.64%)
    1 / 182 (0.55%)
         occurrences all number
    4
    3
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    2 / 182 (1.10%)
         occurrences all number
    1
    2
    2
    Blood glucose decreased
         subjects affected / exposed
    3 / 184 (1.63%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    3
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    2 / 182 (1.10%)
         occurrences all number
    0
    2
    2
    Vitamin D decreased
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    1
    1
    2
    Breath sounds abnormal
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    1
    2
    0
    Fungal test positive
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    1
    1
    1
    Staphylococcus test positive
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    0
    1
    2
    Transaminases increased
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    1
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    2
    0
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Blood immunoglobulin E increased
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Blood phosphorus increased
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Body temperature increased
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Atypical mycobacterium test positive
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Blood calcium increased
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Blood phosphorus abnormal
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Blood sodium decreased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    2
    Blood urea increased
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Forced expiratory volume increased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Glucose tolerance test abnormal
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Glucose urine present
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Haemoglobin increased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Heart rate increased
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Pseudomonas test positive
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Red blood cell count increased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Sputum abnormal
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Urine calcium increased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Vitamin E decreased
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    White blood cells urine positive
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Defect conduction intraventricular
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Pericarditis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    Cystic fibrosis related diabetes
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    0
    2
    0
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    1
    2
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    1
    2
    0
    Lymph node pain
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Thrombocytosis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    66 / 184 (35.87%)
    52 / 183 (28.42%)
    47 / 182 (25.82%)
         occurrences all number
    93
    63
    60
    Haemoptysis
         subjects affected / exposed
    23 / 184 (12.50%)
    22 / 183 (12.02%)
    26 / 182 (14.29%)
         occurrences all number
    29
    27
    34
    Sputum increased
         subjects affected / exposed
    23 / 184 (12.50%)
    15 / 183 (8.20%)
    25 / 182 (13.74%)
         occurrences all number
    25
    16
    27
    Dyspnoea
         subjects affected / exposed
    14 / 184 (7.61%)
    21 / 183 (11.48%)
    17 / 182 (9.34%)
         occurrences all number
    15
    29
    23
    Respiration abnormal
         subjects affected / exposed
    9 / 184 (4.89%)
    26 / 183 (14.21%)
    14 / 182 (7.69%)
         occurrences all number
    10
    32
    16
    Nasal congestion
         subjects affected / exposed
    25 / 184 (13.59%)
    9 / 183 (4.92%)
    11 / 182 (6.04%)
         occurrences all number
    29
    9
    12
    Oropharyngeal pain
         subjects affected / exposed
    10 / 184 (5.43%)
    24 / 183 (13.11%)
    11 / 182 (6.04%)
         occurrences all number
    14
    26
    12
    Rhinorrhoea
         subjects affected / exposed
    5 / 184 (2.72%)
    6 / 183 (3.28%)
    10 / 182 (5.49%)
         occurrences all number
    6
    6
    10
    Wheezing
         subjects affected / exposed
    6 / 184 (3.26%)
    5 / 183 (2.73%)
    5 / 182 (2.75%)
         occurrences all number
    6
    7
    8
    Rales
         subjects affected / exposed
    7 / 184 (3.80%)
    4 / 183 (2.19%)
    4 / 182 (2.20%)
         occurrences all number
    7
    5
    5
    Productive cough
         subjects affected / exposed
    1 / 184 (0.54%)
    6 / 183 (3.28%)
    7 / 182 (3.85%)
         occurrences all number
    1
    8
    7
    Respiratory tract congestion
         subjects affected / exposed
    5 / 184 (2.72%)
    3 / 183 (1.64%)
    4 / 182 (2.20%)
         occurrences all number
    6
    3
    5
    Epistaxis
         subjects affected / exposed
    4 / 184 (2.17%)
    4 / 183 (2.19%)
    2 / 182 (1.10%)
         occurrences all number
    5
    11
    2
    Asthma
         subjects affected / exposed
    3 / 184 (1.63%)
    0 / 183 (0.00%)
    6 / 182 (3.30%)
         occurrences all number
    4
    0
    6
    Bronchospasm
         subjects affected / exposed
    1 / 184 (0.54%)
    3 / 183 (1.64%)
    5 / 182 (2.75%)
         occurrences all number
    1
    3
    6
    Sinus congestion
         subjects affected / exposed
    1 / 184 (0.54%)
    7 / 183 (3.83%)
    1 / 182 (0.55%)
         occurrences all number
    1
    7
    1
    Paranasal sinus hypersecretion
         subjects affected / exposed
    1 / 184 (0.54%)
    4 / 183 (2.19%)
    3 / 182 (1.65%)
         occurrences all number
    1
    4
    3
    Sputum discoloured
         subjects affected / exposed
    3 / 184 (1.63%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences all number
    3
    2
    1
    Nasal inflammation
         subjects affected / exposed
    1 / 184 (0.54%)
    3 / 183 (1.64%)
    1 / 182 (0.55%)
         occurrences all number
    1
    3
    1
    Rhinitis allergic
         subjects affected / exposed
    2 / 184 (1.09%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    2
    1
    2
    Rhonchi
         subjects affected / exposed
    2 / 184 (1.09%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences all number
    2
    2
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    2 / 184 (1.09%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    3
    1
    2
    Dysphonia
         subjects affected / exposed
    2 / 184 (1.09%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    2
    1
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 184 (0.00%)
    3 / 183 (1.64%)
    1 / 182 (0.55%)
         occurrences all number
    0
    3
    1
    Increased upper airway secretion
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    1
    1
    2
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    2
    0
    2
    Painful respiration
         subjects affected / exposed
    2 / 184 (1.09%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    2
    1
    1
    Pharyngeal erythema
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences all number
    1
    2
    1
    Pleuritic pain
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    2
    0
    2
    Lung hyperinflation
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    1
    2
    1
    Throat irritation
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    3
    0
    1
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Nasal polyps
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Obstructive airways disorder
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Paranasal cyst
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Pulmonary congestion
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    0
    2
    0
    Allergic cough
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchial obstruction
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    2
    Bronchiectasis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoxia
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal obstruction
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal oedema
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Nasal septum deviation
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Nasal turbinate hypertrophy
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngeal exudate
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Prolonged expiration
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary pain
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory failure
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory tract irritation
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Rhinalgia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Sneezing
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Throat tightness
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract inflammation
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 184 (13.59%)
    28 / 183 (15.30%)
    29 / 182 (15.93%)
         occurrences all number
    29
    42
    35
    Dizziness
         subjects affected / exposed
    5 / 184 (2.72%)
    5 / 183 (2.73%)
    5 / 182 (2.75%)
         occurrences all number
    6
    5
    6
    Sinus headache
         subjects affected / exposed
    2 / 184 (1.09%)
    3 / 183 (1.64%)
    3 / 182 (1.65%)
         occurrences all number
    2
    5
    3
    Migraine
         subjects affected / exposed
    3 / 184 (1.63%)
    0 / 183 (0.00%)
    3 / 182 (1.65%)
         occurrences all number
    3
    0
    4
    Lethargy
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    2 / 182 (1.10%)
         occurrences all number
    1
    2
    2
    Dysgeusia
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    2
    0
    2
    Poor quality sleep
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    3 / 182 (1.65%)
         occurrences all number
    0
    0
    3
    Dysarthria
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Paraesthesia
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    0
    2
    0
    Syncope
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Tremor
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    0
    0
    5
    Amnesia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Ataxia
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Cognitive disorder
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Epilepsy
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Memory impairment
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Presyncope
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Sciatica
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Tension headache
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    1
    1
    2
    Asthenopia
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Blepharospasm
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Astigmatism
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorder
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Eye pruritus
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 184 (0.54%)
    4 / 183 (2.19%)
    0 / 182 (0.00%)
         occurrences all number
    1
    5
    0
    Ear pain
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences all number
    1
    2
    1
    Cerumen impaction
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    0
    2
    0
    Tympanic membrane disorder
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Tympanic membrane hyperaemia
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Ear canal erythema
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Ear congestion
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 184 (7.07%)
    16 / 183 (8.74%)
    24 / 182 (13.19%)
         occurrences all number
    14
    19
    34
    Abdominal pain
         subjects affected / exposed
    12 / 184 (6.52%)
    11 / 183 (6.01%)
    23 / 182 (12.64%)
         occurrences all number
    15
    17
    31
    Nausea
         subjects affected / exposed
    11 / 184 (5.98%)
    9 / 183 (4.92%)
    14 / 182 (7.69%)
         occurrences all number
    12
    11
    18
    Constipation
         subjects affected / exposed
    11 / 184 (5.98%)
    6 / 183 (3.28%)
    7 / 182 (3.85%)
         occurrences all number
    11
    7
    7
    Abdominal pain upper
         subjects affected / exposed
    10 / 184 (5.43%)
    7 / 183 (3.83%)
    5 / 182 (2.75%)
         occurrences all number
    11
    8
    8
    Flatulence
         subjects affected / exposed
    1 / 184 (0.54%)
    9 / 183 (4.92%)
    11 / 182 (6.04%)
         occurrences all number
    1
    11
    11
    Vomiting
         subjects affected / exposed
    2 / 184 (1.09%)
    8 / 183 (4.37%)
    7 / 182 (3.85%)
         occurrences all number
    2
    9
    8
    Abdominal distension
         subjects affected / exposed
    4 / 184 (2.17%)
    2 / 183 (1.09%)
    5 / 182 (2.75%)
         occurrences all number
    4
    3
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 184 (1.09%)
    3 / 183 (1.64%)
    6 / 182 (3.30%)
         occurrences all number
    2
    3
    6
    Dyspepsia
         subjects affected / exposed
    2 / 184 (1.09%)
    3 / 183 (1.64%)
    4 / 182 (2.20%)
         occurrences all number
    2
    4
    4
    Abdominal discomfort
         subjects affected / exposed
    1 / 184 (0.54%)
    3 / 183 (1.64%)
    3 / 182 (1.65%)
         occurrences all number
    1
    3
    3
    Enteritis
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    3 / 182 (1.65%)
         occurrences all number
    2
    0
    3
    Steatorrhoea
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    3 / 182 (1.65%)
         occurrences all number
    0
    1
    3
    Dry mouth
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    1
    1
    1
    Frequent bowel movements
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    1
    1
    1
    Toothache
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    1
    0
    2
    Abdominal pain lower
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    0
    2
    0
    Faeces soft
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Malabsorption
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Abdominal tenderness
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Anal fissure
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Chapped lips
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Colonic haematoma
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Defaecation urgency
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Faecaloma
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Gastric dilatation
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal sounds abnormal
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Gingival swelling
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Gingivitis ulcerative
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Oesophagitis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Rectal tenesmus
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Tongue coated
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatitis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    1
    2
    0
    Urine odour abnormal
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    2
    0
    0
    Calculus urinary
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Leukocyturia
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Nephropathy
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Nephropathy toxic
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Renal failure acute
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Urine abnormality
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 184 (1.09%)
    8 / 183 (4.37%)
    6 / 182 (3.30%)
         occurrences all number
    2
    8
    6
    Pruritus
         subjects affected / exposed
    1 / 184 (0.54%)
    5 / 183 (2.73%)
    4 / 182 (2.20%)
         occurrences all number
    1
    6
    5
    Acne
         subjects affected / exposed
    5 / 184 (2.72%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    5
    1
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    0
    1
    2
    Night sweats
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences all number
    0
    3
    1
    Urticaria
         subjects affected / exposed
    2 / 184 (1.09%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    2
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Dermatitis allergic
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    2
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    0
    0
    2
    Pruritus allergic
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Pruritus generalised
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Rash macular
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Chloasma
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Cold sweat
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Drug eruption
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Eczema
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Erythema
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Erythema nodosum
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Macule
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Rash generalised
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    2
    Red man syndrome
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Swelling face
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    6 / 184 (3.26%)
    7 / 183 (3.83%)
    3 / 182 (1.65%)
         occurrences all number
    6
    7
    3
    Myalgia
         subjects affected / exposed
    4 / 184 (2.17%)
    3 / 183 (1.64%)
    7 / 182 (3.85%)
         occurrences all number
    5
    3
    7
    Back pain
         subjects affected / exposed
    5 / 184 (2.72%)
    3 / 183 (1.64%)
    5 / 182 (2.75%)
         occurrences all number
    6
    3
    6
    Arthralgia
         subjects affected / exposed
    4 / 184 (2.17%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    4
    1
    2
    Pain in extremity
         subjects affected / exposed
    4 / 184 (2.17%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    4
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    3 / 182 (1.65%)
         occurrences all number
    0
    1
    3
    Flank pain
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences all number
    0
    2
    1
    Muscle spasms
         subjects affected / exposed
    2 / 184 (1.09%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    2
    1
    0
    Joint swelling
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    2
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Tendon pain
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Arthropathy
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Neck pain
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Tendon disorder
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Tendonitis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 184 (2.17%)
    6 / 183 (3.28%)
    6 / 182 (3.30%)
         occurrences all number
    4
    6
    6
    Hypoglycaemia
         subjects affected / exposed
    3 / 184 (1.63%)
    6 / 183 (3.28%)
    2 / 182 (1.10%)
         occurrences all number
    3
    6
    3
    Dehydration
         subjects affected / exposed
    3 / 184 (1.63%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    3
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    2 / 184 (1.09%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    2
    1
    1
    Gout
         subjects affected / exposed
    2 / 184 (1.09%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    2
    1
    0
    Diabetes mellitus
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    2 / 182 (1.10%)
         occurrences all number
    0
    0
    2
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Iron deficiency
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Magnesium deficiency
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Vitamin K deficiency
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    58 / 184 (31.52%)
    57 / 183 (31.15%)
    54 / 182 (29.67%)
         occurrences all number
    86
    79
    75
    Nasopharyngitis
         subjects affected / exposed
    20 / 184 (10.87%)
    9 / 183 (4.92%)
    26 / 182 (14.29%)
         occurrences all number
    23
    13
    33
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 184 (5.43%)
    16 / 183 (8.74%)
    17 / 182 (9.34%)
         occurrences all number
    13
    21
    21
    Rhinitis
         subjects affected / exposed
    12 / 184 (6.52%)
    16 / 183 (8.74%)
    8 / 182 (4.40%)
         occurrences all number
    17
    18
    8
    Sinusitis
         subjects affected / exposed
    12 / 184 (6.52%)
    7 / 183 (3.83%)
    5 / 182 (2.75%)
         occurrences all number
    15
    7
    5
    Influenza
         subjects affected / exposed
    3 / 184 (1.63%)
    8 / 183 (4.37%)
    8 / 182 (4.40%)
         occurrences all number
    3
    8
    8
    Bronchitis
         subjects affected / exposed
    7 / 184 (3.80%)
    9 / 183 (4.92%)
    2 / 182 (1.10%)
         occurrences all number
    11
    11
    4
    Respiratory tract infection
         subjects affected / exposed
    3 / 184 (1.63%)
    2 / 183 (1.09%)
    6 / 182 (3.30%)
         occurrences all number
    5
    2
    7
    Pharyngitis
         subjects affected / exposed
    2 / 184 (1.09%)
    4 / 183 (2.19%)
    4 / 182 (2.20%)
         occurrences all number
    2
    4
    4
    Vulvovaginal mycotic infection
         subjects affected / exposed
    4 / 184 (2.17%)
    2 / 183 (1.09%)
    3 / 182 (1.65%)
         occurrences all number
    4
    2
    5
    Oral candidiasis
         subjects affected / exposed
    3 / 184 (1.63%)
    2 / 183 (1.09%)
    3 / 182 (1.65%)
         occurrences all number
    3
    3
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 184 (1.63%)
    2 / 183 (1.09%)
    3 / 182 (1.65%)
         occurrences all number
    3
    2
    3
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    2 / 184 (1.09%)
    2 / 183 (1.09%)
    3 / 182 (1.65%)
         occurrences all number
    3
    3
    3
    Viral infection
         subjects affected / exposed
    4 / 184 (2.17%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences all number
    4
    2
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    2 / 182 (1.10%)
         occurrences all number
    1
    2
    2
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    3 / 184 (1.63%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    3
    1
    1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    2 / 182 (1.10%)
         occurrences all number
    1
    2
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    3 / 182 (1.65%)
         occurrences all number
    0
    1
    3
    H1N1 influenza
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    1
    1
    2
    Oral herpes
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    2 / 182 (1.10%)
         occurrences all number
    1
    1
    2
    Otitis media
         subjects affected / exposed
    0 / 184 (0.00%)
    3 / 183 (1.64%)
    1 / 182 (0.55%)
         occurrences all number
    0
    3
    1
    Acute sinusitis
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    2
    1
    1
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    1
    2
    0
    Fungal skin infection
         subjects affected / exposed
    2 / 184 (1.09%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    2
    1
    0
    Laryngitis
         subjects affected / exposed
    1 / 184 (0.54%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    1
    2
    0
    Sputum purulent
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    1 / 182 (0.55%)
         occurrences all number
    0
    2
    1
    Bacterial disease carrier
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Chronic sinusitis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    2
    1
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 184 (0.00%)
    2 / 183 (1.09%)
    0 / 182 (0.00%)
         occurrences all number
    0
    3
    0
    Mycobacterium abscessus infection
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    2
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    1
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 184 (0.54%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    1
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    2
    0
    0
    Acute tonsillitis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Body tinea
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis bacterial
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Eye infection
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Genital infection fungal
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Giardiasis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Herpes dermatitis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Herpes simplex
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Lung infection
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Oral fungal infection
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    2
    Otitis externa
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Overgrowth bacterial
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Pseudomonas bronchitis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    2
    0
    Soft tissue infection
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Stoma site infection
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Tinea pedis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Tinea versicolour
         subjects affected / exposed
    0 / 184 (0.00%)
    0 / 183 (0.00%)
    1 / 182 (0.55%)
         occurrences all number
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Tracheitis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Viral rhinitis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    0 / 182 (0.00%)
         occurrences all number
    0
    1
    0
    Viral tonsillitis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 183 (0.00%)
    0 / 182 (0.00%)
         occurrences all number
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    12 / 184 (6.52%)
    15 / 183 (8.20%)
    13 / 182 (7.14%)
         occurrences all number
    15
    19
    19
    Bronchitis bacterial
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 183 (0.55%)
    1 / 182 (0.55%)
         occurrences all number
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jul 2013
    Modified primary endpoint and selected secondary endpoint.
    05 Feb 2014
    Order of primary and key secondary endpoints was revised.
    24 Feb 2014
    Clarification on which subjects were required to complete the Safety Follow-up Visit was provided.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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