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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of VX-770 in Subjects Aged 12 Years and Older With Cystic Fibrosis who are Homozygous for the F508del-CFTR Mutation

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2009-010261-23
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    29 May 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    13 Jul 2016
    First version publication date
    07 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Re-QC per EMA guidance to verify that there are no data-related error in the document due to EudraCT system issues impacting finalized results postings

    Trial information

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    Trial identification
    Sponsor protocol code
    VX08-770-104
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00953706
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, 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-000335-PIP01-08
    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
    27 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 May 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety and efficacy of ivacaftor in subjects with cystic fibrosis (CF) who were aged 12 years or older and were homozygous for the F508del-CF transmembrane conductance regulator (CFTR) mutation.
    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
    21 Sep 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    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
    United States: 140
    Worldwide total number of subjects
    140
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    50
    Adults (18-64 years)
    90
    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 2-week run-in period was included to establish the baseline assessments on Day 1 after ensuring that subjects were properly adhering to their cystic fibrosis (CF) medication.

    Period 1
    Period 1 title
    Part A (16-Week Double-Blind Treatment)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo – Part A
    Arm description
    Placebo matched to ivacaftor tablet orally every 12 hours (q12h) for 16 weeks during Part A (double-blind treatment period).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablet every 12 hours (q12h) for 16 weeks.

    Arm title
    Ivacaftor – Part A
    Arm description
    Ivacaftor 150 milligram (mg) tablet orally q12h for 16 weeks during Part A (double-blind treatment period)
    Arm type
    Experimental

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablet of 150 mg of ivacaftor q12h for 16 weeks.

    Number of subjects in period 1
    Placebo – Part A Ivacaftor – Part A
    Started
    28
    112
    Completed
    26
    104
    Not completed
    2
    8
         Noncompliance with Study Requirements
    -
    2
         Adverse event
    2
    3
         Required Prohibited Medication
    -
    1
         Sponsor Decision
    -
    1
         Lost to follow-up
    -
    1
    Period 2
    Period 2 title
    Part B (96-Week Open-Label Extension)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/Ivacaftor – Part B
    Arm description
    Subjects who received placebo during Part A, received ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).
    Arm type
    Experimental

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablet of 150 mg of ivacaftor q12h for 96 weeks.

    Arm title
    Ivacaftor/Ivacaftor – Part B
    Arm description
    Subjects who received ivacaftor during Part A, received ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).
    Arm type
    Experimental

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablet of 150 mg of ivacaftor q12h for 96 weeks.

    Number of subjects in period 2 [1]
    Placebo/Ivacaftor – Part B Ivacaftor/Ivacaftor – Part B
    Started
    5
    33
    Completed
    0
    0
    Not completed
    5
    33
         Noncompliance with Study Requirements
    -
    1
         Adverse event
    -
    2
         Study Termination by Sponsor
    4
    25
         Unspecified
    -
    2
         Consent withdrawn by subject
    1
    2
         Required Prohibited Medication
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: From Placebo – Part A arm only 5 subjects continued in Part B. From Ivacaftor – Part A arm only 33 subjects continued in Part B.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo – Part A
    Reporting group description
    Placebo matched to ivacaftor tablet orally every 12 hours (q12h) for 16 weeks during Part A (double-blind treatment period).

    Reporting group title
    Ivacaftor – Part A
    Reporting group description
    Ivacaftor 150 milligram (mg) tablet orally q12h for 16 weeks during Part A (double-blind treatment period)

    Reporting group values
    Placebo – Part A Ivacaftor – Part A Total
    Number of subjects
    28 112 140
    Age categorical
    Units: Subjects
        12 to 17 Years
    6 44 50
        18 to 24 Years
    10 32 42
        25 to 39 Years
    12 26 38
        40 to 45 Years
    0 5 5
        > 45 Years
    0 5 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    25 ± 8.35 22.8 ± 10.26 -
    Gender categorical
    Units: Subjects
        Female
    12 54 66
        Male
    16 58 74
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    1 2 3
        Not Hispanic or Latino
    27 110 137
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American
    0 1 1
        White
    28 111 139
    Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1), Categorical
    Percent predicted for age, gender, and height.
    Units: Subjects
        < 70%
    15 38 53
        ≥ 70% to ≤ 90%
    5 35 40
        > 90%
    8 39 47
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    63.2 ± 14.96 58.2 ± 13.49 -
    Body Mass Index
    Units: kilogram per square meter
        arithmetic mean (standard deviation)
    22.2 ± 4.48 21.2 ± 3.25 -
    Sweat Chloride
    Units: millimoles per liter
        arithmetic mean (standard deviation)
    102.4 ± 7.91 101.4 ± 10.28 -
    ppFEV1, Continuous
    Percent predicted for age, gender, and height.
    Units: percentage
        arithmetic mean (standard deviation)
    74.8 ± 24.06 79.7 ± 22.67 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo – Part A
    Reporting group description
    Placebo matched to ivacaftor tablet orally every 12 hours (q12h) for 16 weeks during Part A (double-blind treatment period).

    Reporting group title
    Ivacaftor – Part A
    Reporting group description
    Ivacaftor 150 milligram (mg) tablet orally q12h for 16 weeks during Part A (double-blind treatment period)
    Reporting group title
    Placebo/Ivacaftor – Part B
    Reporting group description
    Subjects who received placebo during Part A, received ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).

    Reporting group title
    Ivacaftor/Ivacaftor – Part B
    Reporting group description
    Subjects who received ivacaftor during Part A, received ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).

    Primary: Part A : Absolute Change from Part A Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 16

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    End point title
    Part A : Absolute Change from Part A Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 16
    End point description
    Spirometry (as measured by ppFEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, race and height) was calculated using the Knudson method. Analysis was performed on Part A Full Analysis Set (FAS) defined as all randomized subjects who received at least 1 dose of study drug during Part A. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Part A baseline through Week 16
    End point values
    Placebo – Part A Ivacaftor – Part A
    Number of subjects analysed
    28
    111
    Units: percent predicted of FEV1
        least squares mean (standard error)
    -0.2 ± 1.1
    1.5 ± 0.5
    Statistical analysis title
    Part A: ppFEV1 Through Week 16
    Statistical analysis description
    The primary analysis for the primary efficacy variable was based on a Mixed-Effects Model for Repeated Measures (MMRM). The model included absolute change from baseline in percent predicted forced expiratory volume in 1 second (FEV1) as the dependent variable, treatment (ivacaftor versus placebo) and visit as fixed effects, and subject as a random effect, with adjustment for age and continuous baseline value of percent predicted FEV1.
    Comparison groups
    Placebo – Part A v Ivacaftor – Part A
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1509
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    4.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2

    Secondary: Part A: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 16 (Respiratory Domain Score, Pooled)

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    End point title
    Part A: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 16 (Respiratory Domain Score, Pooled)
    End point description
    The CFQR 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), score range: 0-100; Higher scores indicating fewer symptoms and better health-related quality of life. Analysis was performed on Part A FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    baseline through 16 weeks
    End point values
    Placebo – Part A Ivacaftor – Part A
    Number of subjects analysed
    28
    111
    Units: score on a scale
        least squares mean (standard error)
    -1.4 ± 1.9
    -0.1 ± 1
    Statistical analysis title
    Part A: CFQ-R Score Through Week 16
    Statistical analysis description
    Analysis for the respiratory domain score endpoint was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with the dependent variable being absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for for age and baseline value for CFQ-R score, using unstructured covariance matrix .
    Comparison groups
    Placebo – Part A v Ivacaftor – Part A
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5408
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.9
         upper limit
    5.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1

    Secondary: Part A: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 16

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    End point title
    Part A: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 16
    End point description
    The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity. Analysis was performed on Part A FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    baseline through 16 weeks
    End point values
    Placebo – Part A Ivacaftor – Part A
    Number of subjects analysed
    28
    111
    Units: millimoles per liter
        least squares mean (standard error)
    0.1 ± 1.2
    -2.7 ± 0.6
    Statistical analysis title
    Part A: Sweat Chloride Through Week 16
    Statistical analysis description
    Analysis for this variable was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable being absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous age and baseline value for age, sweat chloride, using unstructured covariance matrix.
    Comparison groups
    Placebo – Part A v Ivacaftor – Part A
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0384
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.6
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4

    Secondary: Part A: Rate of Change From Baseline in Weight Through Week 16

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    End point title
    Part A: Rate of Change From Baseline in Weight Through Week 16
    End point description
    As malnutrition is common in subjects with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status. Analysis was performed on Part A FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    baseline to 16 weeks
    End point values
    Placebo – Part A Ivacaftor – Part A
    Number of subjects analysed
    28
    112
    Units: kilograms per 112 days
        least squares mean (standard error)
    0.9 ± 0.4
    0.8 ± 0.2
    Statistical analysis title
    Part A: Weight Through Week 16
    Statistical analysis description
    The analysis used the linear mixed model with treatment as fixed effects, visit (days on study) and treatment by visit interaction as random effects, with adjustment for age group (< 18 years and ≥ 18 years) and percent predicted forced expiratory volume (FEV1) severity (< 70%, ≥ 70% to ≤ 90%, > 90%) at screening, with random intercept and random slope. Rate of change in the study period is the slope of weight versus time (days) multiplied by the number of days in the study period (112 days).
    Comparison groups
    Placebo – Part A v Ivacaftor – Part A
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7265
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5

    Secondary: Part B : Absolute Change From Part A and Part B Baseline in ppFEV1 Through Week 64

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    End point title
    Part B : Absolute Change From Part A and Part B Baseline in ppFEV1 Through Week 64
    End point description
    ppFEV1 is defined in primary endpoint. Analysis was performed on Part B FAS defined as all subjects who received at least 1 dose of study drug during Part B. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64
    End point values
    Placebo/Ivacaftor – Part B Ivacaftor/Ivacaftor – Part B
    Number of subjects analysed
    4
    27
    Units: percent predicted of FEV1
    arithmetic mean (standard deviation)
        Change From Part A Baseline at Week 64
    8.9398 ± 9.703
    2.7233 ± 10.52046
        Change From Part B Baseline at Week 64
    3.5593 ± 7.95875
    -5.0565 ± 11.44783
    No statistical analyses for this end point

    Secondary: Part B : Rate of Decline From Part A Baseline in ppFEV1 Through Week 64

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    End point title
    Part B : Rate of Decline From Part A Baseline in ppFEV1 Through Week 64
    End point description
    ppFEV1 is defined in primary endpoint. Analysis was performed on Part B FAS.
    End point type
    Secondary
    End point timeframe
    Part A baseline through Week 64
    End point values
    Placebo/Ivacaftor – Part B Ivacaftor/Ivacaftor – Part B
    Number of subjects analysed
    5
    33
    Units: percent predicted of FEV1 per 448 days
        least squares mean (standard error)
    5.7445 ± 3.681
    -1.0738 ± 1.5025
    No statistical analyses for this end point

    Secondary: Part B : Rate of Decline From Part B Baseline in ppFEV1 Through Week 64

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    End point title
    Part B : Rate of Decline From Part B Baseline in ppFEV1 Through Week 64
    End point description
    ppFEV1 is defined in primary endpoint. Analysis was performed on Part B FAS.
    End point type
    Secondary
    End point timeframe
    Part B baseline through Week 64
    End point values
    Placebo/Ivacaftor – Part B Ivacaftor/Ivacaftor – Part B
    Number of subjects analysed
    5
    33
    Units: percent predicted of FEV1 per 336 days
        least squares mean (standard error)
    5.3409 ± 4.579
    -5.2994 ± 1.8871
    No statistical analyses for this end point

    Secondary: Part B : Absolute Change From Part A and Part B Baseline in CFQ-R Respiratory Domain Score Through Week 64

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    End point title
    Part B : Absolute Change From Part A and Part B Baseline in CFQ-R Respiratory Domain Score Through Week 64
    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), score range: 0-100; Higher scores indicating fewer symptoms and better health-related quality of life. Analysis was performed on Part B FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64
    End point values
    Placebo/Ivacaftor – Part B Ivacaftor/Ivacaftor – Part B
    Number of subjects analysed
    4
    26
    Units: units on a scale
    arithmetic mean (standard deviation)
        Change From Part A Baseline at Week 64
    2.1 ± 11.443
    1.5 ± 15.778
        Change From Part B Baseline at Week 64
    2.08 ± 17.763
    2.62 ± 15.899
    No statistical analyses for this end point

    Secondary: Part B : Absolute Change from Part A and Part B Baseline in Sweat Chloride Concentration Through Week 64

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    End point title
    Part B : Absolute Change from Part A and Part B Baseline in Sweat Chloride Concentration Through Week 64
    End point description
    The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for CF, serving as an indicator of CFTR activity. Analysis was performed on Part B FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64
    End point values
    Placebo/Ivacaftor – Part B Ivacaftor/Ivacaftor – Part B
    Number of subjects analysed
    4
    26
    Units: millimole per liter (mmol/L)
    arithmetic mean (standard deviation)
        Change From Part A Baseline at Week 64
    -7.13 ± 15.612
    -3.65 ± 11.963
        Change From Part B Baseline at Week 64
    -3.88 ± 7.685
    -2.44 ± 11.037
    No statistical analyses for this end point

    Secondary: Part B : Absolute Change From Part A and Part B Baseline in Weight Through Week 64

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    End point title
    Part B : Absolute Change From Part A and Part B Baseline in Weight Through Week 64
    End point description
    As malnutrition is common in subjects with CF because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status. Analysis was performed on Part B FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64
    End point values
    Placebo/Ivacaftor – Part B Ivacaftor/Ivacaftor – Part B
    Number of subjects analysed
    4
    27
    Units: kilograms (kg)
    arithmetic mean (standard deviation)
        Change From Part A Baseline at Week 64
    3 ± 3.55
    2.35 ± 5.6
        Change From Part B Baseline at Week 64
    1.28 ± 2.243
    1.45 ± 3.84
    No statistical analyses for this end point

    Secondary: Part B : Number of Subjects With Pulmonary Exacerbations

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    End point title
    Part B : Number of Subjects With Pulmonary Exacerbations
    End point description
    Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent (%); and radiographic changes indicative of pulmonary infection. Analysis was performed on Part B FAS.
    End point type
    Secondary
    End point timeframe
    Part B baseline through Week 64
    End point values
    Placebo/Ivacaftor – Part B Ivacaftor/Ivacaftor – Part B
    Number of subjects analysed
    5
    33
    Units: subjects
        number (not applicable)
    4
    16
    No statistical analyses for this end point

    Secondary: Part B : Number of Pulmonary Exacerbation Events

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    End point title
    Part B : Number of Pulmonary Exacerbation Events
    End point description
    Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 %; and radiographic changes indicative of pulmonary infection. Analysis was performed on Part B FAS.
    End point type
    Secondary
    End point timeframe
    Part B baseline through Week 64
    End point values
    Placebo/Ivacaftor – Part B Ivacaftor/Ivacaftor – Part B
    Number of subjects analysed
    5
    33
    Units: events
        number (not applicable)
    6
    26
    No statistical analyses for this end point

    Secondary: Part B : Number of Pulmonary Exacerbation Events per Subject per Year

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    End point title
    Part B : Number of Pulmonary Exacerbation Events per Subject per Year
    End point description
    Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 %; and radiographic changes indicative of pulmonary infection. Analysis was performed on Part B FAS.
    End point type
    Secondary
    End point timeframe
    Part B baseline through Week 64
    End point values
    Placebo/Ivacaftor – Part B Ivacaftor/Ivacaftor – Part B
    Number of subjects analysed
    5
    33
    Units: events per subject per year
        number (not applicable)
    1.1
    0.82
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (serious and non-serious) were collected from signing of informed consent through 2 years after last dose (in Part B) of study drug (median treatment duration: 112 days for Part A and 381 days for Part B
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Part A: Placebo
    Reporting group description
    Oral tablet q12h for 16 weeks.

    Reporting group title
    Part A: 150 mg Ivacaftor q12h
    Reporting group description
    Oral tablet of 150 mg of ivacaftor q12h for 16 weeks.

    Reporting group title
    Part B: Placebo/Ivacaftor
    Reporting group description
    Oral tablet of 150 mg of ivacaftor q12h for up to 76 weeks in subjects who received placebo in Part A.

    Reporting group title
    Part B : Ivacaftor/Ivacaftor
    Reporting group description
    Oral tablet of 150 mg of ivacaftor q12h for up to 76 weeks in subjects who received Ivacaftor in Part A.

    Serious adverse events
    Part A: Placebo Part A: 150 mg Ivacaftor q12h Part B: Placebo/Ivacaftor Part B : Ivacaftor/Ivacaftor
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 28 (21.43%)
    15 / 112 (13.39%)
    2 / 5 (40.00%)
    14 / 33 (42.42%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic Brain Injury
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis lung
         subjects affected / exposed
    5 / 28 (17.86%)
    10 / 112 (8.93%)
    2 / 5 (40.00%)
    13 / 33 (39.39%)
         occurrences causally related to treatment / all
    0 / 6
    2 / 12
    0 / 4
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myopathy
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central Line Infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Part A: Placebo Part A: 150 mg Ivacaftor q12h Part B: Placebo/Ivacaftor Part B : Ivacaftor/Ivacaftor
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 28 (89.29%)
    98 / 112 (87.50%)
    5 / 5 (100.00%)
    30 / 33 (90.91%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Surgical and medical procedures
    Wisdom teeth removal
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Focal nodular hyperplasia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin papilloma
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Immune system disorders
    Allergy to animal
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    0
    0
    1
    Seasonal allergy
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Hypersensitivity
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    1 / 5 (20.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 28 (10.71%)
    8 / 112 (7.14%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    3
    8
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 28 (7.14%)
    9 / 112 (8.04%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    2
    10
    0
    3
    Catheter site pain
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    0
    2
    Chills
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Application site pruritus
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Application site rash
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Feeling abnormal
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Generalised oedema
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thirst
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vessel puncture site pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Catheter related complication
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Infusion site pain
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Pain
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 112 (0.89%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
         occurrences all number
    2
    1
    1
    2
    Abnormal dreams
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    1
    0
    3
    Hallucination
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Adjustment disorder
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    Breast tenderness
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Prostatic cyst
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Testicular pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Testicular swelling
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    3
    0
    1
    Skin laceration
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    0
    2
    Foreign body trauma
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Joint injury
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Joint sprain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Procedural site reaction
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Traumatic brain injury
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Animal bite
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    0
    2
    Arthropod sting
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    1 / 5 (20.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Excoriation
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Head injury
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Sunburn
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Wound
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    1 / 5 (20.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    1 / 28 (3.57%)
    6 / 112 (5.36%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    6
    0
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 28 (3.57%)
    5 / 112 (4.46%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    5
    0
    1
    Pulmonary function test decreased
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    2
    4
    0
    2
    Bacteria Sputum Identified
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    4
    0
    1
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    3
    1
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Glucose urine present
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    4
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Blood immunoglobulin G increased
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Breath sounds abnormal
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    2
    0
    1
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    2
    1
    1
    Vitamin D decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Antibiotic level above therapeutic
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bacterial Culture positive
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood glucose decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Bone density decreased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Liver function test abnormal
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    0
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sputum culture positive
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    2
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Sputum abnormal
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Congenital, familial and genetic disorders
    Cystic fibrosis lung
         subjects affected / exposed
    7 / 28 (25.00%)
    19 / 112 (16.96%)
    3 / 5 (60.00%)
    11 / 33 (33.33%)
         occurrences all number
    8
    24
    6
    17
    Cystic fibrosis related diabetes
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 28 (14.29%)
    34 / 112 (30.36%)
    0 / 5 (0.00%)
    15 / 33 (45.45%)
         occurrences all number
    5
    43
    0
    17
    Nasal congestion
         subjects affected / exposed
    2 / 28 (7.14%)
    13 / 112 (11.61%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    2
    14
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    3 / 28 (10.71%)
    10 / 112 (8.93%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    3
    12
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 28 (3.57%)
    9 / 112 (8.04%)
    0 / 5 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    1
    9
    0
    5
    Haemoptysis
         subjects affected / exposed
    1 / 28 (3.57%)
    5 / 112 (4.46%)
    2 / 5 (40.00%)
    2 / 33 (6.06%)
         occurrences all number
    1
    10
    3
    2
    Rhinorrhea
         subjects affected / exposed
    2 / 28 (7.14%)
    4 / 112 (3.57%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    2
    5
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 28 (0.00%)
    5 / 112 (4.46%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    5
    1
    2
    Nasal polyps
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Rales
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    1
    4
    0
    2
    Respiratory tract congestion
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    4
    0
    1
    Nasal mucosal disorder
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    3
    0
    1
    Pharyngeal erythema
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Sinus congestion
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    0
    2
    Wheezing
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Asthma
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    1
    1
    0
    2
    Pleuritic pain
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    0
    1
    Respiration abnormal
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    2
    1
    1
    Bronchospasm
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasal oedema
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Paranasal sinus Hypersecretion
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pharyngeal disorder
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Postnasal Drip
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sputum discoloured
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Tachypnoea
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    1 / 5 (20.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    3
    0
    1
    Lymphadenopathy
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 28 (7.14%)
    11 / 112 (9.82%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    3
    17
    0
    1
    Dizziness
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    2
    3
    0
    0
    Sinus headache
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Burning sensation
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperaesthesia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Presyncope
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Syncope
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye pruritus
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Visual impairment
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Erythema of eyelid
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Middle ear effusion
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 28 (3.57%)
    10 / 112 (8.93%)
    0 / 5 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    1
    11
    0
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 28 (3.57%)
    7 / 112 (6.25%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    4
    8
    0
    3
    Diarrhoea
         subjects affected / exposed
    2 / 28 (7.14%)
    6 / 112 (5.36%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    2
    7
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 28 (3.57%)
    4 / 112 (3.57%)
    3 / 5 (60.00%)
    2 / 33 (6.06%)
         occurrences all number
    1
    5
    3
    2
    Vomiting
         subjects affected / exposed
    0 / 28 (0.00%)
    4 / 112 (3.57%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ascites
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    1
    2
    Dental caries
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Distal ileal obstruction syndrome
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Hiatus hernia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Pancreatic duct dilatation
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Peptic ulcer
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Regurgitation
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tooth impacted
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Sensitivity of teeth
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hepatosplenomegaly
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Calculus bladder
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chromaturia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Proteinuria
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal cyst
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal failure acute
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 28 (0.00%)
    9 / 112 (8.04%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    9
    0
    1
    Dermatitis contact
         subjects affected / exposed
    0 / 28 (0.00%)
    6 / 112 (5.36%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    9
    0
    2
    Pruritus
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Rash vesicular
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Blister
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    0
    0
    1
    Night sweats
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Photodermatosis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Rash macular
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    0
    3
    Urticaria
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Red man syndrome
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    0
    3
    Arthralgia
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    5
    0
    4
    Back pain
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    0
    3
    Pain in extremity
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    0
    3
    Joint swelling
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Arthritis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Clubbing
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    1
    0
    2
    Muscular weakness
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myopathy
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    0
    0
    4
    Arthropathy
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Synovial cyst
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 112 (1.79%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    2
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 112 (2.68%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    0
    2
    Gout
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    1
    1
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Hypovitaminosis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 28 (7.14%)
    11 / 112 (9.82%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
         occurrences all number
    2
    13
    1
    2
    Sinusitis
         subjects affected / exposed
    1 / 28 (3.57%)
    8 / 112 (7.14%)
    1 / 5 (20.00%)
    4 / 33 (12.12%)
         occurrences all number
    1
    9
    1
    5
    Rhinitis
         subjects affected / exposed
    0 / 28 (0.00%)
    5 / 112 (4.46%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 28 (0.00%)
    4 / 112 (3.57%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Ear infection
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    0
    1
    Laryngitis
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Acute sinusitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    1
    0
    0
    1
    Candidiasis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Kidney infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Orchitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory moniliasis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Stenotrophomonas infection
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tinea infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    2
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 112 (0.89%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    1
    0
    3
    Bronchitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    0
    0
    4
    Bacterial disease carrier
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Body tinea
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Helicobacter gastritis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    1 / 5 (20.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infectious mononucleosis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Otitis externa
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Vaginitis bacterial
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 112 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 May 2009
    Timing of multiple pharmacokinetic (PK) assessments and postdose standard digital electrocardiograms (ECGs) were changed. Follow-up criteria were clarified.
    09 Oct 2009
    An open-label extension period (Part B) was added. Inclusion/exclusion criteria were updated.
    08 Apr 2010
    Mandatory liver function tests were added.
    02 Jul 2010
    Subject removal criteria were updated.
    10 Sep 2010
    Clarification on SAEs collection was added.
    27 Oct 2010
    Frequency of liver function testing in Part B beyond Week 40 was adjusted.
    06 Jun 2011
    Extension Period Long-term Follow-up was added to Part B.

    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.
    In Part B, the treatment duration was 96 weeks; however, due to early study termination all analysis were performed up to Week 64, as planned.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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