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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 VX 770 in Subjects with Cystic Fibrosis and the G551D Mutation

    Summary
    EudraCT number
    2008-007416-15
    Trial protocol
    IE   GB   DE   CZ   FR  
    Global end of trial date
    29 Nov 2012

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

    Trial information

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    Trial identification
    Sponsor protocol code
    VX08-770-102
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00909532
    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, +1 617-444-6777, medicalinfo@vrtx.com
    Scientific contact
    Medical Monitor, Vertex, +1 617-444-6777, 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
    15 Mar 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the efficacy of VX-770 after 24 weeks of treatment in subjects with cystic fibrosis (CF) with G551D cystic fibrosis 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
    10 Jun 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 Kingdom: 9
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Ireland: 14
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    United States: 91
    Worldwide total number of subjects
    161
    EEA total number of subjects
    42
    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)
    36
    Adults (18-64 years)
    125
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started on 10 June 2009 (signing of first informed consent). After obtaining consent and assent (where applicable), screening evaluations were completed during a period of 2 to 5 weeks (Day -35 to Day -15) before the first dose of study drug.

    Pre-assignment
    Screening details
    A total of 167 subjects were randomized; 161 subjects received at least 1 dose of the study drug. A 2-week run-in period was included to establish the baseline assessments on Day 1 after ensuring that subjects were properly taking their cystic fibrosis (CF) medication regimens.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo-matched-to-ivacaftor tablet orally every 12 hours (q12h) up to 48 weeks.
    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-ivacaftor tablet orally q12h up to 48 weeks.

    Arm title
    150 mg Ivacaftor q12h
    Arm description
    Ivacaftor 150 mg tablet orally q12h for up to 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX770
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor 150 mg tablet administered orally q12h for up to 48 weeks.

    Number of subjects in period 1
    Placebo 150 mg Ivacaftor q12h
    Started
    78
    83
    Completed Treatment Period, Week 24
    71
    80
    Completed
    68
    77
    Not completed
    10
    6
         Consent withdrawn by subject
    1
    1
         Physician decision
    1
    -
         'Wrong Genotype '
    1
    -
         Pregnancy
    -
    1
         Adverse event
    4
    1
         'Increased Lab Draws, Difficult Lab Stick '
    1
    -
         Noncompliance with Study Requirements
    -
    2
         Prohibited Medication
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo-matched-to-ivacaftor tablet orally every 12 hours (q12h) up to 48 weeks.

    Reporting group title
    150 mg Ivacaftor q12h
    Reporting group description
    Ivacaftor 150 mg tablet orally q12h for up to 48 weeks.

    Reporting group values
    Placebo 150 mg Ivacaftor q12h Total
    Number of subjects
    78 83 161
    Age categorical
    Units: Subjects
        <=18 years
    17 19 36
        Between 18 and 65 years
    61 64 125
        >=65 years
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    24.7 ± 9.21 26.2 ± 9.85 -
    Gender categorical
    Units: Subjects
        Female
    40 44 84
        Male
    38 39 77
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 0 0
        Not Hispanic or Latino
    77 81 158
        Unknown or Not Reported
    1 2 3
    Race/Ethnicity, Customized
    Units: Subjects
        White
    77 81 158
        Not Allowed to Ask Per Local Regulations
    1 2 3
    Region of Enrollment
    Units: Subjects
        North America
    50 50 100
        Europe
    19 23 42
        Australia
    9 10 19
    Percent Predicted FEV1, Categorical
    Units: Subjects
        < 70% predicted FEV1
    45 49 94
        ≥ 70% predicted FEV1
    33 34 67
    Percent Predicted Forced Expiratory Volume in 1 Second (FEV1), Continuous [1]
    Units: percentage
        arithmetic mean (standard deviation)
    63.7 ± 16.83 63.5 ± 16.14 -
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    61.2 ± 13.93 61.7 ± 14.26 -
    Body Mass Index
    Units: kilograms per square meter
        arithmetic mean (standard deviation)
    21.9 ± 3.49 21.7 ± 3.65 -
    Sweat Chloride
    Units: millimoles per liter (mmol/liter)
        arithmetic mean (standard deviation)
    100.1 ± 10.63 100.4 ± 10 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo-matched-to-ivacaftor tablet orally every 12 hours (q12h) up to 48 weeks.

    Reporting group title
    150 mg Ivacaftor q12h
    Reporting group description
    Ivacaftor 150 mg tablet orally q12h for up to 48 weeks.

    Primary: Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24

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    End point title
    Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24
    End point description
    Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. Analysis population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.
    End point type
    Primary
    End point timeframe
    Baseline through 24 weeks
    End point values
    Placebo 150 mg Ivacaftor q12h
    Number of subjects analysed
    78
    83
    Units: percent of predicted volume (L)
        least squares mean (standard error)
    -0.2 ± 0.7
    10.4 ± 0.7
    Statistical analysis title
    Percent Predicted FEV1 Through Week 24
    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 (Day 15, Week 8, Week 16, and Week 24) as fixed effects, and subject as a random effect, with adjustment for the continuous baseline values of age and percent predicted FEV1.
    Comparison groups
    Placebo v 150 mg Ivacaftor q12h
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    10.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.6
         upper limit
    12.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1
    Notes
    [1] - The primary and key secondary endpoints were analyzed using Hochberg’s step-up procedure: test 1, primary (α=0.05); test 2, CFQ-R resp domain (Wk24) and sweat chloride (Wk24)(α=0.05).

    Secondary: Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48

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    End point title
    Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48
    End point description
    Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. Analysis population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.
    End point type
    Secondary
    End point timeframe
    Baseline through 48 weeks
    End point values
    Placebo 150 mg Ivacaftor q12h
    Number of subjects analysed
    78
    83
    Units: percent of predicted volume (L)
        least squares mean (standard error)
    -0.4 ± 0.7
    10.1 ± 0.7
    Statistical analysis title
    Percent Predicted FEV1 Through Week 48
    Statistical analysis description
    Analysis of this variable was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were obtained from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for the continuous baseline values of age and percent predicted forced expiratory volume in 1 second (FEV1),using unstructured covariance matrix.
    Comparison groups
    Placebo v 150 mg Ivacaftor q12h
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    10.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.5
         upper limit
    12.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1
    Notes
    [2] - There was no adjustment for multiple comparisons. Denominator degrees of freedom were estimated using the Kenward-Roger approximation. No imputation of missing data was done.

    Secondary: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)

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    End point title
    Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)
    End point description
    The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID). Analysis population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.
    End point type
    Secondary
    End point timeframe
    Baseline through 24 weeks and 48 weeks
    End point values
    Placebo 150 mg Ivacaftor q12h
    Number of subjects analysed
    71
    80
    Units: score on a scale
    least squares mean (standard error)
        Change from Baseline Through Week 24
    -2.1 ± 1.3
    6 ± 1.2
        Change from Baseline Through Week 48
    -2.7 ± 1.2
    6 ± 1.1
    Statistical analysis title
    CFQ-R Score Through Week 24
    Statistical analysis description
    Through Week 24: 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 dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, domain score, and percent predicted FEV1, using unstructured covariance matrix.
    Comparison groups
    Placebo v 150 mg Ivacaftor q12h
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    8.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.7
         upper limit
    11.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7
    Notes
    [3] - Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg’s step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05).
    Statistical analysis title
    CFQ-R Score Through Week 48
    Statistical analysis description
    Through Week 48: Analysis for the CFQ-R respiratory domain score endpoint was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from MMRM with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age,sweat chloride, and percent predicted FEV1,using unstructured covariance matrix
    Comparison groups
    Placebo v 150 mg Ivacaftor q12h
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    8.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.3
         upper limit
    11.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7
    Notes
    [4] - There was no adjustment for multiple comparisons.

    Secondary: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

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    End point title
    Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48
    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 population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.
    End point type
    Secondary
    End point timeframe
    Baseline through 24 weeks and 48 weeks
    End point values
    Placebo 150 mg Ivacaftor q12h
    Number of subjects analysed
    74
    78
    Units: millimoles per liter
    least squares mean (standard error)
        Change from Baseline Through Week 24
    -0.8 ± 1.3
    -48.7 ± 1.2
        Change from Baseline Through Week 48
    -0.6 ± 1.3
    -48.7 ± 1.2
    Statistical analysis title
    Sweat Chloride Concentration Through Week 24
    Statistical analysis description
    Through Week 24: 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 absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, sweat chloride, and percent predicted FEV1, using unstructured covariance matrix.
    Comparison groups
    Placebo v 150 mg Ivacaftor q12h
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -47.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -51.3
         upper limit
    -44.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7
    Notes
    [5] - Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg’s step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05); test 3 using Hochberg’s on time to pulmonary exacerbation (Wk 48) and weight (Wk 48).
    Statistical analysis title
    Sweat Chloride Concentration Through Week 48
    Statistical analysis description
    Through Week 48: 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 absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, sweat chloride, and percent predicted FEV1, using unstructured covariance matrix.
    Comparison groups
    Placebo v 150 mg Ivacaftor q12h
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -48.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -51.5
         upper limit
    -44.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7
    Notes
    [6] - There was no adjustment for multiple comparisons.

    Secondary: Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48

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    End point title
    Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48
    End point description
    Pulmonary exacerbation was defined as a change in antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of signs/symptoms such as change in sputum; new or increased hemoptysis; increased cough or dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees C; anorexia or weight loss; sinus pain/tenderness and discharge; change in physical examination of the chest; decreased pulmonary function by 10%; and radiographic changes indicative of pulmonary infection. Analysis population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.
    End point type
    Secondary
    End point timeframe
    Baseline through 24 weeks and 48 weeks
    End point values
    Placebo 150 mg Ivacaftor q12h
    Number of subjects analysed
    78
    83
    Units: proportion of event-free participants
    number (confidence interval 95%)
        0 to 15 Days
    0.97 (0.9 to 0.99)
    0.98 (0.91 to 0.99)
        16 to 56 Days
    0.87 (0.77 to 0.93)
    0.89 (0.8 to 0.94)
        57 to 112 Days
    0.72 (0.61 to 0.81)
    0.83 (0.73 to 0.9)
        113 to 168 Days
    0.53 (0.41 to 0.64)
    0.78 (0.68 to 0.86)
        169 to 224 Days
    0.51 (0.39 to 0.61)
    0.75 (0.64 to 0.83)
        225 to 280 Days
    0.44 (0.32 to 0.55)
    0.7 (0.58 to 0.78)
        281 to 336 Days
    0.41 (0.29 to 0.52)
    0.67 (0.55 to 0.76)
    Statistical analysis title
    first Pulmonary Exacerbation Through Week 24
    Statistical analysis description
    Time to first pulmonary exacerbation through Week 24 was analyzed using Cox regression. The model included a covariate for treatment and adjustments for the age group and percent predicted forced expiratory volume in 1 second (FEV1) severity at baseline.
    Comparison groups
    Placebo v 150 mg Ivacaftor q12h
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0016 [7]
    Method
    Regression, Cox
    Parameter type
    Cox proportional hazard
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    0.71
    Notes
    [7] - Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg’s step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05); test 3 using Hochberg’s on time to pulmonary exacerbation (Wk 48) and weight (Wk 48).
    Statistical analysis title
    first Pulmonary Exacerbation Through Week 48
    Statistical analysis description
    Time to first pulmonary exacerbation through Week 48 was analyzed using Cox regression. The model included a covariate for treatment and adjustments for the age group and percent predicted forced expiratory volume in 1 second (FEV1) severity at baseline
    Comparison groups
    Placebo v 150 mg Ivacaftor q12h
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0012 [8]
    Method
    Regression, Cox
    Parameter type
    Cox proportional hazard
    Point estimate
    0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    0.73
    Notes
    [8] - Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg’s step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05); test 3 using Hochberg’s on time to pulmonary exacerbation (Wk 48) and weight (Wk 48).

    Secondary: Absolute Change From Baseline in Weight at Week 24 and Week 48

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    End point title
    Absolute Change From Baseline in Weight at Week 24 and Week 48
    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 population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks and 48 weeks
    End point values
    Placebo 150 mg Ivacaftor q12h
    Number of subjects analysed
    78
    83
    Units: kilograms
    least squares mean (standard error)
        At Week 24
    0.2 ± 0.4
    3 ± 0.4
        At Week 48
    0.4 ± 0.5
    3.1 ± 0.5
    Statistical analysis title
    Weight at Week 24
    Statistical analysis description
    At Week 24: Analysis for this variable was based on a linear mixed effects (LME) model with treatment as a fixed effect, and intercept, visit (days on study) and treatment by visit interaction as random effects, with adjustment for age group and baseline percent predicted forced expiratory volume in 1 second (FEV1) severity
    Comparison groups
    Placebo v 150 mg Ivacaftor q12h
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.8
         upper limit
    3.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5
    Statistical analysis title
    Weight at Week 48
    Statistical analysis description
    At Week 48: Analysis for this variable was based on a linear mixed effects (LME) model with treatment as a fixed effect and visit (days on study) and treatment by visit interaction as random effects, with adjustment for age group and baseline percent predicted forced expiratory volume in 1 second (FEV1) severity.
    Comparison groups
    Placebo v 150 mg Ivacaftor q12h
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    2.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    4.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For enrolled subjects, adverse events were collected through the Follow-up Visit (4 weeks [± 7 days] after the last dose of study drug).
    Adverse event reporting additional description
    For subjects who were screened but were not subsequently enrolled in the study, non-serious adverse event (AEs) were not collected, but serious adverse events (SAEs) were reported. For subjects who completed 48 weeks of study drug treatment and enrolled in the open-label extension study, adverse events were only collected through the Week 48 Visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo-matched-to-ivacaftor tablet orally every 12 hours (q12h) up to 48 weeks.

    Reporting group title
    150 mg Ivacaftor q12h
    Reporting group description
    Ivacaftor 150 mg tablet orally every 12 hours (q12h) up to 48 weeks.

    Serious adverse events
    Placebo 150 mg Ivacaftor q12h
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 78 (42.31%)
    20 / 83 (24.10%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter Related Complication
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular torsion
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis lung
         subjects affected / exposed
    26 / 78 (33.33%)
    11 / 83 (13.25%)
         occurrences causally related to treatment / all
    4 / 37
    3 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic pseudocyst
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting1
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IgA nephropathy
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Implant site infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myringitis bullous
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo 150 mg Ivacaftor q12h
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 78 (100.00%)
    82 / 83 (98.80%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Hot flush
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Peripheral Coldness
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Poor peripheral circulation
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 78 (11.54%)
    10 / 83 (12.05%)
         occurrences all number
    11
    13
    Fatigue
         subjects affected / exposed
    7 / 78 (8.97%)
    7 / 83 (8.43%)
         occurrences all number
    9
    8
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 83 (2.41%)
         occurrences all number
    4
    3
    Chest discomfort
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Chills
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Malaise
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Pain
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Application site burn
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Application site dermatitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Application site scar
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Asthenia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Axillary pain
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Catheter Related Complication
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Catheter Thrombosis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Exercise tolerance decreased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Food allergy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Balanitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Breast inflammation
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Breast Mass
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Epididymitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Gynaecomastia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Nipple disorder
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Nipple pain
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Oligomenorrhoea
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Ovarian cyst
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Prostatitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    33 / 78 (42.31%)
    27 / 83 (32.53%)
         occurrences all number
    59
    38
    Oropharyngeal pain
         subjects affected / exposed
    15 / 78 (19.23%)
    17 / 83 (20.48%)
         occurrences all number
    23
    25
    Nasal congestion
         subjects affected / exposed
    12 / 78 (15.38%)
    17 / 83 (20.48%)
         occurrences all number
    17
    22
    Haemoptysis
         subjects affected / exposed
    15 / 78 (19.23%)
    9 / 83 (10.84%)
         occurrences all number
    21
    17
    Productive cough
         subjects affected / exposed
    11 / 78 (14.10%)
    12 / 83 (14.46%)
         occurrences all number
    19
    15
    Rales
         subjects affected / exposed
    8 / 78 (10.26%)
    9 / 83 (10.84%)
         occurrences all number
    14
    17
    Respiratory tract congestion
         subjects affected / exposed
    6 / 78 (7.69%)
    6 / 83 (7.23%)
         occurrences all number
    9
    7
    Sinus congestion
         subjects affected / exposed
    4 / 78 (5.13%)
    8 / 83 (9.64%)
         occurrences all number
    4
    9
    Rhinorrhoea
         subjects affected / exposed
    6 / 78 (7.69%)
    4 / 83 (4.82%)
         occurrences all number
    6
    4
    Paranasal sinus hypersecretion
         subjects affected / exposed
    6 / 78 (7.69%)
    3 / 83 (3.61%)
         occurrences all number
    7
    3
    Wheezing
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 83 (6.02%)
         occurrences all number
    3
    8
    Dyspnoea
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 83 (2.41%)
         occurrences all number
    5
    2
    Pleuritic pain
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 83 (6.02%)
         occurrences all number
    2
    7
    Dysphonia
         subjects affected / exposed
    3 / 78 (3.85%)
    3 / 83 (3.61%)
         occurrences all number
    3
    3
    Respiration abnormal
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 83 (2.41%)
         occurrences all number
    5
    2
    Epistaxis
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 83 (3.61%)
         occurrences all number
    1
    4
    Lung hyperinflation
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 83 (2.41%)
         occurrences all number
    3
    3
    Nasal mucosal disorder
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 83 (2.41%)
         occurrences all number
    2
    2
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    Nasal inflammation
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 83 (3.61%)
         occurrences all number
    0
    3
    Nasal turbinate abnormality
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    2
    2
    Pharyngeal erythema
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 83 (3.61%)
         occurrences all number
    0
    3
    Rhinitis allergic
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    Rhonchi
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    4
    Asthma
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Postnasal Drip
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Pulmonary congestion
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Sinus disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Sputum discoloured
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    3
    0
    Sputum retention
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Throat irritation
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Bronchial secretion retention
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Hypoventilation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Nasal oedema
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Nasal polyps
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Painful respiration
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Prolonged expiration
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Sneezing
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Stridor
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 83 (3.61%)
         occurrences all number
    1
    3
    Abnormal dreams
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Libido decreased
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Sleep disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Affect lability
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Affective disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Panic attack
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Tobacco withdrawal symptoms
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    11 / 78 (14.10%)
    3 / 83 (3.61%)
         occurrences all number
    14
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 78 (6.41%)
    5 / 83 (6.02%)
         occurrences all number
    6
    9
    C-reactive protein increased
         subjects affected / exposed
    5 / 78 (6.41%)
    4 / 83 (4.82%)
         occurrences all number
    6
    4
    Blood glucose increased
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 83 (6.02%)
         occurrences all number
    3
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 83 (6.02%)
         occurrences all number
    2
    7
    Bacteria Sputum Identified
         subjects affected / exposed
    1 / 78 (1.28%)
    6 / 83 (7.23%)
         occurrences all number
    1
    7
    Hepatic enzyme increased
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 83 (4.82%)
         occurrences all number
    4
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 78 (3.85%)
    3 / 83 (3.61%)
         occurrences all number
    4
    6
    Breath sounds abnormal
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 83 (2.41%)
         occurrences all number
    5
    2
    Weight decreased
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 83 (2.41%)
         occurrences all number
    4
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 83 (2.41%)
         occurrences all number
    4
    5
    Sputum abnormal
         subjects affected / exposed
    2 / 78 (2.56%)
    3 / 83 (3.61%)
         occurrences all number
    2
    3
    Urine leukocyte esterase positive
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 83 (2.41%)
         occurrences all number
    3
    2
    Blood glucose decreased
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 83 (1.20%)
         occurrences all number
    4
    1
    Blood urine present
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 83 (2.41%)
         occurrences all number
    3
    2
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 83 (3.61%)
         occurrences all number
    1
    3
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    3
    Blood bilirubin increased
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 83 (1.20%)
         occurrences all number
    2
    3
    Forced expiratory volume decreased
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 83 (0.00%)
         occurrences all number
    4
    0
    International normalised ratio increased
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 83 (1.20%)
         occurrences all number
    2
    1
    Vitamin D decreased
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    White blood cell count increased
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 83 (0.00%)
         occurrences all number
    4
    0
    Blood glucose fluctuation
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Blood immunoglobulin E increased
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Glucose urine present
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Neutrophil count increased
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    6
    0
    Bacterial Antibody Positive
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Blood immunoglobulin G increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Full blood count abnormal
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Fungus Sputum Test Positive
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Gastrointestinal examination abnormal
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Liver palpable subcostal
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Monocyte count increased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Protein urine present
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Specific gravity urine increased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Spirometry abnormal
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    ELECTROCARDIOGRAM ST-T CHANGE
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Joint Sprain
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 83 (0.00%)
         occurrences all number
    5
    0
    Contusion
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    Limb injury
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 83 (3.61%)
         occurrences all number
    0
    3
    Procedural pain
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    3
    2
    Excoriation
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Hand fracture
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Arthropod bite
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Burns second degree
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Concussion
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Foot fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Joint dislocation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Joint injury
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Medication error
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Muscle strain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Rib fracture
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Skeletal injury
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Stress fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Sunburn
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Cystic fibrosis lung
         subjects affected / exposed
    39 / 78 (50.00%)
    29 / 83 (34.94%)
         occurrences all number
    77
    47
    Cystic fibrosis related diabetes
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 83 (3.61%)
         occurrences all number
    0
    3
    Tachycardia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Extrasystoles
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 78 (16.67%)
    19 / 83 (22.89%)
         occurrences all number
    31
    39
    Dizziness
         subjects affected / exposed
    1 / 78 (1.28%)
    10 / 83 (12.05%)
         occurrences all number
    1
    11
    Sinus headache
         subjects affected / exposed
    4 / 78 (5.13%)
    6 / 83 (7.23%)
         occurrences all number
    4
    6
    Migraine
         subjects affected / exposed
    2 / 78 (2.56%)
    3 / 83 (3.61%)
         occurrences all number
    3
    3
    Lethargy
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Aphonia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Cognitive disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Dizziness postural
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Hemicephalalgia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Hyposmia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Memory impairment
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    2 / 78 (2.56%)
    3 / 83 (3.61%)
         occurrences all number
    2
    3
    Anaemia
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Eosinophilia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Lymph node pain
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Lymphadenitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 78 (0.00%)
    4 / 83 (4.82%)
         occurrences all number
    0
    4
    Ear pain
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 83 (3.61%)
         occurrences all number
    1
    3
    Deafness
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Tinnitus
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Ear congestion
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Ear pruritus
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Middle ear effusion
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Tympanic membrane hyperaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Vestibular disorder
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    2
    2
    Dry eye
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 78 (12.82%)
    13 / 83 (15.66%)
         occurrences all number
    13
    14
    Nausea
         subjects affected / exposed
    9 / 78 (11.54%)
    13 / 83 (15.66%)
         occurrences all number
    12
    22
    Diarrhoea
         subjects affected / exposed
    10 / 78 (12.82%)
    11 / 83 (13.25%)
         occurrences all number
    12
    12
    Vomiting
         subjects affected / exposed
    10 / 78 (12.82%)
    9 / 83 (10.84%)
         occurrences all number
    10
    13
    Abdominal pain upper
         subjects affected / exposed
    6 / 78 (7.69%)
    4 / 83 (4.82%)
         occurrences all number
    7
    5
    Constipation
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 83 (1.20%)
         occurrences all number
    5
    1
    Flatulence
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 83 (2.41%)
         occurrences all number
    5
    2
    Abdominal discomfort
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 83 (1.20%)
         occurrences all number
    2
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 83 (1.20%)
         occurrences all number
    2
    1
    Toothache
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    Abdominal distension
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    6
    1
    Abdominal pain lower
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Faeces pale
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Gastritis
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Haemorrhoids
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Abdominal tenderness
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    DRY MOUTH
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Frequent bowel movements
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Inguinal hernia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Pancreatitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Post-tussive vomiting
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Steatorrhoea
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Tooth impacted
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Cytolytic Hepatitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 78 (5.13%)
    12 / 83 (14.46%)
         occurrences all number
    4
    22
    Acne
         subjects affected / exposed
    3 / 78 (3.85%)
    6 / 83 (7.23%)
         occurrences all number
    3
    6
    Pruritus
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 83 (2.41%)
         occurrences all number
    3
    2
    Dry skin
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 83 (1.20%)
         occurrences all number
    3
    1
    Erythema
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    Night sweats
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    Rash erythematous
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    Rash macular
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 83 (1.20%)
         occurrences all number
    2
    1
    Alopecia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Eczema
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    4
    0
    Rash maculo-papular
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Dermatitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Drug eruption
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Ecchymosis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Hair texture abnormal
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Heat Rash
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Hypoaesthesia Facial
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Photosensitivity Allergic Reaction
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Rash generalised
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Rosacea
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Skin irritation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Dysuria
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Haematuria
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Anuria
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Calculus ureteric
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Polyuria
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 78 (6.41%)
    7 / 83 (8.43%)
         occurrences all number
    5
    11
    Back pain
         subjects affected / exposed
    5 / 78 (6.41%)
    5 / 83 (6.02%)
         occurrences all number
    7
    5
    Myalgia
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 83 (4.82%)
         occurrences all number
    3
    5
    Pain in extremity
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 83 (4.82%)
         occurrences all number
    5
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 78 (2.56%)
    4 / 83 (4.82%)
         occurrences all number
    2
    5
    Musculoskeletal pain
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    Arthritis
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Fibromyalgia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Flank pain
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Neck pain
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Bone pain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Epiphyseal disorder
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Finger deformity
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Jaw disorder
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Muscle atrophy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Muscle tightness
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Synovial cyst
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Torticollis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 78 (15.38%)
    19 / 83 (22.89%)
         occurrences all number
    16
    26
    Nasopharyngitis
         subjects affected / exposed
    10 / 78 (12.82%)
    10 / 83 (12.05%)
         occurrences all number
    14
    13
    Sinusitis
         subjects affected / exposed
    7 / 78 (8.97%)
    6 / 83 (7.23%)
         occurrences all number
    12
    8
    Rhinitis
         subjects affected / exposed
    4 / 78 (5.13%)
    6 / 83 (7.23%)
         occurrences all number
    4
    6
    Viral infection
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 83 (2.41%)
         occurrences all number
    5
    2
    Influenza
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 83 (2.41%)
         occurrences all number
    3
    2
    Pharyngitis
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 83 (2.41%)
         occurrences all number
    3
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 83 (4.82%)
         occurrences all number
    1
    5
    Oral candidiasis
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 83 (3.61%)
         occurrences all number
    1
    4
    Ear infection
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 83 (1.20%)
         occurrences all number
    2
    2
    Tooth infection
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 83 (0.00%)
         occurrences all number
    3
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 83 (2.41%)
         occurrences all number
    1
    2
    Acute sinusitis
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Bacterial disease carrier
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    2
    Laryngitis
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Lung infection
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    0
    6
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Tooth abscess
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 83 (0.00%)
         occurrences all number
    2
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    2
    Abscess
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Bacterial infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Bronchiectasis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Cellulitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Conjunctivitis viral
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Dacryocystitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Diverticulitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Implant site infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Labyrinthitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Lice infestation
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Onychomycosis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Pancreas infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Pulpitis dental
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Rhinovirus infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Skin infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Sputum purulent
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Staphylococcal infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Vaginal infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Viral pharyngitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 83 (3.61%)
         occurrences all number
    4
    3
    Decreased appetite
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 83 (2.41%)
         occurrences all number
    2
    2
    Dehydration
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 83 (1.20%)
         occurrences all number
    2
    2
    Hyperglycaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 83 (1.20%)
         occurrences all number
    1
    1
    Anorexia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Gout
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Hypovitaminosis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 83 (0.00%)
         occurrences all number
    1
    0
    Polydipsia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 83 (1.20%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2009
    Addition of a 24-week Extension Period for a total treatment duration of 48 weeks. Change to the secondary objective to evaluate the safety of VX-770 after both 24 weeks (original objective) and 48 weeks (newly added) of treatment. Addition of a secondary objective “To evaluate the efficacy of VX-770 after 48 weeks of treatment in subjects with CF who have the G551D-CFTR mutation on at least 1 allele”. Addition of a secondary endpoint of “Absolute change from baseline in percent predicted FEV1 through Week 48”. Addition of analysis of secondary and tertiary endpoints at Week 48. Addition of the option for subjects who complete 48 weeks of treatment to enroll in Study VX08-770-105.
    10 Sep 2009
    Addition of the tertiary endpoint of “Pulmonary exacerbations through Weeks 24 and 48”. Changed few of the inclusion/exclusion criteria. Updated the version of the CTCAE used in the study for the grading of adverse events from Version 3.0 to Version 4.0.
    12 Apr 2010
    Changes in study procedures regarding liver function testing and considerations for study drug interruption and discontinuation to ensure the continued safety of subjects in this study. Updated the name of the safety department at Vertex from “Pharmacovigilance” to “Global Patient Safety” (throughout the protocol). Updated contact information.
    09 Jul 2010
    Based on feedback from the US Food and Drug Administration (FDA), an additional criterion for removal of subjects in the study was added to protocol: total bilirubin >2 ULN and/or clinical jaundice, in association with elevation of ALT or AST >3 ULN. Additional clarification of the intended analysis were 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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/22047557
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