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    Clinical Trial Results:
    An Open-Label, Rollover Study to Evaluate the Long Term Safety and Efficacy of VX-770 in Subjects with Cystic Fibrosis

    Summary
    EudraCT number
    2009-012997-11
    Trial protocol
    FR   IE   CZ   GB   DE  
    Global end of trial date
    12 May 2014

    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
    VX08-770-105
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01117012
    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
    02 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of long-term Ivacaftor (VX-770) treatment in subjects with cystic fibrosis (CF).
    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
    08 Jul 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 105
    Country: Number of subjects enrolled
    Australia: 30
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Ireland: 14
    Worldwide total number of subjects
    192
    EEA total number of subjects
    47
    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)
    34
    Adolescents (12-17 years)
    40
    Adults (18-64 years)
    118
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects with Cystic Fibrosis (CF) who had completed the Study VX08-770-102 (Study 102/NCT00909532) and Study VX08-770-103 (Study 103/NCT00909727), were enrolled in this Study VX08-770-105 (Study 105/NCT01117012).

    Pre-assignment
    Screening details
    A total of 192 subjects were enrolled. Efficacy results are presented as per the treatment received in previous study (Placebo/Ivacaftor [VX-770]).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/VX-770
    Arm description
    Subjects who received placebo during the parent study (Study 102 or 103), received VX-770 150 mg tablet orally twice daily q12h.
    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
    150 milligram (mg) tablet orally twice daily (q12h).

    Arm title
    VX-770/VX-770
    Arm description
    Subjects who received VX-770 during the parent study (Study 102 or 103), received VX-770 150 mg tablet orally q12h.
    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
    150 mg tablet orally twice daily q12h.

    Number of subjects in period 1
    Placebo/VX-770 VX-770/VX-770
    Started
    89
    103
    Completed
    81
    98
    Not completed
    8
    5
         Death
    1
    1
         Undefined
    4
    3
         Consent withdrawn by subject
    3
    -
         Adverse Event
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo/VX-770
    Reporting group description
    Subjects who received placebo during the parent study (Study 102 or 103), received VX-770 150 mg tablet orally twice daily q12h.

    Reporting group title
    VX-770/VX-770
    Reporting group description
    Subjects who received VX-770 during the parent study (Study 102 or 103), received VX-770 150 mg tablet orally q12h.

    Reporting group values
    Placebo/VX-770 VX-770/VX-770 Total
    Number of subjects
    89 103 192
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    22 ± 10.94 23.2 ± 11.55 -
    Gender categorical
    Units: Subjects
        Female
    44 58 102
        Male
    45 45 90

    End points

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    End points reporting groups
    Reporting group title
    Placebo/VX-770
    Reporting group description
    Subjects who received placebo during the parent study (Study 102 or 103), received VX-770 150 mg tablet orally twice daily q12h.

    Reporting group title
    VX-770/VX-770
    Reporting group description
    Subjects who received VX-770 during the parent study (Study 102 or 103), received VX-770 150 mg tablet orally q12h.

    Subject analysis set title
    VX-770
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received VX-770 150 mg tablet orally q12h in Study 105.

    Primary: Number of Subjects With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    Adverse Event: any untoward medical occurrence in a subject during the study, including any unfavorable and unintended sign, symptom, or disease whether or not it was considered to be study drug related. This included any newly occurring event or previous condition that increased in severity or frequency after obtaining informed consent and assent (where applicable). SAE: medical event or condition, which resulted in any of following, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event. Non-Serious AEs included all AEs except SAEs. Analysis was performed in Safety Set defined as all subjects who received at least 1 dose of study drug during Study 105.
    End point type
    Primary
    End point timeframe
    Study 105: Day 1 up to Week 168
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this study.
    End point values
    VX-770
    Number of subjects analysed
    192
    Units: Subjects
    number (not applicable)
        Non-Serious AEs
    190
        SAEs
    70
    No statistical analyses for this end point

    Secondary: Annualized Rate of Decline From Study 105 Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 96

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    End point title
    Annualized Rate of Decline From Study 105 Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 96
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Predicted FEV1 (for age, gender, and height) was calculated using the Knudson method. Baseline was defined as Study 105 Day 15. Analysis was performed in Full Analysis Set defined as all subjects who were enrolled and received at least 1 dose of study drug during Study 105.
    End point type
    Secondary
    End point timeframe
    Study 105: Baseline through Week 96
    End point values
    Placebo/VX-770 VX-770/VX-770
    Number of subjects analysed
    89
    103
    Units: percent predicted of FEV1 per year
        least squares mean (confidence interval 95%)
    -0.3 (-2.47 to 1.86)
    -1.23 (-2.1 to -0.35)
    No statistical analyses for this end point

    Secondary: Absolute Change From Study 105 Baseline in Percent Predicted FEV1 Through Week 96

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    End point title
    Absolute Change From Study 105 Baseline in Percent Predicted FEV1 Through Week 96
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Predicted FEV1 (for age, gender, and height) was calculated using the Knudson method. Baseline was defined as the most recent measurement prior to intake of the first dose of study drug in Study 105. Absolute Change at Week 48 and Week 96 are reported. Analysis was performed in Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Study 105: Baseline through Week 96
    End point values
    Placebo/VX-770 VX-770/VX-770
    Number of subjects analysed
    85
    99
    Units: percent predicted of FEV1
    arithmetic mean (standard deviation)
        Absolute Change at Week 48 (n = 85, 99)
    9.2585 ± 9.63822
    -0.4422 ± 8.62332
        Absolute Change at Week 96 (n = 76, 97)
    9.8194 ± 11.22812
    0.1581 ± 9.01629
    No statistical analyses for this end point

    Secondary: Absolute Change From Study 105 Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 96

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    End point title
    Absolute Change From Study 105 Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 96
    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. Absolute Change at Week 48 and Week 96 are reported. Analysis was performed in Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Study 105: Baseline through Week 96
    End point values
    Placebo/VX-770 VX-770/VX-770
    Number of subjects analysed
    86
    99
    Units: units on a scale
    arithmetic mean (standard deviation)
        Absolute Change at Week 48 (n = 86, 99)
    7.43 ± 16.6
    -1.94 ± 16.55
        Absolute Change at Week 96 (n = 77, 97)
    10.05 ± 15.254
    0.77 ± 14.305
    No statistical analyses for this end point

    Secondary: Annualized Pulmonary Exacerbation Event Rate

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    End point title
    Annualized Pulmonary Exacerbation Event Rate
    End point description
    Annualized event rate was calculated by regression with negative binomial distribution. Analysis was performed in Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Study 105: Day 1 through Week 96
    End point values
    Placebo/VX-770 VX-770/VX-770
    Number of subjects analysed
    89
    103
    Units: events per year
        number (not applicable)
    0.463
    0.658
    No statistical analyses for this end point

    Secondary: Annualized Duration of Pulmonary Exacerbation Events

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    End point title
    Annualized Duration of Pulmonary Exacerbation Events
    End point description
    Analysis was performed in Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Study 105: Day 1 through Week 96
    End point values
    Placebo/VX-770 VX-770/VX-770
    Number of subjects analysed
    89
    103
    Units: Days per year
        arithmetic mean (standard deviation)
    10.89 ± 20.124
    17.27 ± 30.974
    No statistical analyses for this end point

    Secondary: Absolute Change From Study 105 Baseline in Weight Through Week 96

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    End point title
    Absolute Change From Study 105 Baseline in Weight Through Week 96
    End point description
    Weight is a measurement of nutritional status. Absolute change in weight, measured in kilograms (kg), at Week 48 and Week 96 are reported. Analysis was performed in Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Study 105: Baseline through Week 96
    End point values
    Placebo/VX-770 VX-770/VX-770
    Number of subjects analysed
    86
    99
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        Absolute Change at Week 48 (n = 86, 99)
    4.03 ± 3.677
    1.26 ± 3.844
        Absolute Change at Week 96 (n = 76, 97)
    4.93 ± 5.577
    2.62 ± 5.909
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study 105: Day 1 through Week 168
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    VX-770
    Reporting group description
    All subjects who received VX-770 150 mg tablet orally q12h in Study 105.

    Serious adverse events
    VX-770
    Total subjects affected by serious adverse events
         subjects affected / exposed
    70 / 192 (36.46%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Device occlusion
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression suicidal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Corneal abrasion
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Chest X-ray abnormal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    7 / 192 (3.65%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Bullous lung disease
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hemiplegic migraine
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Distal ileal obstruction syndrome
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal tubular disorder
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    42 / 192 (21.88%)
         occurrences causally related to treatment / all
    2 / 88
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aspergilloma
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    VX-770
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    190 / 192 (98.96%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Flushing
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Haematoma
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Fibroadenoma of breast
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    9 / 192 (4.69%)
         occurrences all number
    38
    Drug hypersensitivity
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Hypersensitivity
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    4
    Allergy to animal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    35 / 192 (18.23%)
         occurrences all number
    47
    Fatigue
         subjects affected / exposed
    13 / 192 (6.77%)
         occurrences all number
    16
    Catheter site pain
         subjects affected / exposed
    7 / 192 (3.65%)
         occurrences all number
    8
    Chest pain
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    6
    Influenza like illness
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    6
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    6
    Pain
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    8
    Chills
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Malaise
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    4
    Oedema peripheral
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Asthenia
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Chest discomfort
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Injection site pain
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Adverse drug reaction
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Catheter site swelling
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Drug interaction
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Exercise tolerance decreased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Infusion site pain
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Medical device pain
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    11 / 192 (5.73%)
         occurrences all number
    12
    Depression
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Insomnia
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    6
    Sleep disorder
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    3
    Abnormal dreams
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Adjustment disorder
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Mood swings
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Phagophobia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    22
    Breast mass
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Cervix inflammation
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Dyspareunia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Erectile dysfunction
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Menorrhagia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Menstruation irregular
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Metrorrhagia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Ovarian cyst
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Pelvic pain
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    2
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    5
    Laceration
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Ligament sprain
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Contusion
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    4
    Arthropod sting
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Excoriation
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Hand fracture
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Joint dislocation
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Meniscus lesion
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Muscle strain
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    3
    Skeletal injury
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Wrist fracture
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Arthropod bite
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Chest injury
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Corneal abrasion
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Fibula fracture
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Foot fracture
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Foreign body in eye
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    4
    Incision site pain
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Ligament rupture
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Muscle injury
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Muscle rupture
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Post procedural complication
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Post procedural swelling
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Post-traumatic pain
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Radius fracture
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Rib fracture
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Scratch
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Soft tissue injury
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Stab wound
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Sternal injury
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Tendon rupture
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Tongue injury
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Investigations
    Bacterial test positive
         subjects affected / exposed
    16 / 192 (8.33%)
         occurrences all number
    20
    Weight decreased
         subjects affected / exposed
    13 / 192 (6.77%)
         occurrences all number
    14
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 192 (4.69%)
         occurrences all number
    13
    Pulmonary function test decreased
         subjects affected / exposed
    8 / 192 (4.17%)
         occurrences all number
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    11
    Fungal test positive
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    6
    Glucose urine present
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    7
    Vitamin D decreased
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    6
    Blood glucose increased
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    6
    Prothrombin time prolonged
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    5
    Hepatic enzyme increased
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Liver function test abnormal
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    6
    Blood bilirubin increased
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    7
    Blood creatinine increased
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Culture throat positive
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Forced expiratory volume decreased
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    White blood cell count increased
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Blood glucose decreased
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Blood iron decreased
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Blood urine present
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    3
    Body temperature increased
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Breath sounds abnormal
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Cardiac murmur
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    3
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Eosinophil count increased
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Neutrophil count increased
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Platelet count increased
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Protein urine present
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Spirometry abnormal
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Blood albumin increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Blood calcium increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    2
    Blood cortisol increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Blood immunoglobulin E increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Blood pressure increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    2
    Blood urea increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Clostridium test positive
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Coagulation factor increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Electrocardiogram T wave peaked
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Gastrointestinal examination abnormal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Haemoglobin increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Monocyte count increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Nitrite urine present
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Peak expiratory flow rate decreased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Serum ferritin decreased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Sputum abnormal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Urine leukocyte esterase
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Urine leukocyte esterase positive
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Tachycardia
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Angina pectoris
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Intracardiac thrombus
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Cystic fibrosis related diabetes
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Cataract congenital
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Cystic fibrosis pancreatic
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    5
    Coagulopathy
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Neutrophilia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Polycythaemia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    86 / 192 (44.79%)
         occurrences all number
    166
    Oropharyngeal pain
         subjects affected / exposed
    39 / 192 (20.31%)
         occurrences all number
    58
    Nasal congestion
         subjects affected / exposed
    26 / 192 (13.54%)
         occurrences all number
    34
    Haemoptysis
         subjects affected / exposed
    24 / 192 (12.50%)
         occurrences all number
    57
    Productive cough
         subjects affected / exposed
    24 / 192 (12.50%)
         occurrences all number
    45
    Rales
         subjects affected / exposed
    19 / 192 (9.90%)
         occurrences all number
    33
    Sputum increased
         subjects affected / exposed
    17 / 192 (8.85%)
         occurrences all number
    25
    Rhinorrhoea
         subjects affected / exposed
    16 / 192 (8.33%)
         occurrences all number
    29
    Sinus congestion
         subjects affected / exposed
    14 / 192 (7.29%)
         occurrences all number
    15
    Wheezing
         subjects affected / exposed
    14 / 192 (7.29%)
         occurrences all number
    22
    Dyspnoea
         subjects affected / exposed
    10 / 192 (5.21%)
         occurrences all number
    13
    Epistaxis
         subjects affected / exposed
    9 / 192 (4.69%)
         occurrences all number
    10
    Pleuritic pain
         subjects affected / exposed
    9 / 192 (4.69%)
         occurrences all number
    14
    Respiratory tract congestion
         subjects affected / exposed
    9 / 192 (4.69%)
         occurrences all number
    13
    Respiration abnormal
         subjects affected / exposed
    8 / 192 (4.17%)
         occurrences all number
    9
    Nasal polyps
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    8
    Asthma
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    6
    Paranasal sinus hypersecretion
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    6
    Rhinitis allergic
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    6
    Nasal discharge discolouration
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    6
    Pharyngeal erythema
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Rhonchi
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    5
    Dysphonia
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Nasal inflammation
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    4
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Nasal oedema
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Nasal turbinate abnormality
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    3
    Sputum discoloured
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Throat irritation
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Tonsillar hypertrophy
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    4
    Allergic cough
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Atelectasis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Bronchial obstruction
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Nasal discomfort
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Paranasal sinus mucosal hypertrophy
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Pharyngeal oedema
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Pleurisy
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Pneumothorax
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Prolonged expiration
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Sneezing
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    2
    Tonsillar inflammation
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    45 / 192 (23.44%)
         occurrences all number
    90
    Dizziness
         subjects affected / exposed
    12 / 192 (6.25%)
         occurrences all number
    15
    Sinus headache
         subjects affected / exposed
    7 / 192 (3.65%)
         occurrences all number
    9
    Hypoaesthesia
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    8
    Lethargy
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    5
    Paraesthesia
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Migraine
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    5
    Convulsion
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Syncope
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Ageusia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Burning sensation
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Epilepsy
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Memory impairment
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    7
    Vision blurred
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Dry eye
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Eye pruritus
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Lens disorder
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    2
    Meibomian gland dysfunction
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Myopia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Ocular vascular disorder
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Visual acuity reduced
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Visual impairment
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Vitreous floaters
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    6
    Vertigo
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Cerumen impaction
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Deafness
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Ear discomfort
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Ear pruritus
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Middle ear inflammation
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Tinnitus
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Tympanic membrane hyperaemia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    23 / 192 (11.98%)
         occurrences all number
    28
    Constipation
         subjects affected / exposed
    22 / 192 (11.46%)
         occurrences all number
    27
    Diarrhoea
         subjects affected / exposed
    21 / 192 (10.94%)
         occurrences all number
    22
    Vomiting
         subjects affected / exposed
    21 / 192 (10.94%)
         occurrences all number
    23
    Abdominal pain upper
         subjects affected / exposed
    19 / 192 (9.90%)
         occurrences all number
    31
    Nausea
         subjects affected / exposed
    19 / 192 (9.90%)
         occurrences all number
    24
    Dyspepsia
         subjects affected / exposed
    9 / 192 (4.69%)
         occurrences all number
    11
    Gastrooesophageal reflux disease
         subjects affected / exposed
    9 / 192 (4.69%)
         occurrences all number
    9
    Flatulence
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    8
    Toothache
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    6
    Abdominal distension
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    5
    Rectal haemorrhage
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Distal ileal obstruction syndrome
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    4
    Abdominal discomfort
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Haemorrhoids
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Steatorrhoea
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    3
    Duodenitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Gastric hypomotility
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Gastrointestinal hypomotility
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Gingival pain
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Impaired gastric emptying
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Inguinal hernia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Lip dry
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Lip swelling
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Tooth impacted
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Umbilical hernia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Cholelithiasis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    7
    Nephrolithiasis
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    4
    Polyuria
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Cystitis interstitial
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Glycosuria
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Hypertonic bladder
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Proteinuria
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Renal colic
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Renal cyst
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    13 / 192 (6.77%)
         occurrences all number
    14
    Acne
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    5
    Alopecia
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Dermatitis contact
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Night sweats
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Pruritus
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Rash erythematous
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    5
    Dry skin
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    4
    Sunburn
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Urticaria
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    5
    Drug eruption
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Erythema
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Rash generalised
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Rash papular
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Skin wrinkling
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Dermal cyst
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Ecchymosis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Onychoclasis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Petechiae
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Photosensitivity reaction
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Pruritus generalised
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Rash follicular
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Rash macular
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Skin fissures
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Skin odour abnormal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    26 / 192 (13.54%)
         occurrences all number
    34
    Back pain
         subjects affected / exposed
    14 / 192 (7.29%)
         occurrences all number
    15
    Musculoskeletal chest pain
         subjects affected / exposed
    7 / 192 (3.65%)
         occurrences all number
    9
    Pain in extremity
         subjects affected / exposed
    7 / 192 (3.65%)
         occurrences all number
    8
    Musculoskeletal pain
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    5
    Myalgia
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Joint swelling
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Muscle spasms
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Neck pain
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Arthritis
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Arthropathy
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    4
    Fibromyalgia
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    3
    Osteoarthritis
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Clubbing
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Costochondritis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Muscular weakness
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Osteopenia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Periarthritis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Tendon pain
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Tendonitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Groin pain
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Adrenal suppression
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    6
    Hypoglycaemia
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    5
    Glucose tolerance impaired
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Hyperglycaemia
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Vitamin D deficiency
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Hypokalaemia
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Iron deficiency
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Vitamin K deficiency
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Dehydration
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Electrolyte imbalance
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Hypovitaminosis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Increased appetite
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Insulin resistance
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Lactose intolerance
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Vitamin A deficiency
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Zinc deficiency
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    94 / 192 (48.96%)
         occurrences all number
    231
    Upper respiratory tract infection
         subjects affected / exposed
    65 / 192 (33.85%)
         occurrences all number
    144
    Nasopharyngitis
         subjects affected / exposed
    39 / 192 (20.31%)
         occurrences all number
    67
    Sinusitis
         subjects affected / exposed
    29 / 192 (15.10%)
         occurrences all number
    41
    Gastroenteritis
         subjects affected / exposed
    13 / 192 (6.77%)
         occurrences all number
    16
    Rhinitis
         subjects affected / exposed
    10 / 192 (5.21%)
         occurrences all number
    15
    Influenza
         subjects affected / exposed
    9 / 192 (4.69%)
         occurrences all number
    9
    Urinary tract infection
         subjects affected / exposed
    9 / 192 (4.69%)
         occurrences all number
    11
    Respiratory tract infection viral
         subjects affected / exposed
    8 / 192 (4.17%)
         occurrences all number
    11
    Tonsillitis
         subjects affected / exposed
    8 / 192 (4.17%)
         occurrences all number
    8
    Oral candidiasis
         subjects affected / exposed
    7 / 192 (3.65%)
         occurrences all number
    8
    Respiratory tract infection
         subjects affected / exposed
    7 / 192 (3.65%)
         occurrences all number
    14
    Bronchitis
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    14
    Candidiasis
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    13
    Gastroenteritis viral
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    6
    Viral upper respiratory tract infection
         subjects affected / exposed
    6 / 192 (3.13%)
         occurrences all number
    7
    Oral herpes
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    6
    Pharyngitis
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    6
    Vulvovaginal mycotic infection
         subjects affected / exposed
    5 / 192 (2.60%)
         occurrences all number
    6
    Bacterial disease carrier
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    5
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Ear infection
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Pneumonia
         subjects affected / exposed
    4 / 192 (2.08%)
         occurrences all number
    4
    Acute sinusitis
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    4
    Cellulitis
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Cystitis
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Otitis media
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    4
    Pseudomonas infection
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Tooth abscess
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Viral infection
         subjects affected / exposed
    3 / 192 (1.56%)
         occurrences all number
    3
    Conjunctivitis infective
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Folliculitis
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Herpes zoster
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Laryngitis
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Oropharyngeal candidiasis
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Otitis externa
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Tracheobronchitis
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Vulvovaginal candidiasis
         subjects affected / exposed
    2 / 192 (1.04%)
         occurrences all number
    2
    Alveolar osteitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Bacteraemia
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Body tinea
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Diverticulitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Erythema migrans
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Fungal skin infection
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Furuncle
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Gastritis viral
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Genital candidiasis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Genital herpes
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Genital infection fungal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Herpes simplex
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Herpes simplex ophthalmic
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Infection parasitic
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Labyrinthitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Mycobacterial infection
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Nail bed infection bacterial
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Onychomycosis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Rhinotracheitis
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Serratia infection
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Vaginitis bacterial
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Varicella
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 192 (0.52%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2010
    The Data Monitoring Committee (DMC) was removed for this study. Two interim analyses were added.
    11 Jun 2010
    Changes in study procedures regarding liver function testing were made.
    26 Jul 2010
    The DMC was reinstated as a safety monitoring measure for this study. Criteria for subject discontinuation were updated.
    10 Nov 2010
    Frequency of liver function test was changed.
    23 May 2011
    Frequency of liver function test was changed.
    26 Mar 2012
    Ophthalmologic examination (OE) was added. A third interim analysis was added.
    05 Oct 2012
    Additional OEs were added.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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