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    Clinical Trial Results:
    A Phase 2, Multicenter, Double-Blinded, Placebo-Controlled Study to Evaluate Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of VX-661 Monotherapy and VX-661/Ivacaftor Cotherapy in Subjects with Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2011-003821-93
    Trial protocol
    DE   GB  
    Global end of trial date
    25 Mar 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    13 Jul 2016
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    VX11-661-101
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01531673
    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)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of VX-661 monotherapy and VX-661/ivacaftor (also known as VX-770; commercially available as Kalydeco) cotherapy and to evaluate the effect of VX-661 monotherapy and VX-661/ivacaftor cotherapy on cystic fibrosis transmembrane conductance regulator (CFTR) function.
    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
    14 Feb 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Germany: 42
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    United States: 115
    Worldwide total number of subjects
    190
    EEA total number of subjects
    57
    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)
    1
    Adults (18-64 years)
    189
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 194 subjects were randomized of which 190 subjects were treated.

    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, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1-6d Combined: Placebo
    Arm description
    All subjects in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
    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 VX-661 tablet orally once daily (qd) for up to 28 days (for Group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b and 6a) and placebo matched to VX-661 tablet orally every 12 hours (q12h) for up to 28 days (for Group 6d) .

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to ivacaftor tablet orally q12h for up to 28 days (for Group 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a, 6d).

    Arm title
    Group 1: VX-661 10 mg qd
    Arm description
    All subjects in group 1 who received VX-661 10 milligram (mg) tablet orally qd for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 10 mg tablet orally qd for up to 28 days.

    Arm title
    Group 2a: VX-661 30 mg qd
    Arm description
    All subjects in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 30 mg tablet orally qd for up to 28 days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to ivacaftor tablet orally q12h for up to 28 days.

    Arm title
    Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h
    Arm description
    All subjects in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 10 mg tablet orally qd for up to 28 days.

    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
    Ivacaftor 150 mg tablet administered orally q12h for up to 28 days.

    Arm title
    Group 3a: VX-661 100 mg qd
    Arm description
    All subjects in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 100 mg tablet orally qd for up to 28 days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to ivacaftor tablet orally q12h for up to 28 days.

    Arm title
    Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h
    Arm description
    All subjects in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 30 mg tablet orally qd for up to 28 days.

    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
    Ivacaftor 150 mg tablet administered orally q12h for up to 28 days.

    Arm title
    Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h
    Arm description
    All subjects in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 100 mg tablet orally qd for up to 28 days.

    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
    Ivacaftor 150 mg tablet administered orally q12h for up to 28 days.

    Arm title
    Group 5a: VX-661 150 mg qd
    Arm description
    All subjects in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 150 mg tablet orally qd for up to 28 days.

    Arm title
    Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
    Arm description
    All subjects in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 150 mg tablet orally qd for up to 28 days.

    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
    Ivacaftor 150 mg tablet administered orally q12h for up to 28 days.

    Arm title
    Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h
    Arm description
    All subjects in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 100 mg tablet orally qd for up to 28 days.

    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
    Ivacaftor 50 mg tablet orally q12h for up to 28 days.

    Arm title
    Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h
    Arm description
    All subjects in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 50 mg tablet orally q12h for up to 28 days.

    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
    Ivacaftor 150 mg tablet administered orally q12h for up to 28 days.

    Arm title
    Group 7: Placebo
    Arm description
    All subjects in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.
    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 VX-661 tablet orally qd for up to 28 days.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor 150 mg tablet administered orally q12h for up to 28 days.

    Arm title
    Group 7: VX-661 100 mg qd
    Arm description
    All subjects in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-661
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VX-661 100 mg tablet orally qd for up to 28 days.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Kalydeco
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor 150 mg tablet administered orally q12h for up to 28 days.

    Number of subjects in period 1
    Group 1-6d Combined: Placebo Group 1: VX-661 10 mg qd Group 2a: VX-661 30 mg qd Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h Group 3a: VX-661 100 mg qd Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h Group 5a: VX-661 150 mg qd Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h Group 7: Placebo Group 7: VX-661 100 mg qd
    Started
    33
    8
    8
    18
    8
    19
    17
    9
    17
    19
    16
    4
    14
    Completed
    33
    7
    8
    17
    7
    18
    17
    9
    17
    18
    16
    4
    14
    Not completed
    0
    1
    0
    1
    1
    1
    0
    0
    0
    1
    0
    0
    0
         Non-Compliance
    -
    -
    -
    -
    -
    1
    -
    -
    -
    -
    -
    -
    -
         Unspecified
    -
    -
    -
    1
    -
    -
    -
    -
    -
    1
    -
    -
    -
         Adverse Event
    -
    1
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    1
    -
    -
    -
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1-6d Combined: Placebo
    Reporting group description
    All subjects in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.

    Reporting group title
    Group 1: VX-661 10 mg qd
    Reporting group description
    All subjects in group 1 who received VX-661 10 milligram (mg) tablet orally qd for up to 28 days.

    Reporting group title
    Group 2a: VX-661 30 mg qd
    Reporting group description
    All subjects in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.

    Reporting group title
    Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 3a: VX-661 100 mg qd
    Reporting group description
    All subjects in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.

    Reporting group title
    Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 5a: VX-661 150 mg qd
    Reporting group description
    All subjects in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.

    Reporting group title
    Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h
    Reporting group description
    All subjects in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 7: Placebo
    Reporting group description
    All subjects in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.

    Reporting group title
    Group 7: VX-661 100 mg qd
    Reporting group description
    All subjects in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.

    Reporting group values
    Group 1-6d Combined: Placebo Group 1: VX-661 10 mg qd Group 2a: VX-661 30 mg qd Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h Group 3a: VX-661 100 mg qd Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h Group 5a: VX-661 150 mg qd Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h Group 7: Placebo Group 7: VX-661 100 mg qd Total
    Number of subjects
    33 8 8 18 8 19 17 9 17 19 16 4 14 190
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    30.7 ± 8.42 35.3 ± 8.26 30.8 ± 6.63 28.3 ± 7.05 29.1 ± 7.12 29.2 ± 6.39 31 ± 9.3 28.2 ± 8.6 28.2 ± 6.46 27.9 ± 5.58 32.8 ± 11.92 34.5 ± 7.59 26.6 ± 7.01 -
    Gender categorical
    Units: Subjects
        Female
    13 4 4 6 3 6 11 3 10 7 7 3 6 83
        Male
    20 4 4 12 5 13 6 6 7 12 9 1 8 107

    End points

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    End points reporting groups
    Reporting group title
    Group 1-6d Combined: Placebo
    Reporting group description
    All subjects in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.

    Reporting group title
    Group 1: VX-661 10 mg qd
    Reporting group description
    All subjects in group 1 who received VX-661 10 milligram (mg) tablet orally qd for up to 28 days.

    Reporting group title
    Group 2a: VX-661 30 mg qd
    Reporting group description
    All subjects in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.

    Reporting group title
    Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 3a: VX-661 100 mg qd
    Reporting group description
    All subjects in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.

    Reporting group title
    Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 5a: VX-661 150 mg qd
    Reporting group description
    All subjects in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.

    Reporting group title
    Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h
    Reporting group description
    All subjects in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 7: Placebo
    Reporting group description
    All subjects in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.

    Reporting group title
    Group 7: VX-661 100 mg qd
    Reporting group description
    All subjects in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.

    Subject analysis set title
    Group 1-5b Combined Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects in group 1, 2a, 2b, 3a, 3b, 4, 5a and 5b who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.

    Subject analysis set title
    Group 4 and 6 Combined: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects in group 4, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.

    Primary: Safety as Determined by Adverse Events

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    End point title
    Safety as Determined by Adverse Events [1]
    End point description
    An AE is defined as any untoward medical occurrence in a subject during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the Informed Consent Form is signed. An SAE is any AE that results in any of the following: death; life-threatening condition; inpatient hospitalization or prolongation of hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; or other important medical event. Treatment-emergent adverse events are defined as adverse events that were reported or worsened on or after start of study drug through the Follow-up Visit or premature discontinuation. The analysis was done using safety set which included all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Start of study drug through the Follow-up Visit
    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 statistical analysis was planned for safety endpoint.
    End point values
    Group 1-6d Combined: Placebo Group 1: VX-661 10 mg qd Group 2a: VX-661 30 mg qd Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h Group 3a: VX-661 100 mg qd Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h Group 5a: VX-661 150 mg qd Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h Group 7: Placebo Group 7: VX-661 100 mg qd
    Number of subjects analysed
    33
    8
    8
    18
    8
    19
    17
    9
    17
    19
    16
    4
    14
    Units: subjects
    number (not applicable)
        Subjects with AEs
    30
    8
    7
    15
    7
    18
    10
    8
    17
    16
    16
    2
    12
        Subjects with SAEs
    5
    1
    1
    1
    0
    2
    2
    0
    0
    1
    2
    0
    1
    No statistical analyses for this end point

    Primary: Change in Sweat Chloride From Baseline Through Study Day 28

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    End point title
    Change in Sweat Chloride From Baseline Through Study Day 28 [2]
    End point description
    Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. The analysis was done using Full Analysis Set (FAS) which included all randomized subjects who received at least 1 dose of study drug. Here 'Number of subjects analysed' signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline through Day 28
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 1: VX-661 10 mg qd Group 2a: VX-661 30 mg qd Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h Group 3a: VX-661 100 mg qd Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h Group 5a: VX-661 150 mg qd Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h Group 1-5b Combined Placebo
    Number of subjects analysed
    8
    6
    18
    8
    18
    17
    9
    17
    24
    Units: millimole per liter (mmol/L)
        least squares mean (confidence interval 95%)
    3.92 (-0.5 to 8.34)
    -4.76 (-9.75 to 0.22)
    -5.06 (-8.02 to -2.09)
    -20.43 (-24.75 to -16.12)
    -6 (-8.98 to 3.02)
    -6.04 (-9.12 to -2.96)
    -10.46 (-14.53 to -6.39)
    -2.63 (-5.67 to 0.41)
    -0.86 (-3.36 to 1.65)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Group 1: VX-661 10 mg qd v Group 1-5b Combined Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0647
    Method
    Mixed-effect repeated measure (MMRM)
    Parameter type
    Least Squares (LS) Mean Difference
    Point estimate
    4.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    9.84
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Group 2a: VX-661 30 mg qd v Group 1-5b Combined Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1686
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -3.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.5
         upper limit
    1.68
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h v Group 1-5b Combined Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0348
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.1
         upper limit
    -0.31
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Group 3a: VX-661 100 mg qd v Group 1-5b Combined Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -19.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.57
         upper limit
    -14.59
    Statistical analysis title
    Statistical Analysis 5
    Comparison groups
    Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h v Group 1-5b Combined Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0101
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -5.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.03
         upper limit
    -1.25
    Statistical analysis title
    Statistical Analysis 6
    Comparison groups
    Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h v Group 1-5b Combined Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.011
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -5.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.16
         upper limit
    -1.21
    Statistical analysis title
    Copy of Statistical Analysis 7
    Comparison groups
    Group 5a: VX-661 150 mg qd v Group 1-5b Combined Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -9.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.38
         upper limit
    -4.82
    Statistical analysis title
    Copy of Copy of Statistical Analysis 8
    Comparison groups
    Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h v Group 1-5b Combined Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3745
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -1.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.71
         upper limit
    2.17

    Primary: Change in Sweat Chloride From Baseline Through Study Day 28 for Group 6

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    End point title
    Change in Sweat Chloride From Baseline Through Study Day 28 for Group 6 [3]
    End point description
    Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'Number of subjects analysed' signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline through Day 28
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h Group 4 and 6 Combined: Placebo
    Number of subjects analysed
    18
    16
    14
    Units: mmol/L
        least squares mean (confidence interval 95%)
    -6.07 (-10.84 to -1.31)
    -7.89 (-12.3 to -3.48)
    -1.19 (-5.5 to 3.12)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h v Group 4 and 6 Combined: Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0357
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -6.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.94
         upper limit
    -0.46

    Primary: Change in Sweat Chloride From Baseline Through Study Day 28 for Group 7

    Close Top of page
    End point title
    Change in Sweat Chloride From Baseline Through Study Day 28 for Group 7 [4]
    End point description
    Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'Number of subjects analysed' signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline through Day 28
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 7: Placebo Group 7: VX-661 100 mg qd
    Number of subjects analysed
    4
    13
    Units: mmol/L
        least squares mean (confidence interval 95%)
    10.18 (-2.48 to 22.84)
    -7.02 (-14.15 to 0.11)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Group 7: VX-661 100 mg qd v Group 7: Placebo
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0238
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -17.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -31.75
         upper limit
    -2.65

    Secondary: Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28

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    End point title
    Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 [5]
    End point description
    Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'Number of subjects analysed' signifies those subjects who were evaluable for this endpoint and 'n' signifies those subjects who were evaluable for this endpoint at the specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 7, Day 14, Day 21, Day 28
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 1: VX-661 10 mg qd Group 2a: VX-661 30 mg qd Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h Group 3a: VX-661 100 mg qd Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h Group 5a: VX-661 150 mg qd Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h Group 1-5b Combined Placebo
    Number of subjects analysed
    8
    8
    18
    8
    18
    17
    9
    17
    24
    Units: mmol/L
    least squares mean (confidence interval 95%)
        Day 7 (n= 8, 6, 16, 8, 16, 16, 9, 17, 23)
    1.73 (-3.82 to 7.29)
    -3.13 (-9.5 to 3.25)
    -5.37 (-9.24 to -1.49)
    -19.48 (-25 to -13.97)
    -5.02 (-8.85 to -1.19)
    -6.85 (-10.72 to -2.99)
    -13.89 (-19.09 to -8.69)
    -0.59 (-4.38 to 3.2)
    0.22 (-3.01 to 3.45)
        Day 14 (n= 8, 6, 17, 8, 14, 14, 9, 15, 24)
    0.91 (-4.64 to 6.46)
    -7.88 (-14.25 to -1.5)
    -6.55 (-10.34 to -2.76)
    -28.23 (-33.75 to -22.72)
    -6.77 (-10.81 to -2.74)
    -7.37 (-11.44 to -3.3)
    -10.28 (-15.48 to -5.08)
    -2.4 (-6.38 to 1.58)
    -1.32 (-4.5 to 1.87)
        Day 21 (n= 7, 6, 17, 8, 15, 13, 9, 15, 23)
    4.84 (-0.99 to 10.66)
    -4.61 (-10.98 to 1.76)
    -3.7 (-7.48 to 0.09)
    -18.78 (-24.3 to -13.27)
    -5.83 (-9.77 to -1.89)
    -4.26 (-8.44 to -0.08)
    -12.17 (-17.37 to -6.97)
    -3.9 (-7.88 to 0.08)
    -1.05 (-4.29 to 2.18)
        Day 28 (n= 7, 6, 17, 8, 16, 14, 9, 15, 22)
    8.19 (2.37 to 14.02)
    -3.44 (-9.82 to 2.93)
    -4.62 (-8.41 to -0.83)
    -15.23 (-20.75 to -9.72)
    -6.37 (-10.22 to -2.52)
    -5.68 (-9.76 to -1.61)
    -5.5 (-10.7 to 0.3)
    -3.62 (-7.6 to 0.36)
    -1.27 (-4.55 to 2.01)
    No statistical analyses for this end point

    Secondary: Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 6

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    End point title
    Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 6 [6]
    End point description
    Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies those subjects who were evaluable for this endpoint at the specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 7, Day 14, Day 21, Day 28
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h Group 4 and 6 Combined: Placebo
    Number of subjects analysed
    19
    16
    14
    Units: mmol/L
    least squares mean (confidence interval 95%)
        Day 7 (n= 15, 13, 13)
    -6.61 (-12.06 to -1.16)
    -11.04 (-16.37 to -5.7)
    -0.36 (-5.54 to 4.83)
        Day 14 (n= 17, 14, 14)
    -7.9 (-13.25 to -2.55)
    -7.11 (-12.34 to -1.88)
    -2.1 (-7.19 to 2.98)
        Day 21 (n= 13, 14, 13)
    -6.34 (-12 to 0.68)
    -6.98 (-12.2 to -1.76)
    -2.47 (-7.67 to 2.72)
        Day 28 (n= 16, 15, 13)
    -3.44 (-8.85 to 1.97)
    -6.43 (-11.55 to -1.31)
    0.19 (-5.01 to 5.39)
    No statistical analyses for this end point

    Secondary: Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 7

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    End point title
    Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 7 [7]
    End point description
    Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies those subjects who were evaluable for this endpoint at the specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 7, Day 14, Day 21, Day 28
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 7: Placebo Group 7: VX-661 100 mg qd
    Number of subjects analysed
    4
    14
    Units: mmol/L
    least squares mean (confidence interval 95%)
        Day 7 (n= 4, 12)
    4.87 (-8.32 to 18.06)
    -7.28 (-14.76 to 0.2)
        Day 14 (n= 4, 11)
    10.75 (-2.44 to 23.94)
    -8.95 (-16.54 to -1.35)
        Day 21 (n= 4, 10)
    9.37 (-3.82 to 22.56)
    -4.14 (-11.86 to 3.58)
        Day 28 (n= 3, 11)
    15.73 (1.85 to 29.61)
    -7.72 (-15.31 to -0.13)
    No statistical analyses for this end point

    Secondary: Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28

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    End point title
    Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 [8]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies those subjects who were evaluable for the specified time point for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 7, Day 14, Day 21, Day 28
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 1: VX-661 10 mg qd Group 2a: VX-661 30 mg qd Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h Group 3a: VX-661 100 mg qd Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h Group 5a: VX-661 150 mg qd Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h Group 1-5b Combined Placebo
    Number of subjects analysed
    8 [9]
    8
    18
    8
    19
    17
    9
    17
    24
    Units: percent predicted of FEV1
    least squares mean (confidence interval 95%)
        PB Through Day 28 (n= 8,8,18,8,19,17,9,17,24)
    3.49 (0.21 to 6.77)
    1.63 (-1.62 to 4.87)
    1.3 (-0.87 to 3.47)
    1.6 (-1.64 to 4.85)
    2.9 (0.76 to 5.03)
    3.75 (1.47 to 6.02)
    2.54 (-0.53 to 5.61)
    3.61 (1.36 to 5.86)
    -0.14 (-2.02 to 1.74)
        Day 7 (n= 8, 8, 18, 8, 19, 17, 9, 17, 24)
    2.72 (-1.17 to 6.62)
    0.8 (-3.09 to 4.69)
    0.47 (-2.13 to 3.06)
    3 (-0.89 to 6.89)
    2.9 (0.37 to 5.42)
    2.66 (-0.01 to 5.33)
    0.5 (-3.17 to 4.18)
    2.51 (-0.16 to 5.18)
    -0.41 (-2.66 to 1.84)
        Day 14 (n= 8, 8, 18, 8, 18, 15, 8, 16, 24)
    5.25 (1.35 to 9.15)
    3.72 (-0.17 to 7.61)
    0.91 (-1.69 to 3.5)
    1.61 (-2.28 to 5.5)
    1.79 (-0.78 to 4.36)
    4.52 (1.73 to 7.3)
    2.79 (-1 to 6.59)
    3.72 (1 to 6.44)
    0.03 (-2.21 to 2.28)
        Day 21 (n= 7, 8, 18, 8, 17, 15, 9, 16, 24)
    2.71 (-1.34 to 6.76)
    1.8 (-2.09 to 5.69)
    1.84 (-0.75 to 4.44)
    0.25 (-3.64 to 4.15)
    3.88 (1.27 to 6.5)
    3.37 (0.58 to 6.15)
    4.52 (0.85 to 8.19)
    4.08 (1.36 to 6.8)
    0.18 (-2.07 to 2.43)
        Day 28 (n= 7, 8, 17, 8, 17, 15, 9, 16, 23)
    3.26 (-0.79 to 7.32)
    0.19 (-3.7 to 4.08)
    1.99 (-0.65 to 4.63)
    1.55 (-2.34 to 5.45)
    3.02 (0.4 to 5.63)
    4.44 (1.66 to 7.23)
    2.34 (-1.33 to 6.01)
    4.13 (1.41 to 6.86)
    -0.36 (-2.63 to 1.92)
    Notes
    [9] - PB= Post-Baseline
    No statistical analyses for this end point

    Secondary: Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6

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    End point title
    Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 [10]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies those subjects who were evaluable for the specified time point for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 7, Day 14, Day 21, Day 28
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h Group 4 and 6 Combined: Placebo
    Number of subjects analysed
    19
    16
    14
    Units: percent predicted of FEV1
    least squares mean (confidence interval 95%)
        Post-Baseline Through Day 28 (n= 18, 16, 14)
    0.94 (-1.42 to 3.3)
    2.31 (-0.19 to 4.8)
    1.47 (-1.2 to 4.13)
        Day 7 (n= 18, 16, 14)
    1.37 (-1.33 to 4.08)
    1.95 (-0.93 to 4.82)
    1.09 (-1.97 to 4.15)
        Day 14 (n= 17, 16, 14)
    1.2 (-1.55 to 3.95)
    2.52 (-0.36 to 5.4)
    1.37 (-1.69 to 4.44)
        Day 21 (n= 17, 16, 13)
    0.36 (-2.38 to 3.11)
    3.21 (0.33 to 6.08)
    1.73 (-1.39 to 4.85)
        Day 28 (n= 16, 16, 13)
    0.81 (-1.97 to 3.6)
    1.56 (-1.32 to 4.44)
    1.67 (-1.45 to 4.8)
    No statistical analyses for this end point

    Secondary: Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7

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    End point title
    Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 [11]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies those subjects who were evaluable at the specified time point for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 7, Day 14, Day 21, Day 28
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 7: Placebo Group 7: VX-661 100 mg qd
    Number of subjects analysed
    4
    14
    Units: percent predicted of FEV1
    least squares mean (confidence interval 95%)
        Post-Baseline Through Day 28
    1.4 (-5.04 to 7.83)
    4.6 (1.17 to 8.03)
        Day 7
    3 (-3.55 to 9.55)
    4.14 (0.65 to 7.63)
        Day 14
    0.98 (-5.56 to 7.53)
    5.22 (1.73 to 8.71)
        Day 21
    2.72 (-3.83 to 9.27)
    3.88 (0.39 to 7.38)
        Day 28
    -1.12 (-7.66 to 5.43)
    5.16 (1.67 to 8.65)
    No statistical analyses for this end point

    Secondary: Change in FEV1 (Liter [L]) From Baseline to Each Visit and From Baseline Through Study Day 28

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    End point title
    Change in FEV1 (Liter [L]) From Baseline to Each Visit and From Baseline Through Study Day 28 [12]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies those subjects who were evaluable at the specified time point for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 7, Day 14, Day 21, Day 28
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 1: VX-661 10 mg qd Group 2a: VX-661 30 mg qd Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h Group 3a: VX-661 100 mg qd Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h Group 5a: VX-661 150 mg qd Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h Group 1-5b Combined Placebo
    Number of subjects analysed
    8 [13]
    8
    18
    8
    19
    17
    9
    17
    24
    Units: Liters
    least squares mean (confidence interval 95%)
        PB Through Day 28 (n=8,8,18,8,19,17,9,17, 24)
    0.14 (0.02 to 0.26)
    0.07 (-0.05 to 0.19)
    0.05 (-0.03 to 0.13)
    0.04 (-0.08 to 0.16)
    0.1 (0.02 to 0.18)
    0.14 (0.06 to 0.23)
    0.1 (-0.01 to 0.21)
    0.12 (0.04 to 0.21)
    0.01 (-0.06 to 0.08)
        Day 7 (n= 8, 8, 18, 8, 19, 17, 9, 17, 24)
    0.11 (-0.04 to 0.25)
    0.02 (-0.13 to 0.16)
    0.02 (-0.08 to 0.12)
    0.09 (-0.06 to 0.24)
    0.1 (0 to 0.19)
    0.11 (0.01 to 0.21)
    0.02 (-0.12 to 0.16)
    0.08 (-0.02 to 0.18)
    -0.01 (-0.09 to 0.08)
        Day 14 (n= 8, 8, 18, 8, 18, 15, 8, 16, 24)
    0.2 (0.05 to 0.34)
    0.14 (-0.01 to 0.28)
    0.03 (-0.07 to 0.12)
    0.04 (-0.11 to 0.19)
    0.05 (-0.04 to 0.15)
    0.17 (0.06 to 0.27)
    0.11 (-0.03 to 0.25)
    0.12 (0.02 to 0.23)
    0.02 (-0.07 to 0.1)
        Day 21 (n= 7, 8, 18, 8, 17, 15, 9, 16, 24)
    0.12 (-0.03 to 0.27)
    0.08 (-0.06 to 0.23)
    0.07 (-0.03 to 0.17)
    0 (-0.15 to 0.15)
    0.14 (0.04 to 0.23)
    0.13 (0.02 to 0.23)
    0.18 (0.04 to 0.31)
    0.14 (0.04 to 0.24)
    0.02 (-0.06 to 0.1)
        Day 28 (n= 7, 8, 17, 8, 17, 15, 9, 16, 23)
    0.13 (-0.02 to 0.28)
    0.03 (-0.11 to 0.18)
    0.08 (-0.02 to 0.18)
    0.04 (-0.11 to 0.18)
    0.1 (0.01 to 0.2)
    0.16 (0.06 to 0.27)
    0.09 (-0.05 to 0.23)
    0.15 (0.05 to 0.26)
    0.01 (-0.08 to 0.09)
    Notes
    [13] - PB=Post-Baseline
    No statistical analyses for this end point

    Secondary: Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6

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    End point title
    Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 [14]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies those subjects who were evaluable at the specified time point for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 7, Day 14, Day 21, Day 28
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h Group 4 and 6 Combined: Placebo
    Number of subjects analysed
    19
    16
    14
    Units: Liters
    least squares mean (confidence interval 95%)
        Post-Baseline Through Day 28 (n= 18, 16, 14)
    0.02 (-0.07 to 0.11)
    0.09 (-0.01 to 0.18)
    0.07 (-0.04 to 0.17)
        Day 7 (n= 18, 16, 14)
    0.04 (-0.07 to 0.14)
    0.06 (-0.05 to 0.17)
    0.05 (-0.06 to 0.17)
        Day 14 (n= 17, 16, 14)
    0.03 (-0.07 to 0.14)
    0.1 (-0.01 to 0.21)
    0.06 (-0.05 to 0.18)
        Day 21 (n= 17, 16, 13)
    -0.01 (-0.11 to 0.1)
    0.13 (0.02 to 0.24)
    0.08 (-0.04 to 0.2)
        Day 28 (n= 16, 16, 13)
    0.02 (-0.08 to 0.13)
    0.06 (-0.05 to 0.17)
    0.08 (-0.04 to 0.2)
    No statistical analyses for this end point

    Secondary: Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7

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    End point title
    Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 [15]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 7, Day 14, Day 21, Day 28
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 7: Placebo Group 7: VX-661 100 mg qd
    Number of subjects analysed
    4
    14
    Units: Liters
    least squares mean (confidence interval 95%)
        Post-Baseline Through Day 28
    0.09 (-0.16 to 0.34)
    0.16 (0.03 to 0.29)
        Day 7
    0.14 (-0.11 to 0.39)
    0.15 (0.01 to 0.28)
        Day 14
    0.08 (-0.17 to 0.33)
    0.18 (0.05 to 0.32)
        Day 21
    0.14 (-0.11 to 0.4)
    0.13 (-0.01 to 0.26)
        Day 28
    -0.01 (-0.26 to 0.25)
    0.19 (0.05 to 0.32)
    No statistical analyses for this end point

    Secondary: Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit up to Study Day 28

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    End point title
    Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit up to Study Day 28 [16]
    End point description
    The CFQ-R is a validated patient-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.The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies those subjects who were evaluable at the specified time point for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 14, Day 28
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 1: VX-661 10 mg qd Group 2a: VX-661 30 mg qd Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h Group 3a: VX-661 100 mg qd Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h Group 5a: VX-661 150 mg qd Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h Group 1-5b Combined Placebo
    Number of subjects analysed
    8 [17]
    8
    18
    8
    19
    17
    9
    17
    24
    Units: units on a scale
    least squares mean (confidence interval 95%)
        PB Through Day 28 (n=8,8,18,8,18,15,9,16,24)
    4.02 (-4.38 to 12.43)
    5.54 (-2.72 to 13.79)
    3.8 (-1.74 to 9.35)
    0.61 (-7.64 to 8.86)
    3.52 (-2.02 to 9.06)
    5.15 (-0.88 to 11.19)
    2.58 (-5.21 to 10.37)
    7.62 (1.78 to 13.45)
    1.69 (-3.1 to 6.48)
        Day 14 (n= 8, 8, 18, 8, 18, 15, 9, 16, 24)
    6.67 (-2.9 to 16.25)
    4.84 (-4.73 to 14.41)
    4.29 (-2.09 to 10.67)
    0.27 (-9.3 to 9.83)
    2.81 (-3.56 to 9.19)
    4.41 (-2.58 to 11.4)
    4.13 (-4.9 to 13.16)
    7.13 (0.37 to 13.89)
    0.53 (-4.99 to 6.05)
        Day 28 (n= 7, 8, 17, 8, 17, 15, 9, 16, 23)
    1.38 (-8.7 to 11.45)
    6.23 (-3.34 to 15.8)
    3.31 (-3.21 to 9.84)
    0.95 (-8.61 to 10.52)
    4.22 (-2.29 to 10.74)
    5.9 (-1.1 to 12.89)
    1.03 (-8 to 10.06)
    8.1 (1.34 to 14.87)
    2.85 (-2.76 to 8.46)
    Notes
    [17] - PB= Post-Baseline
    No statistical analyses for this end point

    Secondary: Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit up to Study Day 28 for Group 6

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    End point title
    Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit up to Study Day 28 for Group 6 [18]
    End point description
    The CFQ-R is a validated patient-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. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies those subjects who were evaluable at the specified time point for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 14, Day 28
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h Group 4 and 6 Combined: Placebo
    Number of subjects analysed
    19
    16
    14
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Post-Baseline Through Day 28 (n= 17, 16, 14)
    0.87 (-4.44 to 6.19)
    1.91 (-3.5 to 7.33)
    1.65 (-4.18 to 7.49)
        Day 14 (n= 17, 16, 14)
    2.02 (-3.97 to 8.02)
    0.87 (-5.25 to 6.99)
    2.78 (-3.76 to 9.32)
        Day 28 (n= 17, 16, 13)
    -0.27 (-6.27 to 5.72)
    2.96 (-3.16 to 9.08)
    0.53 (-6.18 to 7.23)
    No statistical analyses for this end point

    Secondary: Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit up to Study Day 28 for Group 7

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    End point title
    Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit up to Study Day 28 for Group 7 [19]
    End point description
    The CFQ-R is a validated patient-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. The analysis was done using FAS which included all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies those subjects who were evaluable at the specified time point for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 14, Day 28
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Group 7: Placebo Group 7: VX-661 100 mg qd
    Number of subjects analysed
    4
    14
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Post-Baseline Through Day 28 (n= 4, 14)
    -3.02 (-13.52 to 7.47)
    3.79 (-1.78 to 9.36)
        Day 14 (n= 4, 13)
    1.83 (-10.64 to 14.3)
    5.24 (-1.56 to 12.04)
        Day 28 (n= 4, 14)
    -7.87 (-20.34 to 4.6)
    2.33 (-4.24 to 8.91)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Start of study drug through the Follow-up Visit (28 days after last dose) or premature discontinuation
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Group 1-6d Combined: Placebo
    Reporting group description
    All subjects in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.

    Reporting group title
    Group 1: VX-661 10 mg qd
    Reporting group description
    All subjects in group 1 who received VX661 10 milligram tablet orally qd for up to 28 days.

    Reporting group title
    Group 2a: VX-661 30 mg qd
    Reporting group description
    All subjects in group 2a who received VX661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.

    Reporting group title
    Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 2b who received VX661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 3a: VX-661 100 mg qd
    Reporting group description
    All subjects in group 3a who received VX661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.

    Reporting group title
    Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 3b who received VX661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 4 who received VX661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 5a: VX-661 150 mg qd
    Reporting group description
    All subjects in group 5a who received VX661 150 mg tablet orally qd for up to 28 days.

    Reporting group title
    Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 5b who received VX661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h
    Reporting group description
    All subjects in group 6a who received VX661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h
    Reporting group description
    All subjects in group 6d who received VX661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.

    Reporting group title
    Group 7: Placebo
    Reporting group description
    All subjects in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.

    Reporting group title
    Group 7: VX-661 100 mg qd
    Reporting group description
    All subjects in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.

    Serious adverse events
    Group 1-6d Combined: Placebo Group 1: VX-661 10 mg qd Group 2a: VX-661 30 mg qd Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h Group 3a: VX-661 100 mg qd Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h Group 5a: VX-661 150 mg qd Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h Group 7: Placebo Group 7: VX-661 100 mg qd
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 33 (15.15%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    2 / 19 (10.53%)
    2 / 17 (11.76%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    2 / 16 (12.50%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    5 / 33 (15.15%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    2 / 17 (11.76%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    2 / 16 (12.50%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Group 1-6d Combined: Placebo Group 1: VX-661 10 mg qd Group 2a: VX-661 30 mg qd Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h Group 3a: VX-661 100 mg qd Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h Group 5a: VX-661 150 mg qd Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h Group 7: Placebo Group 7: VX-661 100 mg qd
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 33 (90.91%)
    8 / 8 (100.00%)
    7 / 8 (87.50%)
    15 / 18 (83.33%)
    7 / 8 (87.50%)
    18 / 19 (94.74%)
    9 / 17 (52.94%)
    8 / 9 (88.89%)
    17 / 17 (100.00%)
    16 / 19 (84.21%)
    16 / 16 (100.00%)
    2 / 4 (50.00%)
    12 / 14 (85.71%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 8 (50.00%)
    1 / 8 (12.50%)
    1 / 18 (5.56%)
    1 / 8 (12.50%)
    3 / 19 (15.79%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    2 / 17 (11.76%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    4
    4
    1
    1
    1
    3
    0
    2
    4
    0
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    2
    2
    0
    0
    0
    1
    0
    1
    1
    1
    0
    0
    2
    Application site rash
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Thirst
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Application site erythema
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Catheter site haematoma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Disease progression
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Feeling abnormal
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Infusion site pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Infusion site swelling
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Medical device complication
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vessel puncture site haematoma
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Vessel puncture site reaction
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Thinking abnormal
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Breast tenderness
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Menstrual disorder
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Metrorrhagia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Muscle strain
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Concussion
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Excoriation
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    4
    0
    0
    0
    Laceration
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Post concussion syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Scratch
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Skeletal injury
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Sunburn
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    0
    1
    0
    2
    0
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Blood glucose decreased
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Liver function test abnormal
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal examination abnormal
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Urinary casts present
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Urine colour abnormal
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Vitamin D decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Cystic fibrosis related diabetes
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 33 (18.18%)
    3 / 8 (37.50%)
    3 / 8 (37.50%)
    2 / 18 (11.11%)
    2 / 8 (25.00%)
    3 / 19 (15.79%)
    2 / 17 (11.76%)
    2 / 9 (22.22%)
    3 / 17 (17.65%)
    4 / 19 (21.05%)
    3 / 16 (18.75%)
    0 / 4 (0.00%)
    4 / 14 (28.57%)
         occurrences all number
    7
    3
    3
    3
    2
    3
    2
    3
    5
    6
    4
    0
    4
    Sputum increased
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 8 (25.00%)
    2 / 8 (25.00%)
    2 / 18 (11.11%)
    1 / 8 (12.50%)
    1 / 19 (5.26%)
    2 / 17 (11.76%)
    2 / 9 (22.22%)
    1 / 17 (5.88%)
    2 / 19 (10.53%)
    3 / 16 (18.75%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    2
    2
    2
    1
    1
    2
    3
    1
    3
    3
    0
    0
    Haemoptysis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    2 / 8 (25.00%)
    1 / 19 (5.26%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    3
    0
    0
    2
    2
    1
    0
    1
    0
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    1 / 19 (5.26%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    2 / 16 (12.50%)
    0 / 4 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    3
    0
    1
    0
    1
    1
    1
    0
    0
    1
    2
    0
    2
    Nasal congestion
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    1 / 17 (5.88%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
    1 / 4 (25.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    3
    0
    0
    1
    0
    0
    1
    1
    2
    1
    1
    1
    Rales
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    2 / 18 (11.11%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    2 / 17 (11.76%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 4 (25.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    0
    2
    0
    2
    2
    0
    1
    0
    0
    1
    2
    Respiration abnormal
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    2
    0
    4
    0
    0
    1
    0
    0
    Respiratory tract congestion
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    1 / 17 (5.88%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    1
    1
    1
    0
    0
    1
    0
    0
    Sinus congestion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
    2 / 17 (11.76%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
    1 / 4 (25.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    2
    2
    1
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    1
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Sputum discoloured
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Asthma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Bronchial obstruction
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Bronchial secretion retention
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Bronchiectasis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Increased bronchial secretion
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Nasal obstruction
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Nasal oedema
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Painful respiration
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Paranasal sinus hypersecretion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Respiratory tract irritation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 33 (24.24%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    2 / 18 (11.11%)
    1 / 8 (12.50%)
    4 / 19 (21.05%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    2 / 17 (11.76%)
    4 / 19 (21.05%)
    4 / 16 (25.00%)
    0 / 4 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    9
    1
    1
    3
    2
    4
    0
    1
    3
    5
    7
    0
    4
    Sinus headache
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    1
    0
    0
    1
    0
    0
    1
    1
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    3 / 8 (37.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    1
    0
    0
    2
    0
    0
    Lethargy
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Migraine
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Partial seizures
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Conjunctival irritation
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Dry eye
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    2
    0
    0
    0
    1
    Ear discomfort
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 4 (25.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    2 / 18 (11.11%)
    1 / 8 (12.50%)
    2 / 19 (10.53%)
    1 / 17 (5.88%)
    4 / 9 (44.44%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    5 / 16 (31.25%)
    0 / 4 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    1
    3
    2
    1
    4
    1
    4
    0
    1
    8
    0
    6
    Diarrhoea
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    2 / 18 (11.11%)
    1 / 8 (12.50%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    2 / 16 (12.50%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    2
    1
    2
    1
    1
    0
    1
    1
    0
    2
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 18 (5.56%)
    1 / 8 (12.50%)
    2 / 19 (10.53%)
    0 / 17 (0.00%)
    2 / 9 (22.22%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    1
    1
    2
    0
    2
    1
    0
    2
    0
    1
    Abdominal pain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    3 / 19 (15.79%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    0
    0
    0
    3
    2
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    2 / 17 (11.76%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
    1 / 4 (25.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    2
    2
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    2 / 17 (11.76%)
    0 / 19 (0.00%)
    2 / 16 (12.50%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    2
    0
    2
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Change of bowel habit
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Enteritis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Faecaloma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Faeces discoloured
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Retching
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Urine odour abnormal
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    1
    0
    0
    0
    Night sweats
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    1
    0
    0
    0
    0
    Cold sweat
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Nail disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Rash follicular
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Red man syndrome
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    2 / 18 (11.11%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    2 / 16 (12.50%)
    0 / 4 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    3
    1
    0
    2
    0
    0
    0