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    Clinical Trial Results:
    A Phase 2, Multicenter, Double-Blinded, Placebo-Controlled, Multiple-Dose Study to Evaluate Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Lumacaftor Monotherapy, and Lumacaftor and Ivacaftor Combination Therapy in Subjects with Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2010-020413-90
    Trial protocol
    DE   BE   GB   IE  
    Global end of trial date
    29 Apr 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    13 Jul 2016
    First version publication date
    08 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    requires edit to address results section (Secondary Endpoints data , and reporting groups shuffle) affected by system bug which has now been fixed.

    Trial information

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    Trial identification
    Sponsor protocol code
    VX09-809-102
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01225211
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States, 022101862
    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
    17 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Cohort 1, Cohort 2, and Cohort 3: To evaluate the safety and tolerability when lumacaftor is administered alone or in combination with ivacaftor; To evaluate the effect of lumacaftor administered alone or in combination with ivacaftor on sweat chloride. Cohort 4: To evaluate the safety and tolerability of lumacaftor in combination with ivacaftor; To evaluate the efficacy of lumacaftor in combination with ivacaftor.
    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
    18 Oct 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    New Zealand: 7
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 227
    Country: Number of subjects enrolled
    Australia: 40
    Worldwide total number of subjects
    311
    EEA total number of subjects
    37
    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)
    0
    Adults (18-64 years)
    311
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants in each cohort are mutually exclusive. A total of 312 participants were randomized of which one participant did not receive any treatment and a total of 311 participants were treated.

    Pre-assignment
    Screening details
    Study included 4 cohorts which were studied in sequential manner. For results reporting, combined placebo arm was reported for Cohort 2 and 3 and results for these 2 cohorts are reported collectively.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: Placebo
    Arm description
    Participants homozygous (HO) for the F508del-CF transmembrane conductance regulator gene (CFTR) mutation received lumacaftor matched placebo once daily (qd) (Day 1 through Day 14), followed by lumacaftor matched placebo qd in combination with ivacaftor matched placebo every 12 hours (q12h) (Day 15 through Day 21).
    Arm type
    Placebo

    Investigational medicinal product name
    Lumacaftor Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablet qd as described in reporting group description.

    Investigational medicinal product name
    Ivacaftor Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablet qd as described in reporting group description.

    Arm title
    Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg q12h
    Arm description
    Participants homozygous for the F508del-CFTR mutation received 200 milligram (mg) of lumacaftor (LUM) qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor (IVA) q12h (Day 15 through Day 21).
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor
    Investigational medicinal product code
    Other name
    VX-809, LUM
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lumacaftor tablet qd as described in reporting group description.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    Other name
    VX-770, IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor tablet qd as described in reporting group description.

    Arm title
    Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h
    Arm description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor
    Investigational medicinal product code
    Other name
    VX-809, LUM
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lumacaftor tablet qd as described in reporting group description.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    Other name
    VX-770, IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor tablet qd as described in reporting group description.

    Arm title
    Cohort 2 and 3: Placebo (HO and HE)
    Arm description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28), followed by lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).
    Arm type
    Placebo

    Investigational medicinal product name
    Lumacaftor Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablet qd as described in reporting group description.

    Investigational medicinal product name
    Ivacaftor Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablet qd as described in reporting group description.

    Arm title
    Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO)
    Arm description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor
    Investigational medicinal product code
    Other name
    VX-809, LUM
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lumacaftor tablet qd as described in reporting group description.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    Other name
    VX-770, IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor tablet qd as described in reporting group description.

    Arm title
    Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO)
    Arm description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor
    Investigational medicinal product code
    Other name
    VX-809, LUM
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lumacaftor tablet qd as described in reporting group description.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    Other name
    VX-770, IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor tablet qd as described in reporting group description.

    Arm title
    Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO&HE)
    Arm description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor
    Investigational medicinal product code
    Other name
    VX-809, LUM
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lumacaftor tablet qd as described in reporting group description.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    Other name
    VX-770, IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor tablet qd as described in reporting group description.

    Arm title
    Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO)
    Arm description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor
    Investigational medicinal product code
    Other name
    VX-809, LUM
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lumacaftor tablet qd as described in reporting group description.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    Other name
    VX-770, IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor tablet qd as described in reporting group description.

    Arm title
    Cohort 4: Placebo
    Arm description
    Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).
    Arm type
    Placebo

    Investigational medicinal product name
    Lumacaftor Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablet qd as described in reporting group description.

    Investigational medicinal product name
    Ivacaftor Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablet qd as described in reporting group description.

    Arm title
    Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Arm description
    Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor
    Investigational medicinal product code
    Other name
    VX-809, LUM
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lumacaftor tablet qd as described in reporting group description.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    Other name
    VX-770, IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor tablet qd as described in reporting group description.

    Number of subjects in period 1
    Cohort 1: Placebo Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg q12h Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h Cohort 2 and 3: Placebo (HO and HE) Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO&HE) Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO) Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Started
    21
    20
    21
    27
    23
    21
    42
    11
    63
    62
    Completed
    21
    20
    20
    27
    23
    21
    41
    11
    62
    57
    Not completed
    0
    0
    1
    0
    0
    0
    1
    0
    1
    5
         Adverse event, non-fatal
    -
    -
    1
    -
    -
    -
    -
    -
    -
    1
         Unspecified
    -
    -
    -
    -
    -
    -
    -
    -
    -
    1
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    -
    1
    -
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Placebo
    Reporting group description
    Participants homozygous (HO) for the F508del-CF transmembrane conductance regulator gene (CFTR) mutation received lumacaftor matched placebo once daily (qd) (Day 1 through Day 14), followed by lumacaftor matched placebo qd in combination with ivacaftor matched placebo every 12 hours (q12h) (Day 15 through Day 21).

    Reporting group title
    Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg q12h
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 milligram (mg) of lumacaftor (LUM) qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor (IVA) q12h (Day 15 through Day 21).

    Reporting group title
    Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).

    Reporting group title
    Cohort 2 and 3: Placebo (HO and HE)
    Reporting group description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28), followed by lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO)
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO)
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO&HE)
    Reporting group description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO)
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 4: Placebo
    Reporting group description
    Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).

    Reporting group title
    Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Reporting group description
    Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).

    Reporting group values
    Cohort 1: Placebo Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg q12h Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h Cohort 2 and 3: Placebo (HO and HE) Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO&HE) Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO) Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h Total
    Number of subjects
    21 20 21 27 23 21 42 11 63 62 311
    Age categorical
    Units: Subjects
        <=18 years
    0 0 0 0 0 0 0 0 0 0 0
        Between 18 and 65 years
    21 20 21 27 23 21 42 11 63 62 311
        >=65 years
    0 0 0 0 0 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    10 8 13 9 11 9 19 5 31 29 144
        Male
    11 12 8 18 12 12 23 6 32 33 167

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Placebo
    Reporting group description
    Participants homozygous (HO) for the F508del-CF transmembrane conductance regulator gene (CFTR) mutation received lumacaftor matched placebo once daily (qd) (Day 1 through Day 14), followed by lumacaftor matched placebo qd in combination with ivacaftor matched placebo every 12 hours (q12h) (Day 15 through Day 21).

    Reporting group title
    Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg q12h
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 milligram (mg) of lumacaftor (LUM) qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor (IVA) q12h (Day 15 through Day 21).

    Reporting group title
    Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).

    Reporting group title
    Cohort 2 and 3: Placebo (HO and HE)
    Reporting group description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28), followed by lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO)
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO)
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO&HE)
    Reporting group description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO)
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 4: Placebo
    Reporting group description
    Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).

    Reporting group title
    Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Reporting group description
    Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).

    Subject analysis set title
    Cohort 1: Placebo – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd in combination with ivacaftor matched placebo q12h (Day 15 through Day 21).

    Subject analysis set title
    Cohort 1: LUM 200 mg qd – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14).

    Subject analysis set title
    Cohort 1: Placebo – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 14).

    Subject analysis set title
    Cohort 1: LUM 200 mg qd+IVA 150 mg q12h – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor q12h (Day 15 through Day 21).

    Subject analysis set title
    Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).

    Subject analysis set title
    Cohort 2 and 3: Placebo (HO and HE) – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28).

    Subject analysis set title
    Cohort 2: LUM 200 mg qd – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28).

    Subject analysis set title
    Cohort 2: LUM 400 mg qd – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28).

    Subject analysis set title
    Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 3: LUM 400 mg q12h – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28).

    Subject analysis set title
    Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO&HE) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).

    Subject analysis set title
    Cohort 1: LUM 200 mg qd+IVA 150 mg q12h – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor q12h (Day 15 through Day 21).

    Subject analysis set title
    Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).

    Subject analysis set title
    Cohort 1: Placebo – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd in combination with ivacaftor matched placebo q12h (Day 15 through Day 21).

    Subject analysis set title
    Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 1: Placebo – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 14).

    Subject analysis set title
    Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2: LUM 200 mg qd – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28).

    Subject analysis set title
    Cohort 1: LUM 200 mg qd – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14).

    Subject analysis set title
    Cohort 2: LUM 400 mg qd – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd (HO) – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd (HE) – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28).

    Subject analysis set title
    Cohort 2 and 3: Placebo (HO and HE) – Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HE)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants heterozygous (HE) for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HE)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants heterozygous (HE) for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Subject analysis set title
    Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).

    Primary: Cohort 1: Safety and Tolerability Based on Adverse Events (AEs)

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    End point title
    Cohort 1: Safety and Tolerability Based on Adverse Events (AEs) [1]
    End point description
    AE: any untoward medical occurrence during study; irrespective of relationship with treatment, including any newly occurring event or previous condition that has increased in severity/frequency after informed consent. SAE: medical event or condition, which falls into any of the following categories, regardless of its relationship to study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. AE that started at/after initial dosing of study drug, or increased in severity after initial dosing of study drug is considered treatment-emergent. Results are reported separately for monotherapy period (Period 1: Day 1 to Day 14) and combination therapy period (Period 2: Day 15 to Day 21). Analysis was performed on Cohort 1 Safety Set, which included all participants who received at least 1 dose of study drug in Cohort 1.
    End point type
    Primary
    End point timeframe
    Cohort 1: Day 1 up to 28 days after last dose (Last dose = Day 21)
    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 this endpoint.
    End point values
    Cohort 1: Placebo – Period 2 Cohort 1: LUM 200 mg qd – Period 1 Cohort 1: Placebo – Period 1 Cohort 1: LUM 200 mg qd+IVA 150 mg q12h – Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2
    Number of subjects analysed
    21
    41
    21
    20
    20
    Units: participants
    number (not applicable)
        Participants with any AEs
    15
    29
    12
    14
    12
        Participants with SAEs
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Cohort 2 and 3: Safety and Tolerability Based on Adverse Events (AEs)

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    End point title
    Cohort 2 and 3: Safety and Tolerability Based on Adverse Events (AEs) [2]
    End point description
    Detailed description is provided in Outcome Measure 1. Results are reported separately for monotherapy period (Period 1: Day 1 to Day 28) and combination therapy period (Period 2: Day 29 to Day 56). Analysis was performed on Cohort 2 and 3 Safety Set, which included all participants who received at least 1 dose of study drug in Cohort 2 or 3.
    End point type
    Primary
    End point timeframe
    Cohort 2 and 3: Day 1 up to 28 days after last dose (Last dose = Day 56)
    Notes
    [2] - 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 this endpoint.
    End point values
    Cohort 2 and 3: Placebo (HO and HE) – Period 1 Cohort 2: LUM 200 mg qd – Period 1 Cohort 2: LUM 400 mg qd – Period 1 Cohort 2 and 3: Placebo (HO and HE) – Period 2 Cohort 3: LUM 400 mg q12h – Period 1 Cohort 2: LUM 600 mg qd – Period 1 Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO&HE) – Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2
    Number of subjects analysed
    27
    23
    21
    27
    11
    42
    21
    20
    38
    11
    Units: participants
    number (not applicable)
        Participants with any AEs
    23
    18
    18
    20
    7
    37
    12
    15
    26
    10
        Participants with SAEs
    1
    2
    0
    4
    2
    3
    0
    1
    4
    1
    No statistical analyses for this end point

    Primary: Cohort 4: Safety and Tolerability Assessed by Number of Participants With AEs and SAEs

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    End point title
    Cohort 4: Safety and Tolerability Assessed by Number of Participants With AEs and SAEs [3] [4]
    End point description
    AEs and SAEs are defined in Outcome Measure 1. Analysis was performed on Cohort 4 Safety Set, which included all participants who received at least 1 dose of study drug in Cohort 4.
    End point type
    Primary
    End point timeframe
    Cohort 4: Day 1 up to 28 days after last dose (Last dose = Day 56)
    Notes
    [3] - 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 this endpoint.
    [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 related to the specified cohort are reported.
    End point values
    Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Number of subjects analysed
    63
    62
    Units: participants
    number (not applicable)
        Participants with any AEs
    53
    52
        Participants with SAEs
    5
    9
    No statistical analyses for this end point

    Primary: Cohort 1: Absolute Change from Day 14 in Sweat Chloride at Day 21

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    End point title
    Cohort 1: Absolute Change from Day 14 in Sweat Chloride at Day 21
    End point description
    Analysis was performed on Cohort 1 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 1. Results are reported for combination therapy period (Period 2: Day 15 to Day 21).
    End point type
    Primary
    End point timeframe
    Cohort 1: Day 14, Day 21
    End point values
    Cohort 1: LUM 200 mg qd+IVA 150 mg q12h – Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2 Cohort 1: Placebo – Period 2
    Number of subjects analysed
    19
    14
    17
    Units: millimole per liter (mmol/L)
        least squares mean (confidence interval 95%)
    -2.131 (-5.381 to 1.119)
    -9.128 (-12.893 to -5.362)
    0.548 (-2.955 to 4.052)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Cohort 1: Placebo – Period 2 v Cohort 1: LUM 200 mg qd+IVA 150 mg q12h – Period 2
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.267
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -2.679
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.484
         upper limit
    2.125
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2 v Cohort 1: Placebo – Period 2
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -9.676
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.801
         upper limit
    -4.551

    Primary: Cohort 2 And 3: Absolute Change from Day 28 in Sweat Chloride at Day 56

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    End point title
    Cohort 2 And 3: Absolute Change from Day 28 in Sweat Chloride at Day 56
    End point description
    Analysis was performed on Cohort 2 and 3 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Results are reported for combination therapy period (Period 2: Day 29 to Day 56).
    End point type
    Primary
    End point timeframe
    Cohort 2 and 3: Day 28, Day 56
    End point values
    Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) – Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Number of subjects analysed
    21
    19
    17
    9
    20
    24
    Units: mmol/L
        least squares mean (confidence interval 95%)
    0.321 (-4.208 to 4.849)
    -1.043 (-5.8 to 3.714)
    -1.24 (-6.287 to 3.807)
    -2.154 (-9.177 to 4.87)
    -2.9 (-7.542 to 1.743)
    1.627 (-2.661 to 5.915)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) – Period 2 v Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.68
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -1.306
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.565
         upper limit
    4.953
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2 v Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.409
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -2.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.053
         upper limit
    3.712
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) – Period 2 v Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.161
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -4.526
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.888
         upper limit
    1.835
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) – Period 2 v Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.396
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -2.867
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.543
         upper limit
    3.81
    Statistical analysis title
    Statistical Analysis 5
    Comparison groups
    Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2 v Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.365
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -3.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.028
         upper limit
    4.467

    Primary: Cohort 4: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 56

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    End point title
    Cohort 4: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 56 [5]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) was calculated using the Hankinson method. Analysis was performed on Cohort 4 Full Analysis Set, which included all randomized participants who received any amount of study drug in Cohort 4.
    End point type
    Primary
    End point timeframe
    Cohort 4: Baseline, Day 56
    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 related to the specified cohort are reported.
    End point values
    Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Number of subjects analysed
    60
    55
    Units: percent predicted of FEV1
        least squares mean (standard error)
    -1.23 ± 0.801
    -0.62 ± 0.829
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h v Cohort 4: Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5978
    Method
    Mixed Model Repeated Measure (MMRM)
    Parameter type
    LS Mean difference
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.66
         upper limit
    2.86

    Secondary: Cohort 1: Absolute Change from Baseline in Sweat Chloride at Day 14

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    End point title
    Cohort 1: Absolute Change from Baseline in Sweat Chloride at Day 14
    End point description
    Analysis was performed on Cohort 1 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 1. Results are reported for monotherapy period (Period 1: Day 1 to Day 14).
    End point type
    Secondary
    End point timeframe
    Cohort 1: Baseline, Day 14
    End point values
    Cohort 1: Placebo – Period 1 Cohort 1: LUM 200 mg qd – Period 1
    Number of subjects analysed
    17
    36
    Units: mmol/L
        least squares mean (confidence interval 95%)
    -1.668 (-5.606 to 2.271)
    -4.442 (-7.141 to -1.742)
    No statistical analyses for this end point

    Secondary: Cohort 2 And 3: Absolute Change from Baseline in Sweat Chloride at Day 14

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    End point title
    Cohort 2 And 3: Absolute Change from Baseline in Sweat Chloride at Day 14
    End point description
    Analysis was performed on Cohort 2 and 3 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Results are reported for monotherapy period (Period 1: Day 1 to Day 28).
    End point type
    Secondary
    End point timeframe
    Cohort 2: Baseline, Day 14
    End point values
    Cohort 3: LUM 400 mg q12h – Period 1 Cohort 2: LUM 200 mg qd – Period 1 Cohort 2: LUM 400 mg qd – Period 1 Cohort 2: LUM 600 mg qd (HO) – Period 1 Cohort 2: LUM 600 mg qd (HE) – Period 1 Cohort 2 and 3: Placebo (HO and HE) – Period 1
    Number of subjects analysed
    11
    19
    17
    21
    17
    25
    Units: mmol/L
        least squares mean (confidence interval 95%)
    -9.179 (-15.47 to -2.888)
    -6.49 (-11.226 to -1.755)
    -5.901 (-10.91 to -0.892)
    -9.442 (-13.953 to -4.931)
    -3.137 (-8.167 to 1.893)
    0.048 (-4.162 to 4.258)
    No statistical analyses for this end point

    Secondary: Cohort 4: Absolute Change from Baseline in Sweat Chloride at Day 56

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    End point title
    Cohort 4: Absolute Change from Baseline in Sweat Chloride at Day 56 [6]
    End point description
    Analysis was performed on Cohort 4 Full Analysis Set, which included all randomized participants who received any amount of study drug in Cohort 4.
    End point type
    Secondary
    End point timeframe
    Cohort 4: Baseline, Day 56
    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 related to the specified cohort are reported.
    End point values
    Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Number of subjects analysed
    59
    54
    Units: mmol/L
        least squares mean (standard error)
    -0.78 ± 1.23
    -11.82 ± 1.281
    No statistical analyses for this end point

    Secondary: Cohort 1: Absolute Change From Day 14 in FEV1 at Day 21

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    End point title
    Cohort 1: Absolute Change From Day 14 in FEV1 at Day 21
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Analysis was performed on Cohort 1 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 1. Results are reported for combination therapy period (Period 2: Day 15 to Day 21).
    End point type
    Secondary
    End point timeframe
    Cohort 1: Day 14, Day 21
    End point values
    Cohort 1: Placebo – Period 2 Cohort 1: LUM 200 mg qd+IVA 150 mg q12h – Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2
    Number of subjects analysed
    21
    20
    18
    Units: liters
        least squares mean (confidence interval 95%)
    -0.046 (-0.138 to 0.047)
    0.128 (0.03 to 0.225)
    0.015 (-0.094 to 0.124)
    No statistical analyses for this end point

    Secondary: Cohort 1: Absolute Change From Day 14 in ppFEV1 at Day 21

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    End point title
    Cohort 1: Absolute Change From Day 14 in ppFEV1 at Day 21
    End point description
    FEV1 and ppFEV1 are defined in sixth primary endpoint. Analysis was performed on Cohort 1 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 1. Results are reported for combination therapy period (Period 2: Day 15 to Day 21).
    End point type
    Secondary
    End point timeframe
    Cohort 1: Day 14, Day 21
    End point values
    Cohort 1: Placebo – Period 2 Cohort 1: LUM 200 mg qd+IVA 150 mg q12h – Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2
    Number of subjects analysed
    21
    20
    18
    Units: percent predicted of FEV1
        least squares mean (confidence interval 95%)
    -1.44 (-3.89 to 1.01)
    3.46 (0.87 to 6.05)
    0.63 (-2.2 to 3.46)
    No statistical analyses for this end point

    Secondary: Cohort 2 and 3: Absolute Change From Day 28 in ppFEV1 at Day 56

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    End point title
    Cohort 2 and 3: Absolute Change From Day 28 in ppFEV1 at Day 56
    End point description
    FEV1 and ppFEV1 are defined in sixth primary endpoint. Analysis was performed on Cohort 2 and 3 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Results are reported for combination therapy period (Period 2: Day 29 to Day 56).
    End point type
    Secondary
    End point timeframe
    Cohort 2 and 3: Day 28, Day 56
    End point values
    Cohort 2 and 3: Placebo (HO and HE) – Period 2 Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) – Period 2
    Number of subjects analysed
    24
    21
    20
    10
    17
    20
    Units: percent predicted of FEV1
        least squares mean (confidence interval 95%)
    -1.57 (-4.24 to 1.09)
    1.96 (-0.84 to 4.76)
    1.99 (-0.87 to 4.84)
    6.09 (2.02 to 10.16)
    2.29 (-0.82 to 5.39)
    6.15 (3.27 to 9.02)
    No statistical analyses for this end point

    Secondary: Cohort 2 and 3: Relative Change From Day 28 in ppFEV1 at Day 56

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    End point title
    Cohort 2 and 3: Relative Change From Day 28 in ppFEV1 at Day 56
    End point description
    FEV1 and ppFEV1 are defined in sixth primary endpoint. Analysis was performed on Cohort 2 and 3 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Results are reported for combination therapy period (Period 2: Day 29 to Day 56).
    End point type
    Secondary
    End point timeframe
    Cohort 2 and 3: Day 28, Day 56
    End point values
    Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Number of subjects analysed
    21
    20
    10
    17
    20
    24
    Units: percent change
        least squares mean (confidence interval 95%)
    3.13 (-1.29 to 7.54)
    2.98 (-1.52 to 7.48)
    8.24 (1.83 to 14.65)
    4.3 (-0.59 to 9.19)
    9.7 (5.17 to 14.23)
    -2.05 (-6.25 to 2.15)
    No statistical analyses for this end point

    Secondary: Cohort 2 and 3: Absolute Change From Baseline in ppFEV1 at Day 28 and 56

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    End point title
    Cohort 2 and 3: Absolute Change From Baseline in ppFEV1 at Day 28 and 56 [7]
    End point description
    FEV1 and ppFEV1 are defined in sixth primary endpoint. Analysis was performed on Cohort 2 and 3 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3.
    End point type
    Secondary
    End point timeframe
    Cohort 2 and 3: Baseline, Day 28 and 56
    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 related to the specified cohort are reported.
    End point values
    Cohort 2 and 3: Placebo (HO and HE) Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO) Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HE)
    Number of subjects analysed
    27
    23
    21
    11
    21
    21
    Units: percent predicted of FEV1
    least squares mean (confidence interval 95%)
        Day 28: (n= 27, 21, 20, 11, 20, 18)
    -0.03 (-2.68 to 2.62)
    0.21 (-2.77 to 3.19)
    -1.35 (-4.39 to 1.69)
    -4.52 (-8.65 to -0.39)
    -2.62 (-5.67 to 0.42)
    -3.82 (-7.03 to -0.61)
        Day 56: (n= 24, 21, 20, 10, 20, 17)
    -2.02 (-4.97 to 0.93)
    1.82 (-1.28 to 4.91)
    0.64 (-2.52 to 3.8)
    2.16 (-2.34 to 6.66)
    3.59 (0.41 to 6.77)
    -1.68 (-5.12 to 1.75)
    No statistical analyses for this end point

    Secondary: Cohort 2 and 3: Relative Change From Baseline in FEV1 at Day 28 and 56

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    End point title
    Cohort 2 and 3: Relative Change From Baseline in FEV1 at Day 28 and 56 [8]
    End point description
    FEV1 and ppFEV1 are defined in Outcome Measure 6. Analysis was performed on Cohort 2 and 3 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3.
    End point type
    Secondary
    End point timeframe
    Cohort 2 and 3: Baseline, Day 28 and 56
    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 related to the specified cohort are reported.
    End point values
    Cohort 2 and 3: Placebo (HO and HE) Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO) Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HE)
    Number of subjects analysed
    27
    23
    21
    11
    21
    21
    Units: percent change
    least squares mean (confidence interval 95%)
        Day 28: (n= 27, 21, 20, 11, 20, 18)
    1.89 (-2.12 to 5.9)
    0.24 (-4.27 to 4.75)
    -1.15 (-5.75 to 3.45)
    -6.39 (-12.65 to -0.14)
    -3.13 (-7.74 to 1.48)
    -5.46 (-10.32 to -0.6)
        Day 56: (n= 24, 21, 20, 10, 20, 17)
    -2.42 (-6.91 to 2.08)
    2.51 (-2.21 to 7.23)
    1.72 (-3.09 to 6.53)
    2.96 (-3.9 to 9.81)
    5.55 (0.7 to 10.39)
    -2.34 (-7.57 to 2.89)
    No statistical analyses for this end point

    Secondary: Cohort 4: Relative Change From Baseline in Percent Predicted FEV1 at Day 56

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    End point title
    Cohort 4: Relative Change From Baseline in Percent Predicted FEV1 at Day 56 [9]
    End point description
    FEV1 and ppFEV1 are defined in sixth primary outcome. Analysis was performed on Cohort 2 and 3 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3.
    End point type
    Secondary
    End point timeframe
    Cohort 4: Baseline, Day 56
    Notes
    [9] - 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 related to the specified cohort are reported.
    End point values
    Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Number of subjects analysed
    60
    55
    Units: percent change
        least squares mean (standard error)
    -2.2 ± 1.373
    -0.69 ± 1.423
    No statistical analyses for this end point

    Secondary: Cohort 2 and 3: Absolute Change From Day 28 in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Day 56

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    End point title
    Cohort 2 and 3: Absolute Change From Day 28 in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Day 56
    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. Analysis was performed on Cohort 2 and 3 Full Analysis Set, which included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Results are reported for combination therapy period (Period 2: Day 29 to Day 56).
    End point type
    Secondary
    End point timeframe
    Cohort 2 and 3: Day 28, Day 56
    End point values
    Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2 Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Number of subjects analysed
    21
    20
    17
    20
    10
    25
    Units: units on a scale
        least squares mean (confidence interval 95%)
    3.3 (-3.6 to 10.1)
    7.9 (0.8 to 14.9)
    5.5 (-2.1 to 13.1)
    8.9 (1.9 to 15.9)
    11.2 (1.3 to 21.1)
    -8.6 (-14.9 to -2.2)
    No statistical analyses for this end point

    Secondary: Cohort 4: Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 56

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    End point title
    Cohort 4: Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 56 [10]
    End point description
    CFQ-R respiratory domain is defined in previous endpoint. Analysis was performed on Cohort 4 Full Analysis Set, which included all randomized participants who received any amount of study drug in Cohort 4.
    End point type
    Secondary
    End point timeframe
    Cohort 4: Baseline, Day 56
    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 related to the specified cohort are reported.
    End point values
    Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Number of subjects analysed
    60
    55
    Units: units on a scale
        least squares mean (standard error)
    -0.82 ± 1.802
    5.66 ± 1.864
    No statistical analyses for this end point

    Secondary: Cohort 4: Absolute Change From Baseline in Body Mass Index (BMI) at Day 56

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    End point title
    Cohort 4: Absolute Change From Baseline in Body Mass Index (BMI) at Day 56 [11]
    End point description
    BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2). Analysis was performed on Cohort 4 Full Analysis Set, which included all randomized participants who received any amount of study drug in Cohort 4.
    End point type
    Secondary
    End point timeframe
    Cohort 4: Baseline, Day 56
    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 related to the specified cohort are reported.
    End point values
    Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Number of subjects analysed
    60
    56
    Units: kg/m^2
        least squares mean (standard error)
    0.08 ± 0.075
    -0.04 ± 0.077
    No statistical analyses for this end point

    Secondary: Cohort 4: Absolute Change From Baseline in Weight at Day 56

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    End point title
    Cohort 4: Absolute Change From Baseline in Weight at Day 56 [12]
    End point description
    Analysis was performed on Cohort 4 Full Analysis Set, which included all randomized participants who received any amount of study drug in Cohort 4.
    End point type
    Secondary
    End point timeframe
    Cohort 4: Baseline, Day 56
    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 related to the specified cohort are reported.
    End point values
    Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Number of subjects analysed
    60
    56
    Units: kg
        least squares mean (standard error)
    0.16 ± 0.211
    -0.11 ± 0.216
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Cohort 1: Day 1 up to 28 days after last dose (Last dose = Day 21); Cohort 2 and 3: Day 1 up to 28 days after last dose (Last dose = Day 56); Cohort 4: Day 1 up to 28 days after last dose (Last dose = Day 56)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Cohort 1: LUM 200 mg qd+IVA 150 mg q12h – Period 2
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor q12h (Day 15 through Day 21).

    Reporting group title
    Cohort 1: LUM 200 mg qd – Period 1
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14).

    Reporting group title
    Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).

    Reporting group title
    Cohort 1: Placebo – Period 1
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 14).

    Reporting group title
    Cohort 1: Placebo – Period 2
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd in combination with ivacaftor matched placebo q12h (Day 15 through Day 21).

    Reporting group title
    Cohort 2: LUM 200 mg qd – Period 1
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28).

    Reporting group title
    Cohort 2: LUM 400 mg qd – Period 1
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28).

    Reporting group title
    Cohort 2: LUM 600 mg qd – Period 1
    Reporting group description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28).

    Reporting group title
    Cohort 3: LUM 400 mg q12h – Period 1
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28).

    Reporting group title
    Cohort 2 and 3: Placebo (HO and HE) – Period 1
    Reporting group description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28).

    Reporting group title
    Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) – Period 2
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO&HE) – Period 2
    Reporting group description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2
    Reporting group description
    Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 2 and 3: Placebo (HO and HE) – Period 2
    Reporting group description
    Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).

    Reporting group title
    Cohort 4: Placebo
    Reporting group description
    Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).

    Reporting group title
    Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Reporting group description
    Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).

    Serious adverse events
    Cohort 1: LUM 200 mg qd+IVA 150 mg q12h – Period 2 Cohort 1: LUM 200 mg qd – Period 1 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2 Cohort 1: Placebo – Period 1 Cohort 1: Placebo – Period 2 Cohort 2: LUM 200 mg qd – Period 1 Cohort 2: LUM 400 mg qd – Period 1 Cohort 2: LUM 600 mg qd – Period 1 Cohort 3: LUM 400 mg q12h – Period 1 Cohort 2 and 3: Placebo (HO and HE) – Period 1 Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO&HE) – Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2 Cohort 2 and 3: Placebo (HO and HE) – Period 2 Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    2 / 23 (8.70%)
    0 / 21 (0.00%)
    3 / 42 (7.14%)
    2 / 11 (18.18%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    4 / 38 (10.53%)
    1 / 11 (9.09%)
    4 / 27 (14.81%)
    5 / 63 (7.94%)
    9 / 62 (14.52%)
         number of deaths (all causes)
    0
    0
    0
    0
    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
    0
    0
    0
    0
    Investigations
    Spirometry abnormal
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         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 / 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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         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
    1 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    CYSTIC FIBROSIS LUNG
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    1 / 11 (9.09%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    3 / 38 (7.89%)
    1 / 11 (9.09%)
    4 / 27 (14.81%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    1 / 1
    0 / 0
    0 / 1
    0 / 3
    0 / 1
    1 / 4
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    HYPERSENSITIVITY
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         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
    0 / 0
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATION ABNORMAL
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    1 / 11 (9.09%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         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 / 0
    0 / 0
    1 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    3 / 63 (4.76%)
    7 / 62 (11.29%)
         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 / 0
    0 / 0
    0 / 0
    0 / 4
    1 / 7
         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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Cohort 1: LUM 200 mg qd+IVA 150 mg q12h – Period 2 Cohort 1: LUM 200 mg qd – Period 1 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h – Period 2 Cohort 1: Placebo – Period 1 Cohort 1: Placebo – Period 2 Cohort 2: LUM 200 mg qd – Period 1 Cohort 2: LUM 400 mg qd – Period 1 Cohort 2: LUM 600 mg qd – Period 1 Cohort 3: LUM 400 mg q12h – Period 1 Cohort 2 and 3: Placebo (HO and HE) – Period 1 Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) – Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO&HE) – Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) – Period 2 Cohort 2 and 3: Placebo (HO and HE) – Period 2 Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 20 (70.00%)
    29 / 41 (70.73%)
    12 / 20 (60.00%)
    12 / 21 (57.14%)
    15 / 21 (71.43%)
    17 / 23 (73.91%)
    18 / 21 (85.71%)
    37 / 42 (88.10%)
    6 / 11 (54.55%)
    23 / 27 (85.19%)
    12 / 21 (57.14%)
    15 / 20 (75.00%)
    26 / 38 (68.42%)
    10 / 11 (90.91%)
    20 / 27 (74.07%)
    53 / 63 (84.13%)
    51 / 62 (82.26%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    1
    1
    0
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    3 / 21 (14.29%)
    0 / 23 (0.00%)
    1 / 21 (4.76%)
    3 / 42 (7.14%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    6 / 63 (9.52%)
    4 / 62 (6.45%)
         occurrences all number
    1
    1
    0
    1
    3
    0
    1
    4
    0
    1
    0
    1
    1
    0
    1
    6
    6
    PYREXIA
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 41 (7.32%)
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    6 / 42 (14.29%)
    0 / 11 (0.00%)
    3 / 27 (11.11%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    9 / 63 (14.29%)
    7 / 62 (11.29%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    0
    7
    0
    4
    0
    1
    1
    0
    1
    10
    7
    PAIN
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 41 (7.32%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    3 / 63 (4.76%)
    0 / 62 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    APPLICATION SITE PRURITUS
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    CATHETER SITE HAEMORRHAGE
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    CATHETER SITE PAIN
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    CHEST DISCOMFORT
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    CHILLS
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    2 / 63 (3.17%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    1
    0
    0
    3
    0
    FEELING HOT
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    2 / 63 (3.17%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    4
    0
    INJECTION SITE HAEMORRHAGE
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    0
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    1
    0
    0
    0
    0
    APPLICATION SITE IRRITATION
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    FEELING OF BODY TEMPERATURE CHANGE
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    1 / 21 (4.76%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    INSOMNIA
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    1 / 21 (4.76%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    2 / 21 (9.52%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    1
    0
    0
    0
    2
    0
    0
    0
    0
    1
    0
    MOOD SWINGS
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    DEPRESSED MOOD
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Abnormal dreams
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Reproductive system and breast disorders
    MENSTRUATION DELAYED
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    BREAST TENDERNESS
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    MENOMETRORRHAGIA
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    MENORRHAGIA
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    1 / 11 (9.09%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    MENSTRUAL DISORDER
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    2 / 63 (3.17%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    1
    Vulvovaginal burning sensation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Vulvovaginal discomfort
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    CHEST INJURY
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    EXCORIATION
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    JOINT SPRAIN
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    LIMB INJURY
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    MUSCLE STRAIN
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    THERMAL BURN
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    2 / 63 (3.17%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Procedural pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    1 / 11 (9.09%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    1
    Arthropod sting
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    JOINT INJURY
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    2
    0
    0
    1
    0
    Rib fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Road traffic accident
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    SUNBURN
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    VERTEBRAL INJURY
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Animal bite
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    ARTHROPOD BITE
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Investigations
    BLOOD GLUCOSE INCREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    1
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    5 / 42 (11.90%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    5 / 63 (7.94%)
    2 / 62 (3.23%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    0
    5
    0
    0
    0
    0
    0
    0
    0
    6
    2
    GLUCOSE URINE PRESENT
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    LIVER FUNCTION TEST ABNORMAL
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 41 (4.88%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    2 / 23 (8.70%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    0
    0
    0
    1
    0
    0
    1
    0
    0
    0
    1
    PROTHROMBIN TIME PROLONGED
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    PULMONARY FUNCTION TEST DECREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 41 (4.88%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    2 / 11 (18.18%)
    0 / 27 (0.00%)
    2 / 63 (3.17%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    2
    0
    2
    3
    ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    4 / 62 (6.45%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    4
    BLOOD IMMUNOGLOBULIN E INCREASED
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    BLOOD SODIUM DECREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    BLOOD URINE PRESENT
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    INTERNATIONAL NORMALISED RATIO INCREASED
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    4 / 63 (6.35%)
    4 / 62 (6.45%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    1
    4
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    4 / 62 (6.45%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    1
    1
    0
    0
    1
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    1 / 11 (9.09%)
    1 / 27 (3.70%)
    0 / 63 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    1
    0
    0
    2
    1
    1
    0
    3
    Sputum abnormal
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Blood creatinine decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    1
    Blood immunoglobulin G increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Interleukin level increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    2 / 27 (7.41%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    0
    0
    0
    0
    1
    0
    Protein total increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Transaminases increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    1 / 21 (4.76%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    1
    0
    0
    0
    0
    0
    1
    0
    WHITE BLOOD CELL COUNT INCREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    BLOOD GLUCOSE DECREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    1 / 27 (3.70%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    NEUTROPHIL COUNT INCREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    BACTERIA URINE IDENTIFIED
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    BLOOD PHOSPHORUS DECREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    BLOOD POTASSIUM INCREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    1 / 11 (9.09%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    CULTURE THROAT POSITIVE
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    FUNGUS SPUTUM TEST POSITIVE
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    PROTEIN URINE PRESENT
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    URINE KETONE BODY PRESENT
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    WHITE BLOOD CELLS URINE POSITIVE
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    SINUS BRADYCARDIA
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    CYSTIC FIBROSIS LUNG
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 41 (4.88%)
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 23 (0.00%)
    2 / 21 (9.52%)
    7 / 42 (16.67%)
    1 / 11 (9.09%)
    2 / 27 (7.41%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
    3 / 38 (7.89%)
    1 / 11 (9.09%)
    4 / 27 (14.81%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    2
    2
    1
    0
    1
    0
    2
    7
    1
    2
    1
    1
    3
    1
    4
    1
    0
    Cystic fibrosis related diabetes
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    LYMPHADENOPATHY
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Eosinophilia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Increased tendency to bruise
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    4 / 20 (20.00%)
    6 / 41 (14.63%)
    1 / 20 (5.00%)
    1 / 21 (4.76%)
    4 / 21 (19.05%)
    3 / 23 (13.04%)
    8 / 21 (38.10%)
    12 / 42 (28.57%)
    1 / 11 (9.09%)
    6 / 27 (22.22%)
    3 / 21 (14.29%)
    5 / 20 (25.00%)
    5 / 38 (13.16%)
    3 / 11 (27.27%)
    6 / 27 (22.22%)
    12 / 63 (19.05%)
    13 / 62 (20.97%)
         occurrences all number
    5
    6
    1
    1
    4
    3
    8
    13
    1
    6
    5
    5
    6
    4
    6
    15
    16
    PRODUCTIVE COUGH
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 41 (7.32%)
    0 / 20 (0.00%)
    2 / 21 (9.52%)
    3 / 21 (14.29%)
    2 / 23 (8.70%)
    2 / 21 (9.52%)
    6 / 42 (14.29%)
    2 / 11 (18.18%)
    5 / 27 (18.52%)
    2 / 21 (9.52%)
    1 / 20 (5.00%)
    1 / 38 (2.63%)
    2 / 11 (18.18%)
    1 / 27 (3.70%)
    3 / 63 (4.76%)
    3 / 62 (4.84%)
         occurrences all number
    1
    3
    0
    2
    3
    2
    2
    7
    2
    5
    3
    1
    1
    2
    1
    4
    3
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 41 (4.88%)
    2 / 20 (10.00%)
    0 / 21 (0.00%)
    2 / 21 (9.52%)
    2 / 23 (8.70%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    1 / 11 (9.09%)
    1 / 27 (3.70%)
    1 / 21 (4.76%)
    4 / 20 (20.00%)
    0 / 38 (0.00%)
    2 / 11 (18.18%)
    1 / 27 (3.70%)
    5 / 63 (7.94%)
    3 / 62 (4.84%)
         occurrences all number
    1
    2
    2
    0
    2
    2
    0
    1
    1
    1
    1
    5
    0
    2
    1
    6
    3
    NASAL CONGESTION
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    3 / 20 (15.00%)
    0 / 21 (0.00%)
    2 / 21 (9.52%)
    1 / 23 (4.35%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    3 / 27 (11.11%)
    2 / 21 (9.52%)
    3 / 20 (15.00%)
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    4 / 63 (6.35%)
    5 / 62 (8.06%)
         occurrences all number
    1
    0
    3
    0
    2
    1
    0
    0
    0
    3
    2
    3
    2
    0
    1
    5
    7
    RHINORRHOEA
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 41 (4.88%)
    1 / 20 (5.00%)
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    3 / 27 (11.11%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    0 / 38 (0.00%)
    1 / 11 (9.09%)
    1 / 27 (3.70%)
    3 / 63 (4.76%)
    4 / 62 (6.45%)
         occurrences all number
    1
    2
    1
    2
    0
    0
    0
    0
    0
    3
    0
    1
    0
    1
    1
    4
    4
    DYSPNOEA
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 41 (7.32%)
    0 / 20 (0.00%)
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    1 / 21 (4.76%)
    10 / 42 (23.81%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    4 / 63 (6.35%)
    9 / 62 (14.52%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    1
    10
    0
    0
    0
    0
    1
    0
    0
    5
    10
    RALES
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    3 / 21 (14.29%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    2 / 63 (3.17%)
    2 / 62 (3.23%)
         occurrences all number
    0
    1
    0
    0
    4
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    2
    2
    RESPIRATION ABNORMAL
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 41 (2.44%)
    1 / 20 (5.00%)
    1 / 21 (4.76%)
    1 / 21 (4.76%)
    0 / 23 (0.00%)
    2 / 21 (9.52%)
    7 / 42 (16.67%)
    2 / 11 (18.18%)
    0 / 27 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    9 / 63 (14.29%)
    17 / 62 (27.42%)
         occurrences all number
    0
    1
    1
    1
    1
    0
    2
    8
    2
    0
    2
    0
    2
    0
    0
    9
    20
    WHEEZING
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    2 / 21 (9.52%)
    2 / 21 (9.52%)
    0 / 23 (0.00%)
    2 / 21 (9.52%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    1 / 27 (3.70%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    2
    2
    0
    2
    1
    0
    1
    0
    0
    2
    0
    0
    0
    0
    LUNG HYPERINFLATION
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    3 / 21 (14.29%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    RESPIRATORY TRACT CONGESTION
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    1 / 20 (5.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    1 / 42 (2.38%)
    0 / 11 (0.00%)
    2 / 27 (7.41%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    1 / 11 (9.09%)
    0 / 27 (0.00%)
    6 / 63 (9.52%)
    5 / 62 (8.06%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    1
    0
    2
    0
    0
    1
    1
    0
    6
    6
    BRONCHIAL SECRETION RETENTION
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 41 (0.00%)
    0 / 20 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 23 (0.00%)
    0 / 21 (0.00%)
    0 / 42 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    0 / 38 (0.00%)
    0 / 11 (0.00%)
    0 / 27 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0