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    Clinical Trial Results:
    A Phase 3, Rollover Study to Evaluate the Safety and Efficacy of Long-term Treatment With Lumacaftor in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

    Summary
    EudraCT number
    2013-000604-41
    Trial protocol
    IT   CZ   SE   AT   BE   GB   DE   NL   ES   IE   DK  
    Global end of trial date
    07 Apr 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Oct 2016
    First version publication date
    23 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX12-809-105
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01931839
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States, 02210-1862
    Public contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, + 1 617-341-6777, medicalinfo@vrtx.com
    Scientific contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, + 1 617-341-6777, medicalinfo@vrtx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001582-PIP01-13
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long term safety and tolerability of lumacaftor (LUM) in combination with ivacaftor (IVA) in subjects with cystic fibrosis (CF), homozygous or heterozygous for the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation, who were in the Part A and Part B Treatment Cohorts.
    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
    24 Oct 2013
    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
    Australia: 103
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 36
    Country: Number of subjects enrolled
    Canada: 41
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    France: 70
    Country: Number of subjects enrolled
    Germany: 83
    Country: Number of subjects enrolled
    Ireland: 13
    Country: Number of subjects enrolled
    Italy: 51
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    United States: 649
    Country: Number of subjects enrolled
    United Kingdom: 41
    Worldwide total number of subjects
    1163
    EEA total number of subjects
    370
    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)
    283
    Adults (18-64 years)
    880
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study conducted in 2 parts: A and B. Part A consisted of Treatment Cohorts and an Observational Cohort, which enrolled subjects from Study VX12-809-103 and Study VX12-809-104. Part B consisted of Treatment Cohorts which enrolled subjects from Cohort 4 of Study VX09-809-102. Of 1164 subjects enrolled, 1163 were dosed and included in EudraCT results.

    Pre-assignment
    Screening details
    As per planned analysis, endpoint evaluation may also include subjects from the parent study VX12-809-103 (2012-003989-40), VX12-809-104 (2012-003990-24) or Cohort 4 of VX09-809-102 (2010-020413-90) irrespective of whether they were enrolled in the current study or not.

    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
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h
    Arm description
    Subjects who received LUM 600 milligram (mg) once daily (qd) in fixed dose combination with IVA 250 mg every 12 hours (q12h) in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received the same treatment in this study VX12-809-105 (2013-000604-41) up to Week 96.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 600 mg plus IVA 250 mg as a fixed dose combination in morning up to Week 96.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor 250 mg in evening up to Week 96.

    Arm title
    Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h
    Arm description
    Subjects who received placebo matched to LUM and IVA in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received LUM 600 mg qd in fixed dose combintion with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 600 mg plus IVA 250 mg as a fixed dose combination in morning up to Week 96.

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor 250 mg in evening up to Week 96.

    Arm title
    Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h
    Arm description
    Subjects who received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received the same treatment in this study VX12-809-105 (2013-000604-41) up to Week 96.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 400 mg plus IVA 250 mg as a fixed dose combination in morning and evening up to Week 96.

    Arm title
    Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Arm description
    Subjects who received placebo matched to LUM and IVA in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 400 mg plus IVA 250 mg as a fixed dose combination in morning and evening up to Week 96.

    Arm title
    Arm 5: Part A Observational Cohort
    Arm description
    Subjects who received either LUM 600 mg qd in fixed dose combination with IVA 250 mg q12h or LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h or placebo matched to LUM and IVA q12h in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), were observed (did not receive study drug) in this study VX12-809-105 (2013-000604-41) for up to 2 years.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h
    Arm description
    Subjects who received LUM 400 mg q12h in fixed dose combination with IVA 250 q12h in Cohort 4 of the previous study VX09-809-102 (2010-020413-90), received the same treatment in this VX12-809-105 (2013-000604-41) up to Week 96.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 400 mg plus IVA 250 mg as a fixed dose combination in morning and evening up to Week 96.

    Arm title
    Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Arm description
    Subjects who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (2010-020413-90), received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 400 mg plus IVA 250 mg as a fixed dose combination in morning and evening up to Week 96.

    Number of subjects in period 1
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h Arm 5: Part A Observational Cohort Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Started
    335
    178
    340
    176
    19
    55
    60
    Completed
    294
    152
    301
    162
    18
    50
    56
    Not completed
    41
    26
    39
    14
    1
    5
    4
         Death
    -
    1
    2
    -
    -
    -
    -
         Other
    4
    2
    6
    -
    -
    -
    -
         Physician decision
    1
    -
    1
    -
    -
    -
    1
         Withdrawal of consent
    -
    -
    -
    -
    1
    -
    -
         Adverse event
    9
    4
    1
    3
    -
    -
    1
         Withdrawal of consent (not due to AE)
    11
    8
    13
    3
    -
    2
    2
         Other non-compliance
    15
    9
    12
    3
    -
    3
    -
         Lost to follow-up
    1
    2
    4
    5
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h
    Reporting group description
    Subjects who received LUM 600 milligram (mg) once daily (qd) in fixed dose combination with IVA 250 mg every 12 hours (q12h) in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received the same treatment in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h
    Reporting group description
    Subjects who received placebo matched to LUM and IVA in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received LUM 600 mg qd in fixed dose combintion with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received the same treatment in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received placebo matched to LUM and IVA in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 5: Part A Observational Cohort
    Reporting group description
    Subjects who received either LUM 600 mg qd in fixed dose combination with IVA 250 mg q12h or LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h or placebo matched to LUM and IVA q12h in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), were observed (did not receive study drug) in this study VX12-809-105 (2013-000604-41) for up to 2 years.

    Reporting group title
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received LUM 400 mg q12h in fixed dose combination with IVA 250 q12h in Cohort 4 of the previous study VX09-809-102 (2010-020413-90), received the same treatment in this VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (2010-020413-90), received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h Arm 5: Part A Observational Cohort Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h Total
    Number of subjects
    335 178 340 176 19 55 60 1163
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    24.1 ± 8.97 25.7 ± 10.74 25.1 ± 9.35 24.9 ± 10.1 27.2 ± 11.08 29.3 ± 7.82 31 ± 8.98 -
    Gender categorical
    Units: Subjects
        Female
    166 89 164 86 12 25 31 573
        Male
    169 89 176 90 7 30 29 590

    End points

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    End points reporting groups
    Reporting group title
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h
    Reporting group description
    Subjects who received LUM 600 milligram (mg) once daily (qd) in fixed dose combination with IVA 250 mg every 12 hours (q12h) in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received the same treatment in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h
    Reporting group description
    Subjects who received placebo matched to LUM and IVA in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received LUM 600 mg qd in fixed dose combintion with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received the same treatment in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received placebo matched to LUM and IVA in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 5: Part A Observational Cohort
    Reporting group description
    Subjects who received either LUM 600 mg qd in fixed dose combination with IVA 250 mg q12h or LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h or placebo matched to LUM and IVA q12h in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), were observed (did not receive study drug) in this study VX12-809-105 (2013-000604-41) for up to 2 years.

    Reporting group title
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received LUM 400 mg q12h in fixed dose combination with IVA 250 q12h in Cohort 4 of the previous study VX09-809-102 (2010-020413-90), received the same treatment in this VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (2010-020413-90), received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Subject analysis set title
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were randomized to LUM 600 milligram (mg) once daily (qd) in fixed dose combination with IVA 250 mg every 12 hours (q12h) in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24).

    Subject analysis set title
    Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were randomized to placebo matched to LUM and IVA in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received LUM 600 mg qd in fixed dose combintion with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Subject analysis set title
    Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were randomized to LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24).

    Subject analysis set title
    Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were randomized to placebo matched to LUM and IVA in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Subject analysis set title
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were randomized to LUM 400 mg q12h in fixed dose combination with IVA 250 q12h in Cohort 4 of the previous study VX09-809-102 (2010-020413-90).

    Subject analysis set title
    Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were randomized to placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (2010-020413-90).

    Primary: Part A Treatment Cohort: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Part A Treatment Cohort: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [1] [2]
    End point description
    AE: as any untoward medical occurrence in a subject during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the 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. Any AE that increased in severity or newly developed at or after initial dosing of study drug to 28 days after last dose of study drug was considered treatment-emergent. Safety Set (study 105) included all subjects in Treatment Cohort Part A who were exposed to any amount of study drug.
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 105
    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: Only descriptive statistics were reported, inferential statistics were not planned for primary endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    335
    178
    340
    176
    Units: subjects
        Subjects with AEs
    331
    177
    333
    176
        Subjects with SAEs
    156
    77
    143
    89
    No statistical analyses for this end point

    Primary: Part B Treatment Cohort: Number of Subjects With Treatment-Emergent AEs and SAEs

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    End point title
    Part B Treatment Cohort: Number of Subjects With Treatment-Emergent AEs and SAEs [3] [4]
    End point description
    AE: as any untoward medical occurrence in a subject during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the 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. Any AE that increased in severity or newly developed at or after initial dosing of study drug to 28 days after last dose of study drug was considered treatment-emergent. Safety Set (study 105) included all subjects in the Treatment Cohort Part B who were exposed to any amount of study drug.
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 105
    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: Only descriptive statistics were reported, inferential statistics were not planned for primary 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 which are applicable to the endpoint are reported.
    End point values
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    55
    60
    Units: subjects
        Subjects with AEs
    52
    57
        Subjects with SAEs
    18
    21
    No statistical analyses for this end point

    Secondary: Part A Treatment Cohort: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) At Day 15, Week 8, 16, 24, 36, 48, 60 and 72

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    End point title
    Part A Treatment Cohort: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) At Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [5]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 12 to 17 years and for female subjects aged 12 to 15 years. Full Analysis Set (FAS) study 105 (2013-000604-41) included all subjects randomized in the Part A Treatment Cohort and dosed. Analysis was performed using baseline of the previous study VX12-809-103 (2012-003989-40) and Study VX12-809-104 (2012-003990-24) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (2013-000604-41) for Arm 2 and 4. Here "Number of subjects analysed" = those subjects who were evaluable for this endpoint and "n" = those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 103/104/105); Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    319
    173
    317
    165
    Units: percent predicted of FEV1
    least squares mean (standard error)
        Absolute Change at Day 15 (n= 319, 173, 317, 165)
    3 ± 0.5
    2.8 ± 0.6
    2.8 ± 0.5
    3 ± 0.6
        Absolute Change at Week 8 (n= 309, 164, 316, 165)
    3.1 ± 0.5
    2.8 ± 0.6
    3.4 ± 0.5
    4.2 ± 0.6
        Absolute Change at Week 16 (n= 307, 166, 313, 160)
    2.6 ± 0.5
    2.7 ± 0.6
    2.5 ± 0.5
    3.6 ± 0.7
        Absolute Change at Week 24 (n= 291, 158, 295, 154)
    2.9 ± 0.5
    2.4 ± 0.6
    2.7 ± 0.5
    3.4 ± 0.7
        Absolute Change at Week 36 (n= 292, 155, 294, 150)
    2.7 ± 0.5
    2.2 ± 0.7
    1.9 ± 0.5
    3.1 ± 0.7
        Absolute Change at Week 48 (n= 279, 153, 286, 143)
    1.5 ± 0.5
    1.8 ± 0.7
    1.4 ± 0.5
    2.1 ± 0.7
        Absolute Change at Week 60 (n= 276, 146, 282, 140)
    1.7 ± 0.5
    2.1 ± 0.7
    1.6 ± 0.5
    1.4 ± 0.7
        Absolute Change at Week 72 (n= 275, 146, 273, 134)
    1.2 ± 0.5
    1.9 ± 0.7
    0.5 ± 0.5
    1.5 ± 0.7
    No statistical analyses for this end point

    Secondary: Part B Treatment Cohort: Absolute Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72

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    End point title
    Part B Treatment Cohort: Absolute Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [6]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 12 to 17 years and for female subjects aged 12 to 15 years. FAS (study 105) included all subjects randomized in the Part B Treatment Cohort and dosed. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (2010-020413-90) for Arm 6 and 7.Here "Number of subjects analysed" = those subjects who were evaluable for this endpoint and "n" = those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    52
    57
    Units: percent predicted of FEV1
    arithmetic mean (standard deviation)
        Absolute Change at Day 15 (n= 52, 57)
    -2 ± 8
    -3.4 ± 6.6
        Absolute Change at Week 8 (n= 49, 55)
    -3.9 ± 7.4
    -1.8 ± 6.4
        Absolute Change at Week 16 (n= 50, 52)
    -3.1 ± 9
    -2.8 ± 6.8
        Absolute Change at Week 24 (n= 36, 36)
    -2.9 ± 7.7
    -2.5 ± 7.3
        Absolute Change at Week 36 (n= 20, 19)
    -3.2 ± 7.9
    -2.3 ± 7.9
        Absolute Change at Week 48 (n= 15, 17)
    -5.4 ± 11.2
    -2 ± 6
        Absolute Change at Week 60 (n= 12, 16)
    -1.8 ± 10.1
    -1.9 ± 8.2
        Absolute Change at Week 72 (n= 11, 15)
    -2.8 ± 9.2
    -7.8 ± 8.3
    No statistical analyses for this end point

    Secondary: Part A Treatment Cohort: Relative Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72

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    End point title
    Part A Treatment Cohort: Relative Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [7]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 12 to 17 years and for female subjects aged 12 to 15 years. FAS study 105 (2013-000604-41) included all subjects randomized in the Part A Treatment Cohort and dosed. Analysis was performed using baseline of the previous study VX12-809-103 (2012-003989-40) and Study VX12-809-104 (2012-003990-24) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (2013-000604-41) for Arm 2 and 4. Here "Number of subjects analysed" = those subjects who were evaluable for this endpoint and "n" = those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    319
    173
    317
    165
    Units: percent change
    least squares mean (standard error)
        Relative Change at Day 15 (n= 319, 173, 317, 165)
    5.3 ± 0.9
    5.1 ± 1.2
    5.3 ± 0.9
    4.8 ± 1.2
        Relative Change at Week 8 (n= 309, 164, 316, 165)
    5.6 ± 0.9
    5.6 ± 1.2
    6.2 ± 0.9
    7.1 ± 1.2
        Relative Change at Week 16 (n= 307, 166, 313, 160)
    4.9 ± 0.9
    5.4 ± 1.2
    4.8 ± 0.9
    6.5 ± 1.2
        Relative Change at Week 24 (n= 291, 158, 295, 154)
    5.1 ± 0.9
    4.9 ± 1.2
    5 ± 0.9
    6.1 ± 1.2
        Relative Change at Week 36 (n= 292, 155, 294, 150)
    4.7 ± 0.9
    4 ± 1.2
    3.6 ± 0.9
    5.5 ± 1.2
        Relative Change at Week 48 (n= 279, 153, 286, 143)
    2.7 ± 0.9
    3.6 ± 1.2
    2.9 ± 0.9
    3.6 ± 1.2
        Relative Change at Week 60 (n= 276, 146, 282, 140)
    2.9 ± 0.9
    4.1 ± 1.2
    2.7 ± 0.9
    3.1 ± 1.2
        Relative Change at Week 72 (n= 275, 146, 273, 134)
    2.4 ± 0.9
    3.8 ± 1.2
    1.4 ± 0.9
    2.6 ± 1.2
    No statistical analyses for this end point

    Secondary: Part B Treatment Cohort: Relative Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72

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    End point title
    Part B Treatment Cohort: Relative Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [8]
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 12 to 17 years and for female subjects aged 12 to 15 years. FAS (study 105) included all subjects randomized in the Part B Treatment Cohort and dosed. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (2010-020413-90) for Arm 6 and 7.Here "Number of subjects analysed" = those subjects who were evaluable for this endpoint and "n" = those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    52
    57
    Units: percent change
    arithmetic mean (standard deviation)
        Relative Change at Day 15 (n= 52, 57)
    -2.2 ± 13.6
    -5.8 ± 11.4
        Relative Change at Week 8 (n= 49, 55)
    -5.2 ± 12.8
    -3.1 ± 11.4
        Relative Change at Week 16 (n= 50, 52)
    -4.2 ± 15.8
    -4.9 ± 11.8
        Relative Change at Week 24 (n= 36, 36)
    -3.4 ± 13.2
    -4.2 ± 12.6
        Relative Change at Week 36 (n= 20, 19)
    -4.1 ± 12.5
    -3.5 ± 14.2
        Relative Change at Week 48 (n= 15, 17)
    -6.9 ± 15.9
    -2.8 ± 10.6
        Relative Change at Week 60 (n= 12, 16)
    -0.7 ± 16.6
    -2.6 ± 13.9
        Relative Change at Week 72 (n= 11, 15)
    -3.3 ± 13.3
    -11.8 ± 10.7
    No statistical analyses for this end point

    Secondary: Part A Treatment Cohort: Absolute Change From Baseline in Body Mass Index (BMI) at Day 15, Week 8, 16, 24, 36, 48, 60 and 72

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    End point title
    Part A Treatment Cohort: Absolute Change From Baseline in Body Mass Index (BMI) at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [9]
    End point description
    BMI = (Weight in kilogram [kg]) divided by (Stature in meters [m]) ^2. FAS study 105 (2013-000604-41) included all subjects randomized in the Part A Treatment Cohort and dosed. Analysis was performed using baseline of the previous study VX12-809-103 (2012-003989-40) and Study VX12-809-104 (2012-003990-24) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (2013-000604-41) for Arm 2 and 4. Here "Number of subjects analysed" = those subjects who were evaluable for this endpoint and "n" = those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)
    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 which are applicable to the endpoint are reported.
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    329
    178
    338
    175
    Units: Kilogram per square meter (kg/m^2)
    least squares mean (standard error)
        Absolute Change at Day 15 (n= 328, 178, 338, 175)
    0.56 ± 0.06
    0.06 ± 0.08
    0.5 ± 0.06
    0.1 ± 0.08
        Absolute Change at Week 8 (n= 329, 173, 331, 172)
    0.58 ± 0.06
    0.14 ± 0.08
    0.55 ± 0.06
    0.27 ± 0.08
        Absolute Change at Week 16 (n= 321, 173, 325, 170)
    0.58 ± 0.06
    0.19 ± 0.08
    0.53 ± 0.06
    0.35 ± 0.08
        Absolute Change at Week 24 (n= 312, 169, 319, 165)
    0.61 ± 0.06
    0.22 ± 0.08
    0.62 ± 0.06
    0.41 ± 0.08
        Absolute Change at Week 36 (n= 304, 165, 315, 160)
    0.66 ± 0.06
    0.33 ± 0.08
    0.72 ± 0.06
    0.59 ± 0.08
        Absolute Change at Week 48 (n= 299, 162, 307, 151)
    0.63 ± 0.06
    0.42 ± 0.08
    0.71 ± 0.06
    0.62 ± 0.09
        Absolute Change at Week 60 (n= 296, 158, 298, 147)
    0.71 ± 0.06
    0.54 ± 0.08
    0.8 ± 0.06
    0.62 ± 0.09
        Absolute Change at Week 72 (n= 287, 152, 289, 145)
    0.72 ± 0.06
    0.52 ± 0.08
    0.69 ± 0.06
    0.62 ± 0.09
    No statistical analyses for this end point

    Secondary: Part B Treatment Cohort: Absolute Change From Baseline in BMI at Day 15, Week 8, 16, 24, 36, 48, 60 and 72

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    End point title
    Part B Treatment Cohort: Absolute Change From Baseline in BMI at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [10]
    End point description
    BMI = (Weight [in kg]) divided by (Stature [in meters]) ^2. FAS (study 105) included all subjects randomized in the Part B Treatment Cohort and dosed. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (2010-020413-90) for Arm 6 and 7. Here "n" = those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    55
    60
    Units: kg/m^2
    arithmetic mean (standard deviation)
        Absolute Change at Day 15 (n= 55, 60)
    -0.05 ± 0.52
    -0.03 ± 0.69
        Absolute Change at Week 8 (n= 54, 57)
    -0.01 ± 0.82
    0.14 ± 0.84
        Absolute Change at Week 16 (n= 51, 53)
    0.08 ± 1.02
    0.2 ± 1.09
        Absolute Change at Week 24 (n= 39, 37)
    0.04 ± 0.92
    0.14 ± 1.08
        Absolute Change at Week 36 (n= 20, 20)
    0.07 ± 0.54
    0.85 ± 1.23
        Absolute Change at Week 48 (n= 17, 17)
    0.05 ± 0.64
    0.81 ± 1.55
        Absolute Change at Week 60 (n= 12, 16)
    0.08 ± 0.7
    0.58 ± 1.23
        Absolute Change at Week 72 (n= 13, 15)
    0.08 ± 0.71
    0.41 ± 1.28
    No statistical analyses for this end point

    Secondary: Part A Treatment Cohort: Number of Pulmonary Exacerbations Events per Patient-Year

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    End point title
    Part A Treatment Cohort: Number of Pulmonary Exacerbations Events per Patient-Year
    End point description
    Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events per patient year were reported, where patient years = total number of days on study/336. FAS (Study 103/104) was used for Arm 1 and 3, and included all subjects randomized in the previous studies and dosed. FAS (Study 105) was used for Arm 2 and 4, and included all subjects randomized in the Part A Treatment Cohort and dosed in current study 105. Analysis includes all events in the Cumulative Study Period for Arm 1 and 3, and all events in the Current Study period (Study 105) for Arm 2 and 4. Here "Number of subjects analysed" = those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period)
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    368
    179
    369
    176
    Units: events per patient year
        number (confidence interval 95%)
    0.38 (0.32 to 0.46)
    0.42 (0.33 to 0.54)
    0.32 (0.26 to 0.38)
    0.37 (0.29 to 0.49)
    No statistical analyses for this end point

    Secondary: Part A Treatment Cohort: Absolute Change From Baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) Respiratory Domain Score at Day 15, Week 8, 16, 24, 48 and 72

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    End point title
    Part A Treatment Cohort: Absolute Change From Baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) Respiratory Domain Score at Day 15, Week 8, 16, 24, 48 and 72 [11]
    End point description
    The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. FAS study 105 (2013-000604-41) included all subjects randomized in the Part A Treatment Cohort and dosed. Analysis was performed using baseline of the previous study VX12-809-103 (2012-003989-40) and Study VX12-809-104 (2012-003990-24) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (2013-000604-41) for Arm 2 and 4. Here "Number of subjects analysed" = those subjects who were evaluable for this endpoint and "n" = those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 48, 72 (Study 105)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    324
    174
    325
    170
    Units: units on a scale
    least squares mean (standard error)
        Absolute Change at Day 15 (n= 324, 174, 325, 170)
    5.9 ± 0.9
    2.3 ± 1.2
    6.2 ± 0.9
    3.5 ± 1.2
        Absolute Change at Week 8 (n= 323, 164, 319, 166)
    5 ± 0.9
    4.1 ± 1.2
    5.1 ± 0.9
    6.8 ± 1.2
        Absolute Change at Week 16 (n= 313, 167, 312, 160)
    4.1 ± 0.9
    2.8 ± 1.2
    6.4 ± 0.9
    7 ± 1.2
        Absolute Change at Week 24 (n= 305, 161, 304, 155)
    6 ± 0.9
    3.8 ± 1.2
    6.1 ± 0.9
    4.7 ± 1.3
        Absolute Change at Week 48 (n= 290, 152, 290, 140)
    2 ± 0.9
    3.1 ± 1.3
    3.7 ± 0.9
    1.5 ± 1.3
        Absolute Change at Week 72 (n= 265, 141, 269, 135)
    3.2 ± 0.9
    3.3 ± 1.3
    5.7 ± 0.9
    3.3 ± 1.3
    No statistical analyses for this end point

    Secondary: Part B Treatment Cohort: Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 15, Week 8, 16, 24, 48 and 72

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    End point title
    Part B Treatment Cohort: Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 15, Week 8, 16, 24, 48 and 72 [12]
    End point description
    The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.FAS (study 105) included all subjects randomized in the Part B Treatment Cohort and dosed. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (2010-020413-90) for Arm 6 and 7.Here "Number of subjects analysed" = those subjects who were evaluable for this endpoint and "n" = those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 102 Study), Day 15, Week 8, 16, 24, 48, 72 (Study 105)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    55
    59
    Units: units on a scale
    arithmetic mean (standard deviation)
        Absolute Change at Day 15 (n= 55, 59)
    3.9 ± 18
    -4.1 ± 18.1
        Absolute Change at Week 8 (n= 54, 57)
    4.8 ± 18.6
    1 ± 18.2
        Absolute Change at Week 16 (n= 51, 53)
    6.2 ± 17.2
    -0.2 ± 17
        Absolute Change at Week 24 (n= 39, 37)
    6.8 ± 19.1
    -1.2 ± 17.9
        Absolute Change at Week 48 (n= 19, 17)
    2 ± 14
    4.9 ± 15.6
        Absolute Change at Week 72 (n= 13, 15)
    8.5 ± 21.8
    2.2 ± 18.8
    No statistical analyses for this end point

    Secondary: Part A Treatment Cohort: Absolute Change From Baseline in BMI z-score at Day 15, Week 8, 16, 24, 36, 48, 60 and 72

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    End point title
    Part A Treatment Cohort: Absolute Change From Baseline in BMI z-score at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [13]
    End point description
    z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is with range from -infinity to +infinity; 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the pediatric population. FAS study 105 (2013-000604-41) included all subjects randomized in the Part A Treatment Cohort and dosed. Analysis was performed using baseline of the previous study VX12-809-103 (2012-003989-40) and Study VX12-809-104 (2012-003990-24) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (2013-000604-41) for Arm 2 and 4. Here "Number of subjects analysed" = those subjects who were evaluable for this endpoint and "n" = those subjects who were evaluable at the specified time points for each arm,
    End point type
    Secondary
    End point timeframe
    Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    117
    56
    109
    60
    Units: z-score
    least squares mean (standard error)
        Absolute Change at Day 15 (n= 117, 56, 109, 60)
    0.16 ± 0.04
    -0.01 ± 0.06
    0.14 ± 0.04
    -0.02 ± 0.05
        Absolute Change at Week 8 (n= 114, 53, 105, 60)
    0.15 ± 0.04
    0.04 ± 0.06
    0.16 ± 0.04
    0.08 ± 0.05
        Absolute Change at Week 16 (n= 112, 53, 101, 58)
    0.12 ± 0.04
    0.08 ± 0.06
    0.15 ± 0.04
    0.07 ± 0.05
        Absolute Change at Week 24 (n= 110, 49, 100, 56)
    0.14 ± 0.04
    0.08 ± 0.06
    0.17 ± 0.04
    0.1 ± 0.05
        Absolute Change at Week 36 (n= 100, 46, 100, 52)
    0.14 ± 0.04
    0.13 ± 0.06
    0.16 ± 0.04
    0.14 ± 0.05
        Absolute Change at Week 48 (n= 95, 46, 97, 47)
    0.09 ± 0.04
    0.13 ± 0.06
    0.11 ± 0.04
    0.12 ± 0.06
        Absolute Change at Week 60 (n= 91, 45, 90, 44)
    0.11 ± 0.04
    0.16 ± 0.06
    0.14 ± 0.04
    0.13 ± 0.06
        Absolute Change at Week 72 (n= 85, 45, 89, 42)
    0.06 ± 0.04
    0.12 ± 0.06
    0.04 ± 0.04
    0.08 ± 0.06
    No statistical analyses for this end point

    Secondary: Part A Treatment Cohort: Absolute Change From Baseline in Body Weight at Day 15, Week 8, 16, 24, 36, 48, 60 and 72

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    End point title
    Part A Treatment Cohort: Absolute Change From Baseline in Body Weight at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [14]
    End point description
    Full Analysis Set (FAS) study 105 (2013-000604-41) included all subjects randomized in the Part A Treatment Cohort and dosed. Analysis was performed using baseline of the previous study VX12-809-103 (2012-003989-40) and Study VX12-809-104 (2012-003990-24) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (2013-000604-41) for Arm 2 and 4. Here "Number of subjects analysed" = those subjects who were evaluable for this endpoint and "n" = those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    329
    178
    338
    175
    Units: kilograms (kg)
    arithmetic mean (standard deviation)
        Absolute Change at Day 15 (n= 328, 178, 338, 175)
    1.7 ± 2.6
    -0.1 ± 1.8
    1.3 ± 2.9
    0.1 ± 1.2
        Absolute Change at Week 8 (n= 329, 173, 331, 172)
    1.8 ± 2.9
    0.2 ± 2.1
    1.5 ± 3.1
    0.6 ± 1.9
        Absolute Change at Week 16 (n= 321, 173, 325, 170)
    1.9 ± 3.2
    0.4 ± 2.6
    1.6 ± 3.3
    1 ± 2.5
        Absolute Change at Week 24 (n= 312, 169, 319, 165)
    2.2 ± 3.5
    0.6 ± 2.6
    2 ± 3.6
    1.2 ± 2.8
        Absolute Change at Week 36 (n= 304, 165, 315, 160)
    2.3 ± 3.8
    1 ± 3.4
    2.4 ± 3.8
    1.9 ± 3.4
        Absolute Change at Week 48 (n= 299, 162, 307, 151)
    2.4 ± 4.2
    1.3 ± 3.7
    2.5 ± 4.3
    2.1 ± 3.7
        Absolute Change at Week 60 (n= 296, 158, 298, 147)
    2.7 ± 4.6
    1.7 ± 4.2
    2.9 ± 4.6
    2.2 ± 4.4
        Absolute Change at Week 72 (n= 287, 152, 289, 145)
    2.9 ± 4.9
    1.7 ± 4.8
    2.7 ± 4.9
    2.3 ± 4.7
    No statistical analyses for this end point

    Secondary: Part B Treatment Cohort: Absolute Change From Baseline in Body Weight at Day 15, Week 8, 16, 24, 36, 48, 60 and 72

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    End point title
    Part B Treatment Cohort: Absolute Change From Baseline in Body Weight at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [15]
    End point description
    FAS (study 105) included all subjects randomized in the Part B Treatment Cohort and dosed. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (2010-020413-90) for Arm 6 and 7.Here "n" = those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    55
    60
    Units: Kg
    arithmetic mean (standard deviation)
        Absolute Change at Day 15 (n= 55, 60)
    -0.1 ± 1.5
    -0.1 ± 1.8
        Absolute Change at Week 8 (n= 54, 57)
    0 ± 2.3
    0.4 ± 2.3
        Absolute Change at Week 16 (n= 51, 53)
    0.3 ± 2.8
    0.6 ± 2.9
        Absolute Change at Week 24 (n= 39, 37)
    0.2 ± 2.6
    0.4 ± 3
        Absolute Change at Week 36 (n= 20, 20)
    0.3 ± 1.7
    2.3 ± 3.3
        Absolute Change at Week 48 (n= 17, 17)
    0.2 ± 2
    2.2 ± 4.3
        Absolute Change at Week 60 (n= 12, 16)
    0.3 ± 2.3
    1.5 ± 3.3
        Absolute Change at Week 72 (n= 13, 15)
    0.2 ± 2.3
    1.1 ± 3.4
    No statistical analyses for this end point

    Secondary: Part A Treatment Cohort: Time-to-First Pulmonary Exacerbation

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    End point title
    Part A Treatment Cohort: Time-to-First Pulmonary Exacerbation
    End point description
    Time-to-first pulmonary exacerbation was analyzed using the Kaplan-Meier estimates. Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. FAS (Study 103/104) was used for Arm 1 and 3, and included all subjects randomized in the previous studies and dosed. FAS (Study 105) was used for Arm 2 and 4, and included all subjects randomized in the Part A Treatment Cohort and dosed in current study 105. Analysis was performed for the the Cumulative Study Period for Arm 1 and 3, and for the current study period (Study 105) for Arm 2 and 4. Here, 99999 represents data for Q3 inter-quartile range was not available.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period)
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    368
    179
    369
    176
    Units: Days
        median (inter-quartile range (Q1-Q3))
    364 (99 to 99999)
    505 (111 to 99999)
    481 (132 to 99999)
    466 (153 to 99999)
    No statistical analyses for this end point

    Secondary: Part A Treatment Cohort: Percentage of Subjects With at Least 1 Pulmonary Exacerbation

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    End point title
    Part A Treatment Cohort: Percentage of Subjects With at Least 1 Pulmonary Exacerbation
    End point description
    Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. FAS (Study 103/104) was used for Arm 1 and 3, and included all subjects randomized in the previous studies and dosed. FAS (Study 105) was used for Arm 2 and 4, and included all subjects randomized in the Part A Treatment Cohort and dosed in current study 105. Analysis was performed for the the Cumulative Study Period for Arm 1 and 3, and for the current study period (Study 105) for Arm 2 and 4.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period)
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    368
    179
    369
    176
    Units: percentage of subjects
        number (confidence interval 95%)
    64.7 (59.8 to 69.6)
    53.6 (46.3 to 60.9)
    59.9 (54.9 to 64.9)
    55.7 (48.3 to 63)
    No statistical analyses for this end point

    Secondary: Part A Treatment Cohort: Percentage of Subjects With Response Based on Relative Change in Percent Predicted FEV1 From Baseline

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    End point title
    Part A Treatment Cohort: Percentage of Subjects With Response Based on Relative Change in Percent Predicted FEV1 From Baseline
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). Percentage of subjects with at least 5% and 10% relative change in percent predicted FEV1 from Baseline were reported. FAS (Study 103/104) was used for Arm 1 and 3, and included all subjects randomized in the previous studies and dosed. FAS (Study 105) was used for Arm 2 and 4, and included all subjects randomized in the Part A Treatment Cohort and dosed in current study 105. Analysis was performed using baseline of the previous study VX12-809-103 (2012-003989-40) or Study VX12-809-104 (2012-003990-24) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (2013-000604-41) for Arm 2 and 4.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 103/104/105); Day 15, Week 8, 16, 24, 36, 48, 60, 72, 84, 96 (Study 105)
    End point values
    Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    368
    179
    369
    176
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Day 15: >=5% Change
    39.4 (34.4 to 44.4)
    42.5 (35.2 to 49.7)
    40.9 (35.9 to 45.9)
    42.6 (35.3 to 49.9)
        Day 15: >=10% Change
    25 (20.6 to 29.4)
    26.8 (20.3 to 33.3)
    24.7 (20.3 to 29.1)
    26.7 (20.2 to 33.2)
        Week 8: >=5% Change
    39.7 (34.7 to 44.7)
    38 (30.9 to 45.1)
    39.3 (34.3 to 44.3)
    48.9 (41.5 to 56.2)
        Week 8: >=10% Change
    26.9 (22.4 to 31.4)
    23.5 (17.3 to 29.7)
    26.6 (22.1 to 31.1)
    35.8 (28.7 to 42.9)
        Week 16: >=5% Change
    37.2 (32.3 to 42.2)
    36.9 (29.8 to 43.9)
    36.9 (31.9 to 41.8)
    46.6 (39.2 to 54)
        Week 16: >=10% Change
    25.5 (21.1 to 30)
    25.1 (18.8 to 31.5)
    26.3 (21.8 to 30.8)
    28.4 (21.7 to 35.1)
        Week 24: >=5% Change
    35.6 (30.7 to 40.5)
    38 (30.9 to 45.1)
    33.6 (28.8 to 38.4)
    42.6 (35.3 to 49.9)
        Week 24: >=10% Change
    24.5 (20.1 to 28.8)
    21.8 (15.7 to 27.8)
    22.5 (18.2 to 26.8)
    32.4 (25.5 to 39.3)
        Week 36: >=5% Change
    35.3 (30.4 to 40.2)
    32.4 (25.5 to 39.3)
    31.7 (27 to 36.5)
    38.6 (31.4 to 45.8)
        Week 36: >=10% Change
    23.4 (19 to 27.7)
    22.9 (16.7 to 29.1)
    22.2 (18 to 26.5)
    27.3 (20.7 to 33.9)
        Week 48: >=5% Change
    30.2 (25.5 to 34.9)
    32.4 (25.5 to 39.3)
    30.9 (26.2 to 35.6)
    36.4 (29.3 to 43.5)
        Week 48: >=10% Change
    21.7 (17.5 to 26)
    21.8 (15.7 to 27.8)
    21.4 (17.2 to 25.6)
    19.9 (14 to 25.8)
        Week 60: >=5% Change
    30.4 (25.7 to 35.1)
    32.4 (25.5 to 39.3)
    29.3 (24.6 to 33.9)
    38.6 (31.4 to 45.8)
        Week 60: >=10% Change
    20.4 (16.3 to 24.5)
    25.1 (18.8 to 31.5)
    19.2 (15.2 to 23.3)
    24.4 (18.1 to 30.8)
        Week 72: >=5% Change
    29.3 (24.7 to 34)
    34.6 (27.7 to 41.6)
    25.5 (21 to 29.9)
    33 (26 to 39.9)
        Week 72: >=10% Change
    18.2 (14.3 to 22.1)
    22.3 (16.2 to 28.4)
    18.2 (14.2 to 22.1)
    23.3 (17.1 to 29.5)
        Week 84: >=5% Change
    23.1 (18.8 to 27.4)
    28.5 (21.9 to 35.1)
    23.3 (19 to 27.6)
    26.1 (19.6 to 32.6)
        Week 84: >=10% Change
    14.9 (11.3 to 18.6)
    21.2 (15.2 to 27.2)
    15.7 (12 to 19.4)
    19.9 (14 to 25.8)
        Week 96: >=5% Change
    15.5 (11.8 to 19.2)
    14.5 (9.4 to 19.7)
    13.8 (10.3 to 17.3)
    15.3 (10 to 20.7)
        Week 96: >=10% Change
    8.7 (5.8 to 11.6)
    10.1 (5.7 to 14.5)
    10.3 (7.2 to 13.4)
    9.1 (4.8 to 13.3)
    No statistical analyses for this end point

    Secondary: Part B Treatment Cohort: Percentage of Subjects With Response Based on Relative Change in Percent Predicted FEV1 From Baseline

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    End point title
    Part B Treatment Cohort: Percentage of Subjects With Response Based on Relative Change in Percent Predicted FEV1 From Baseline
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). Percentage of subjects with at least 5% relative change in percent predicted FEV1 from Baseline were reported. FAS (Study 102) was used for Arm 6 and 7, and included all subjects randomized in the cohort 4 of study 102 and dosed. Analysis was performed using baseline of the previous study VX09-809-102 (2010-020413-90) for Arm 6 and 7.
    End point type
    Secondary
    End point timeframe
    Baseline (Study 102); Day 15, Week 8, 16, 24, 36, 48, 60, 72, 84, 96 (Study 105)
    End point values
    Arm 6: Part B - LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
    Number of subjects analysed
    62
    63
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Day 15: >=5% Change
    21 (10.8 to 31.1)
    12.7 (4.5 to 20.9)
        Week 8: >=5% Change
    11.3 (3.4 to 19.2)
    19 (9.4 to 28.7)
        Week 16: >=5% Change
    19.4 (9.5 to 29.2)
    15.9 (6.8 to 24.9)
        Week 24: >=5% Change
    12.9 (4.6 to 21.2)
    12.7 (4.5 to 20.9)
        Week 36: >=5% Change
    6.5 (0.3 to 12.6)
    6.3 (0.3 to 12.4)
        Week 48: >=5% Change
    6.5 (0.3 to 12.6)
    4.8 (0 to 10)
        Week 60: >=5% Change
    6.5 (0.3 to 12.6)
    6.3 (0.3 to 12.4)
        Week 72: >=5% Change
    3.2 (0 to 7.6)
    0 (0 to 0)
        Week 84: >=5% Change
    1.6 (0 to 4.7)
    1.6 (0 to 4.7)
        Week 96: >=5% Change
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Part A Observation Cohort: Number of Subjects With Serious Adverse Events (SAEs)

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    End point title
    Part A Observation Cohort: Number of Subjects With Serious Adverse Events (SAEs) [16]
    End point description
    AE: as any untoward medical occurrence in a subject during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the 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. Safety Set (study 105) included all subjects who were enrolled in Part A Observation Cohort.
    End point type
    Secondary
    End point timeframe
    up to 2 years
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Arm 5: Part A Observational Cohort
    Number of subjects analysed
    19
    Units: subjects
        number (not applicable)
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 105
    Adverse event reporting additional description
    Non-SAEs were not collected for Arm 5: Part A Observational Cohort. Only SAEs were collected.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Arm 1: Part A LUM 600 mg qd/ IVA 250 mg q12h
    Reporting group description
    Subjects who received LUM 600 mg qd in fixed dose combination with IVA 250 mg in the previous study VX12-809-103 (2012-003989-40) and VX12-809-104 (2012-003990-24), received the same treatment in this study 105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 2: Part A PlaceboLUM 600 mg qd/ IVA 250 mg q12h
    Reporting group description
    Subjects who received placebo matched to LUM and IVA in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received LUM 600 mg qd in fixed dose combintion with IVA 250 mg q12h in this study 105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 3: Part A LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received the same treatment in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 4: Part A - Placebo - LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received placebo matched to LUM and IVA n the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in this study 105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 5: Part A Observational Cohort
    Reporting group description
    Subjects who received either LUM 600 mg qd in fixed dose combination with IVA 250 mg q12h or LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h or placebo matched to LUM and IVA q12h in the previous study VX12-809-103 (2012-003989-40) or VX12-809-104 (2012-003990-24), were observed (did not receive study drug) in this study VX12-809-105 (2013-000604-41) for up to 2 years.

    Reporting group title
    Arm 6: Part B LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received LUM 400 mg q12h in fixed dose combination with IVA 250 q12h in Cohort 4 of the previous study VX09-809-102 (2010-020413-90), received the same treatment in this VX12-809-105 (2013-000604-41) up to Week 96.

    Reporting group title
    Arm 7: Part B - Placebo - LUM 400 mg q12h/ IVA 250 mg q12h
    Reporting group description
    Subjects who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (2010-020413-90), received LUM 400 mg q12h in fixed dose combination with IVA 250 mg q12h in this study VX12-809-105 (2013-000604-41) up to Week 96.

    Serious adverse events
    Arm 1: Part A LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A PlaceboLUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo - LUM 400 mg q12h/ IVA 250 mg q12h Arm 5: Part A Observational Cohort Arm 6: Part B LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo - LUM 400 mg q12h/ IVA 250 mg q12h
    Total subjects affected by serious adverse events
         subjects affected / exposed
    156 / 335 (46.57%)
    77 / 178 (43.26%)
    143 / 340 (42.06%)
    89 / 176 (50.57%)
    7 / 19 (36.84%)
    18 / 55 (32.73%)
    21 / 60 (35.00%)
         number of deaths (all causes)
    0
    1
    2
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Hypertensive crisis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 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
    Anaphylactic reaction
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Serum sickness
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Type IV hypersensitivity reaction
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Chest pain
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Fatigue
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Pyrexia
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Medical device site thrombosis
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    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
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 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
    Adjustment disorder
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Adjustment disorder with depressed mood
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Major depression
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Suicidal ideation
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    1 / 19 (5.26%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Ligament rupture
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Lower limb fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Pelvic fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Upper limb fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Facial bones fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    1 / 55 (1.82%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    3 / 335 (0.90%)
    1 / 178 (0.56%)
    3 / 340 (0.88%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    1 / 55 (1.82%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 4
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    2 / 176 (1.14%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    1 / 2
    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
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    2 / 176 (1.14%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    1 / 2
    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
    Bacterial test positive
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 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
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    3 / 176 (1.70%)
    0 / 19 (0.00%)
    1 / 55 (1.82%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 4
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Influenza B virus test positive
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Liver function test increased
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Weight decreased
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    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
    Influenza A virus test positive
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    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
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 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
    Cardiac arrest
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Myocardial ischaemia
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Ventricular tachycardia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Cardiomyopathy
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    1 / 19 (5.26%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis related diabetes
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 178 (0.00%)
    3 / 340 (0.88%)
    3 / 176 (1.70%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 3
    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
    Cystic fibrosis pancreatic
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Blood and lymphatic system disorders
    Haemolytic anaemia
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Leukocytosis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    17 / 335 (5.07%)
    7 / 178 (3.93%)
    10 / 340 (2.94%)
    6 / 176 (3.41%)
    1 / 19 (5.26%)
    0 / 55 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    1 / 24
    1 / 7
    0 / 16
    3 / 9
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    5 / 335 (1.49%)
    1 / 178 (0.56%)
    3 / 340 (0.88%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 1
    0 / 5
    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
    Respiration abnormal
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    3 / 176 (1.70%)
    0 / 19 (0.00%)
    1 / 55 (1.82%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    3 / 3
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 335 (0.30%)
    2 / 178 (1.12%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    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
    Nasal polyps
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Acute respiratory failure
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Asthma
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Bronchiectasis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Dyspnoea
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Hypoxia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Lower respiratory tract congestion
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Pleural effusion
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Pleuritic pain
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Pulmonary bulla
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Pulmonary embolism
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Respiratory distress
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Respiratory failure
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cauda equina syndrome
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Dizziness
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Juvenile myoclonic epilepsy
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Neurological symptom
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Vocal cord paralysis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Eye disorders
    Cataract subcapsular
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    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
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    2 / 335 (0.60%)
    1 / 178 (0.56%)
    6 / 340 (1.76%)
    10 / 176 (5.68%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 8
    1 / 10
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    5 / 335 (1.49%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    2 / 176 (1.14%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 1
    0 / 2
    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
    Abdominal pain
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 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
    Abdominal pain upper
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    3 / 176 (1.70%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    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
    Constipation
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 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
    Diarrhoea
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 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
    Intestinal obstruction
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    2 / 176 (1.14%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    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
    Gastritis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 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
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 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
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Faecaloma
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Food poisoning
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Gastrointestinal angiodysplasia
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Hiatus hernia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Inguinal hernia
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Mechanical ileus
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Pancreatitis
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    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
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 335 (0.60%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    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
    Biliary colic
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Cholangitis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 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
    Nephrolithiasis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 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
    Renal colic
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 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
    Nephrotic syndrome
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Rash maculo-papular
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    Pathological fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Polyarthritis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Rhabdomyolysis
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    Dehydration
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Hyperglycaemia
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Hypoglycaemia
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    113 / 335 (33.73%)
    61 / 178 (34.27%)
    111 / 340 (32.65%)
    59 / 176 (33.52%)
    5 / 19 (26.32%)
    15 / 55 (27.27%)
    15 / 60 (25.00%)
         occurrences causally related to treatment / all
    8 / 219
    2 / 130
    4 / 212
    5 / 107
    0 / 11
    2 / 20
    2 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 335 (1.79%)
    4 / 178 (2.25%)
    5 / 340 (1.47%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    3 / 6
    0 / 6
    0 / 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
    Influenza
         subjects affected / exposed
    0 / 335 (0.00%)
    2 / 178 (1.12%)
    6 / 340 (1.76%)
    3 / 176 (1.70%)
    1 / 19 (5.26%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 6
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    3 / 335 (0.90%)
    2 / 178 (1.12%)
    1 / 340 (0.29%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 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
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    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
    Acute sinusitis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 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
    Bronchitis
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    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
    Device related infection
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 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
    Device related sepsis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 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
    Gastroenteritis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    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
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    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
    Sepsis
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    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
    Tracheobronchitis
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    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
    Anal abscess
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Bacteraemia
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Cellulitis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Chronic sinusitis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Hepatitis E
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Infection
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    1 / 19 (5.26%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Mediastinitis
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Mycobacterium abscessus infection
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Nasopharyngitis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Parotitis
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Periorbital abscess
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Peritonitis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Peritonsillar abscess
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Pneumonia bacterial
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Post procedural infection
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Rhinovirus infection
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Sinusitis
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 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
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Tooth abscess
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    Kidney infection
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Arm 1: Part A LUM 600 mg qd/ IVA 250 mg q12h Arm 2: Part A PlaceboLUM 600 mg qd/ IVA 250 mg q12h Arm 3: Part A LUM 400 mg q12h/ IVA 250 mg q12h Arm 4: Part A - Placebo - LUM 400 mg q12h/ IVA 250 mg q12h Arm 5: Part A Observational Cohort Arm 6: Part B LUM 400 mg q12h/ IVA 250 mg q12h Arm 7: Part B - Placebo - LUM 400 mg q12h/ IVA 250 mg q12h
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    328 / 335 (97.91%)
    177 / 178 (99.44%)
    332 / 340 (97.65%)
    173 / 176 (98.30%)
    0 / 19 (0.00%)
    52 / 55 (94.55%)
    57 / 60 (95.00%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    7 / 335 (2.09%)
    3 / 178 (1.69%)
    8 / 340 (2.35%)
    3 / 176 (1.70%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    7
    3
    9
    3
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    10 / 335 (2.99%)
    3 / 178 (1.69%)
    8 / 340 (2.35%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    12
    3
    9
    0
    0
    0
    3
    Ligament sprain
         subjects affected / exposed
    5 / 335 (1.49%)
    2 / 178 (1.12%)
    5 / 340 (1.47%)
    6 / 176 (3.41%)
    0 / 19 (0.00%)
    2 / 55 (3.64%)
    0 / 60 (0.00%)
         occurrences all number
    6
    3
    5
    8
    0
    2
    0
    Muscle strain
         subjects affected / exposed
    5 / 335 (1.49%)
    4 / 178 (2.25%)
    2 / 340 (0.59%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    1 / 55 (1.82%)
    1 / 60 (1.67%)
         occurrences all number
    5
    4
    2
    1
    0
    1
    1
    Arthropod bite
         subjects affected / exposed
    4 / 335 (1.19%)
    3 / 178 (1.69%)
    3 / 340 (0.88%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    2 / 55 (3.64%)
    0 / 60 (0.00%)
         occurrences all number
    4
    3
    3
    1
    0
    2
    0
    Laceration
         subjects affected / exposed
    2 / 335 (0.60%)
    3 / 178 (1.69%)
    5 / 340 (1.47%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    1 / 55 (1.82%)
    0 / 60 (0.00%)
         occurrences all number
    2
    3
    5
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    5 / 340 (1.47%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    5
    1
    0
    0
    0
    Joint dislocation
         subjects affected / exposed
    2 / 335 (0.60%)
    1 / 178 (0.56%)
    3 / 340 (0.88%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    4
    1
    4
    1
    0
    0
    0
    Joint injury
         subjects affected / exposed
    3 / 335 (0.90%)
    0 / 178 (0.00%)
    4 / 340 (1.18%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    3
    0
    4
    0
    0
    0
    0
    Rib fracture
         subjects affected / exposed
    4 / 335 (1.19%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    4
    0
    2
    2
    0
    0
    0
    Concussion
         subjects affected / exposed
    2 / 335 (0.60%)
    2 / 178 (1.12%)
    1 / 340 (0.29%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    2
    1
    1
    0
    0
    0
    Sunburn
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    2 / 55 (3.64%)
    1 / 60 (1.67%)
         occurrences all number
    1
    0
    0
    1
    0
    2
    1
    Ligament rupture
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    1 / 55 (1.82%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Limb injury
         subjects affected / exposed
    4 / 335 (1.19%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    1 / 55 (1.82%)
    0 / 60 (0.00%)
         occurrences all number
    4
    0
    2
    0
    0
    1
    0
    Periorbital haemorrhage
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    1 / 55 (1.82%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Post procedural swelling
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    1
    Tooth fracture
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 178 (0.56%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    1 / 55 (1.82%)
    0 / 60 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    1
    0
    Foot fracture
         subjects affected / exposed
    2 / 335 (0.60%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    2 / 176 (1.14%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    1
    1
    2
    0
    0
    0
    Road traffic accident
         subjects affected / exposed
    5 / 335 (1.49%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    5
    0
    0
    1
    0
    0
    0
    Chest injury
         subjects affected / exposed
    3 / 335 (0.90%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    3
    0
    2
    0
    0
    0
    0
    Post-traumatic pain
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    2
    1
    0
    0
    0
    Facial bones fracture
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    2 / 176 (1.14%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    0
    0
    Back injury
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    Hand fracture
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    Ligament injury
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    Meniscus injury
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    0
    Sports injury
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    Superficial injury of eye
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    Animal bite
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Arthropod sting
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Incisional hernia
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Post procedural discomfort
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    2 / 340 (0.59%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    0
    Procedural nausea
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Stoma site discomfort
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Stoma site irritation
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Traumatic haematoma
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Wrist fracture
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Accidental exposure to product
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Animal scratch
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Ankle fracture
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Avulsion fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Burns second degree
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Confusion postoperative
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Corneal abrasion
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Ear injury
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Epicondylitis
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Excoriation
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Exposure to toxic agent
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Eye injury
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Face injury
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Forearm fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Head injury
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Heat stroke
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Incision site haematoma
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Limb crushing injury
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Lip injury
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Muscle injury
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Muscle rupture
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Neck injury
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nerve injury
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Peripheral nerve injury
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Post procedural complication
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Procedural anxiety
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Procedural headache
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Procedural vomiting
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Radius fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Sinus barotrauma
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    1 / 176 (0.57%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Soft tissue injury
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Splinter
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Stoma site erythema
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 178 (0.00%)
    1 / 340 (0.29%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Stoma site pain
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 178 (0.00%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Stoma site ulcer
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 178 (0.56%)
    0 / 340 (0.00%)
    0 / 176 (0.00%)
    0 / 19 (0.00%)
    0 / 55 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Stress fracture