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    Clinical Trial Results:
    A Phase 1/2 Study of VX-445 in Subjects With Cystic Fibrosis

    Summary
    EudraCT number
    2017-000797-11
    Trial protocol
    NL   BE  
    Global end of trial date
    27 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Apr 2019
    First version publication date
    12 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX16-445-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03227471
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States,
    Public contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 877 634 8789, medicalinfo@vrtx.com
    Scientific contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 877 634 8789, medicalinfo@vrtx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety, tolerability, and efficacy of VX-445 in triple combination (TC) with Tezacaftor/Ivacaftor (TEZ/IVA) or with TEZ/VX-561.
    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
    19 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 88
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Belgium: 6
    Worldwide total number of subjects
    125
    EEA total number of subjects
    22
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    125
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This study included 6 parts: Part D, E, and F were conducted in adult subjects with cystic fibrosis (CF).

    Period 1
    Period 1 title
    Triple Combination Treatment Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part D: Placebo
    Arm description
    Subjects received placebo matched to VX-445/TEZ/IVA triple combination (TC) for 4 weeks in the TC treatment period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-445)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-445 once daily.

    Investigational medicinal product name
    Placebo (matched to TEZ/IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to IVA once daily in the evening.

    Arm title
    Part D: VX-445/TEZ/IVA TC - Low Dose
    Arm description
    Subjects received VX-445/TEZ/IVA TC low dose for 4 weeks in the TC treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-445
    Investigational medicinal product code
    VX-445
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-445 low dose once daily.

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA once daily in the evening.

    Arm title
    Part D: VX-445/TEZ/IVA TC - Medium Dose
    Arm description
    Subjects received VX-445/TEZ/IVA TC medium dose for 4 weeks in the TC treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-445
    Investigational medicinal product code
    VX-445
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-445 medium dose once daily.

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA once daily in the evening.

    Arm title
    Part D: VX-445/TEZ/IVA TC - High Dose
    Arm description
    Subjects received VX-445/TEZ/IVA TC high dose for 4 weeks in the TC treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-445
    Investigational medicinal product code
    VX-445
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-445 high dose once daily.

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA once daily in the evening.

    Arm title
    Part E: TEZ/IVA
    Arm description
    Following run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA and placebo matched to VX-445 for 4 weeks in the TC treatment period.
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo (matched to VX-445)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-445 once daily.

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA once daily in the evening.

    Arm title
    Part E: VX-445/TEZ/IVA TC
    Arm description
    Following run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-445
    Investigational medicinal product code
    VX-445
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-445 once daily.

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ/IVA once daily in the morning.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA once daily in the evening.

    Arm title
    Part F: Placebo
    Arm description
    Subjects received placebo matched to VX-445/TEZ/VX-561 for 4 weeks in the TC treatment period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-445)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-445 once daily.

    Investigational medicinal product name
    Placebo (matched to TEZ)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to TEZ once daily.

    Investigational medicinal product name
    Placebo (matched to VX-561)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-561 once daily.

    Arm title
    Part F: VX-445/TEZ/VX-561 TC
    Arm description
    Subjects received VX-445/TEZ/VX-561 TC for 4 weeks in the TC treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-445
    Investigational medicinal product code
    VX-445
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-445 once daily.

    Investigational medicinal product name
    TEZ
    Investigational medicinal product code
    VX-661
    Other name
    Tezacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ once daily.

    Investigational medicinal product name
    VX-561
    Investigational medicinal product code
    VX-561
    Other name
    CTP-656
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-561 once daily.

    Number of subjects in period 1 [1]
    Part D: Placebo Part D: VX-445/TEZ/IVA TC - Low Dose Part D: VX-445/TEZ/IVA TC - Medium Dose Part D: VX-445/TEZ/IVA TC - High Dose Part E: TEZ/IVA Part E: VX-445/TEZ/IVA TC Part F: Placebo Part F: VX-445/TEZ/VX-561 TC
    Started
    12
    10
    22
    21
    7
    21
    8
    21
    Completed
    12
    10
    22
    21
    7
    20
    8
    21
    Not completed
    0
    0
    0
    0
    0
    1
    0
    0
         Withdrawal of consent (not due to AE)
    -
    -
    -
    -
    -
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 125 subjects were enrolled in the Parts DEF. 2 subjects were dosed in the run-in period in Part E, but never got dosed in TC period. 1 subject in Part F was randomized but never dosed in TC period. Therefore, 122 over the total of 125 enrolled subjects entered the TC period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part D: Placebo
    Reporting group description
    Subjects received placebo matched to VX-445/TEZ/IVA triple combination (TC) for 4 weeks in the TC treatment period.

    Reporting group title
    Part D: VX-445/TEZ/IVA TC - Low Dose
    Reporting group description
    Subjects received VX-445/TEZ/IVA TC low dose for 4 weeks in the TC treatment period.

    Reporting group title
    Part D: VX-445/TEZ/IVA TC - Medium Dose
    Reporting group description
    Subjects received VX-445/TEZ/IVA TC medium dose for 4 weeks in the TC treatment period.

    Reporting group title
    Part D: VX-445/TEZ/IVA TC - High Dose
    Reporting group description
    Subjects received VX-445/TEZ/IVA TC high dose for 4 weeks in the TC treatment period.

    Reporting group title
    Part E: TEZ/IVA
    Reporting group description
    Following run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA and placebo matched to VX-445 for 4 weeks in the TC treatment period.

    Reporting group title
    Part E: VX-445/TEZ/IVA TC
    Reporting group description
    Following run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period.

    Reporting group title
    Part F: Placebo
    Reporting group description
    Subjects received placebo matched to VX-445/TEZ/VX-561 for 4 weeks in the TC treatment period.

    Reporting group title
    Part F: VX-445/TEZ/VX-561 TC
    Reporting group description
    Subjects received VX-445/TEZ/VX-561 TC for 4 weeks in the TC treatment period.

    Reporting group values
    Part D: Placebo Part D: VX-445/TEZ/IVA TC - Low Dose Part D: VX-445/TEZ/IVA TC - Medium Dose Part D: VX-445/TEZ/IVA TC - High Dose Part E: TEZ/IVA Part E: VX-445/TEZ/IVA TC Part F: Placebo Part F: VX-445/TEZ/VX-561 TC Total
    Number of subjects
    12 10 22 21 7 21 8 21 122
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    29.7 ± 7.5 27.1 ± 7.4 31.8 ± 8.3 33.3 ± 10.3 27.9 ± 8.0 29.9 ± 7.6 27.8 ± 5.2 30.6 ± 9.5 -
    Gender categorical
    Units: Subjects
        Female
    2 6 7 11 1 9 5 10 51
        Male
    10 4 15 10 6 12 3 11 71

    End points

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    End points reporting groups
    Reporting group title
    Part D: Placebo
    Reporting group description
    Subjects received placebo matched to VX-445/TEZ/IVA triple combination (TC) for 4 weeks in the TC treatment period.

    Reporting group title
    Part D: VX-445/TEZ/IVA TC - Low Dose
    Reporting group description
    Subjects received VX-445/TEZ/IVA TC low dose for 4 weeks in the TC treatment period.

    Reporting group title
    Part D: VX-445/TEZ/IVA TC - Medium Dose
    Reporting group description
    Subjects received VX-445/TEZ/IVA TC medium dose for 4 weeks in the TC treatment period.

    Reporting group title
    Part D: VX-445/TEZ/IVA TC - High Dose
    Reporting group description
    Subjects received VX-445/TEZ/IVA TC high dose for 4 weeks in the TC treatment period.

    Reporting group title
    Part E: TEZ/IVA
    Reporting group description
    Following run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA and placebo matched to VX-445 for 4 weeks in the TC treatment period.

    Reporting group title
    Part E: VX-445/TEZ/IVA TC
    Reporting group description
    Following run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period.

    Reporting group title
    Part F: Placebo
    Reporting group description
    Subjects received placebo matched to VX-445/TEZ/VX-561 for 4 weeks in the TC treatment period.

    Reporting group title
    Part F: VX-445/TEZ/VX-561 TC
    Reporting group description
    Subjects received VX-445/TEZ/VX-561 TC for 4 weeks in the TC treatment period.

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

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    End point title
    Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    The number of subjects analysed included only subjects who received at least one dose of study drug in the TC treatment period.
    End point type
    Primary
    End point timeframe
    From first dose of study drug in TC treatment period up to 28 days after last dose of study drug
    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 planned. No statistical comparisons were planned for primary safety endpoint.
    End point values
    Part D: Placebo Part D: VX-445/TEZ/IVA TC - Low Dose Part D: VX-445/TEZ/IVA TC - Medium Dose Part D: VX-445/TEZ/IVA TC - High Dose Part E: TEZ/IVA Part E: VX-445/TEZ/IVA TC Part F: Placebo Part F: VX-445/TEZ/VX-561 TC
    Number of subjects analysed
    12
    10
    22
    21
    7
    21
    8
    21
    Units: Subjects
        Subjects with AEs
    12
    10
    21
    18
    5
    19
    7
    19
        Subjects with SAEs
    2
    1
    2
    0
    1
    0
    1
    0
    No statistical analyses for this end point

    Primary: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

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    End point title
    Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [2]
    End point description
    The number of subjects analysed included all randomized subjects who carry the intended CFTR allele mutation and received at least 1 dose of study drug in the TC treatment period.
    End point type
    Primary
    End point timeframe
    From Baseline through Day 29
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The study was designed to perform within treatment group comparisons. Because only between treatment comparisons can be reported in the EudraCT database, no statistical analyses are reported.
    End point values
    Part D: Placebo Part D: VX-445/TEZ/IVA TC - Low Dose Part D: VX-445/TEZ/IVA TC - Medium Dose Part D: VX-445/TEZ/IVA TC - High Dose Part E: TEZ/IVA Part E: VX-445/TEZ/IVA TC Part F: Placebo Part F: VX-445/TEZ/VX-561 TC
    Number of subjects analysed
    11
    10
    22
    21
    6
    21
    8
    21
    Units: Percentage points
        least squares mean (standard error)
    0.0 ± 2.0
    11.1 ± 2.1
    7.9 ± 1.4
    13.8 ± 1.4
    0.4 ± 2.8
    11.0 ± 1.5
    1.2 ± 2.6
    11.7 ± 1.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug in TC treatment period up to 28 days after last dose of study drug
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Part D: Placebo
    Reporting group description
    Subjects received placebo matched to VX-445/TEZ/IVA TC for 4 weeks in the TC treatment period.

    Reporting group title
    Part D: VX-445/TEZ/IVA TC - Low Dose
    Reporting group description
    Subjects received VX-445/TEZ/IVA TC low dose for 4 weeks in the TC treatment period.

    Reporting group title
    Part D: VX-445/TEZ/IVA TC - Medium Dose
    Reporting group description
    Subjects received VX-445/TEZ/IVA TC medium dose for 4 weeks in the TC treatment period.

    Reporting group title
    Part D: VX-445/TEZ/IVA TC - High Dose
    Reporting group description
    Subjects received VX-445/TEZ/IVA TC high dose for 4 weeks in the TC treatment period.

    Reporting group title
    Part E: TEZ/IVA
    Reporting group description
    Following run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA and placebo matched to VX-445 for 4 weeks in the TC treatment period.

    Reporting group title
    Part E: VX-445/TEZ/IVA TC
    Reporting group description
    Following run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA TC for 4 weeks in the TC treatment period.

    Reporting group title
    Part F: Placebo
    Reporting group description
    Subjects received placebo matched to VX-445/TEZ/VX-561 TC for 4 weeks in the TC treatment period.

    Reporting group title
    Part F: VX-445/TEZ/VX-561 TC
    Reporting group description
    Subjects with CF received VX-445/TEZ/VX-561 TC for 4 weeks in the TC treatment period.

    Serious adverse events
    Part D: Placebo Part D: VX-445/TEZ/IVA TC - Low Dose Part D: VX-445/TEZ/IVA TC - Medium Dose Part D: VX-445/TEZ/IVA TC - High Dose Part E: TEZ/IVA Part E: VX-445/TEZ/IVA TC Part F: Placebo Part F: VX-445/TEZ/VX-561 TC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Investigations
    Influenza A virus test positive
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part D: Placebo Part D: VX-445/TEZ/IVA TC - Low Dose Part D: VX-445/TEZ/IVA TC - Medium Dose Part D: VX-445/TEZ/IVA TC - High Dose Part E: TEZ/IVA Part E: VX-445/TEZ/IVA TC Part F: Placebo Part F: VX-445/TEZ/VX-561 TC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    10 / 10 (100.00%)
    19 / 22 (86.36%)
    17 / 21 (80.95%)
    5 / 7 (71.43%)
    18 / 21 (85.71%)
    7 / 8 (87.50%)
    17 / 21 (80.95%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 12 (33.33%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    4 / 21 (19.05%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    4
    1
    0
    0
    0
    4
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    5 / 22 (22.73%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
    3 / 21 (14.29%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    5
    1
    1
    3
    0
    0
    Malaise
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    0
    1
    Pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    1
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    2
    Chills
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    3 / 21 (14.29%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    Chest discomfort
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Radiation injury
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    2 / 21 (9.52%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    2
    2
    0
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    4 / 21 (19.05%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    0
    1
    0
    4
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    3 / 21 (14.29%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    0
    1
    Forced expiratory volume decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 10 (40.00%)
    5 / 22 (22.73%)
    7 / 21 (33.33%)
    1 / 7 (14.29%)
    7 / 21 (33.33%)
    2 / 8 (25.00%)
    5 / 21 (23.81%)
         occurrences all number
    1
    4
    6
    9
    1
    8
    2
    5
    Sputum increased
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 10 (30.00%)
    4 / 22 (18.18%)
    5 / 21 (23.81%)
    0 / 7 (0.00%)
    8 / 21 (38.10%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
         occurrences all number
    3
    4
    4
    7
    0
    10
    1
    4
    Haemoptysis
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 10 (0.00%)
    5 / 22 (22.73%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    3 / 21 (14.29%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    3
    0
    9
    4
    0
    4
    3
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    2 / 22 (9.09%)
    2 / 21 (9.52%)
    1 / 7 (14.29%)
    1 / 21 (4.76%)
    2 / 8 (25.00%)
    5 / 21 (23.81%)
         occurrences all number
    2
    2
    2
    2
    1
    1
    2
    5
    Nasal congestion
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    2 / 22 (9.09%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
         occurrences all number
    3
    2
    2
    2
    0
    0
    1
    3
    Dyspnoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    1
    2
    0
    Sinus congestion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    1
    1
    1
    1
    0
    2
    Paranasal sinus hypersecretion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    2
    0
    0
    1
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    3
    Respiration abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    2 / 21 (9.52%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    2
    1
    0
    Sputum discoloured
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    2 / 21 (9.52%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    1
    1
    Paranasal sinus discomfort
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    3 / 22 (13.64%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    0
    0
    Lower respiratory tract congestion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Pleuritic pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Bronchiectasis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Pulmonary mass
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    2 / 22 (9.09%)
    2 / 21 (9.52%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    2
    2
    2
    3
    1
    0
    2
    1
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    3 / 22 (13.64%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    3
    0
    0
    0
    1
    1
    Nausea
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 10 (20.00%)
    3 / 22 (13.64%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
    1 / 21 (4.76%)
    3 / 8 (37.50%)
    2 / 21 (9.52%)
         occurrences all number
    3
    2
    3
    1
    1
    2
    6
    3
    Abdominal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    2 / 21 (9.52%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    3
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    2 / 8 (25.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 22 (4.55%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    1
    1
    0
    0
    1
    Abdominal discomfort
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Acne
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 10 (20.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    1
    Pruritus generalised
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    0
    0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 10 (20.00%)
    4 / 22 (18.18%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
    5 / 21 (23.81%)
    3 / 8 (37.50%)
    3 / 21 (14.29%)
         occurrences all number
    4
    2
    4
    2
    0
    6
    4
    3
    Nasopharyngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    4 / 21 (19.05%)
    1 / 7 (14.29%)
    1 / 21 (4.76%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    4
    1
    1
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    2
    Oral candidiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Catheter site infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2017
    - Revised study design to include Parts D and E
    28 Jun 2017
    - Updated eligibility criteria, revised data analysis plans, defined dose levels for parts D and E
    08 Aug 2017
    - Revised study design to include Part F

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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