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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-659 Combination Therapy in Subjects Aged 18 Years and Older With Cystic Fibrosis

    Summary
    EudraCT number
    		 2016-003585-11
    Trial protocol
    		 IE   GB  
    Global end of trial date
    28 Feb 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Jul 2021
    First version publication date
    16 Mar 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Secondary endpoints results need to be added

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    VX16-659-101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03224351
    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
    28 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 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-659 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 Council on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Aug 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 Kingdom: 29
    Country: Number of subjects enrolled
    Ireland: 11
    Country: Number of subjects enrolled
    United States: 77
    Country: Number of subjects enrolled
    Israel: 7
    Worldwide total number of subjects
    124
    EEA total number of subjects
    40
    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)
    124
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study included 3 parts and was 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 1: Placebo
    Arm description
    		 Subjects received placebo matched to VX-659/TEZ/IVA in TC treatment period for 4 weeks and placebo matched to TEZ/IVA in washout period for 4 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (matched to VX-659)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-659 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 1: VX-659/TEZ/IVA TC - Low Dose
    Arm description
    		 Subjects received VX-659 80 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-659
    Investigational medicinal product code
    VX-659
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-659 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 1: VX-659/TEZ/IVA TC - Medium Dose
    Arm description
    		 Subjects received VX-659 240 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-659
    Investigational medicinal product code
    VX-659
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-659 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 1: VX-659/TEZ/IVA TC - High Dose
    Arm description
    		 Subjects received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-659
    Investigational medicinal product code
    VX-659
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-659 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 2: TEZ/IVA
    Arm description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo (matched to VX-659)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-659 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 2: VX-659/TEZ/IVA TC
    Arm description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-659
    Investigational medicinal product code
    VX-659
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-659 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 3: Placebo
    Arm description
    		 Subjects received placebo matched to VX-659/TEZ/VX-561 in TC treatment period for 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (matched to VX-659)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-659 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 3: VX-659/TEZ/VX-561 TC
    Arm description
    		 Subjects received VX-659 400 mg qd/TEZ 100 mg qd/VX-561 200 mg qd in TC treatment period for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-659
    Investigational medicinal product code
    VX-659
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-659 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 1: Placebo Part 1: VX-659/TEZ/IVA TC - Low Dose Part 1: VX-659/TEZ/IVA TC - Medium Dose Part 1: VX-659/TEZ/IVA TC - High Dose Part 2: TEZ/IVA Part 2: VX-659/TEZ/IVA TC Part 3: Placebo Part 3: VX-659/TEZ/VX-561 TC
    Started
    10
    11
    20
    22
    11
    18
    6
    19
    Completed
    10
    11
    20
    22
    11
    18
    6
    19
    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: There were 117 subjects dosed in the TC treatment period for all 3 parts. 7 subjects were dosed in the run-in period in part 2 but were not dosed in TC treatment period. Therefore, the total enrolled subjects are 124 where as the subjects reported in disposition and baseline are 117.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 Subjects received placebo matched to VX-659/TEZ/IVA in TC treatment period for 4 weeks and placebo matched to TEZ/IVA in washout period for 4 days.

    Reporting group title
    Part 1: VX-659/TEZ/IVA TC - Low Dose
    Reporting group description
    		 Subjects received VX-659 80 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.

    Reporting group title
    Part 1: VX-659/TEZ/IVA TC - Medium Dose
    Reporting group description
    		 Subjects received VX-659 240 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.

    Reporting group title
    Part 1: VX-659/TEZ/IVA TC - High Dose
    Reporting group description
    		 Subjects received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.

    Reporting group title
    Part 2: TEZ/IVA
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks.

    Reporting group title
    Part 2: VX-659/TEZ/IVA TC
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks.

    Reporting group title
    Part 3: Placebo
    Reporting group description
    		 Subjects received placebo matched to VX-659/TEZ/VX-561 in TC treatment period for 4 weeks.

    Reporting group title
    Part 3: VX-659/TEZ/VX-561 TC
    Reporting group description
    		 Subjects received VX-659 400 mg qd/TEZ 100 mg qd/VX-561 200 mg qd in TC treatment period for 4 weeks.

    Reporting group values
    		 Part 1: Placebo Part 1: VX-659/TEZ/IVA TC - Low Dose Part 1: VX-659/TEZ/IVA TC - Medium Dose Part 1: VX-659/TEZ/IVA TC - High Dose Part 2: TEZ/IVA Part 2: VX-659/TEZ/IVA TC Part 3: Placebo Part 3: VX-659/TEZ/VX-561 TC Total
    Number of subjects
    		 10 11 20 22 11 18 6 19 117
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 26.6 ( 6.0 ) 32.0 ( 11.7 ) 31.4 ( 9.7 ) 27.2 ( 6.6 ) 32.5 ( 7.5 ) 33.4 ( 9.2 ) 24.5 ( 5.3 ) 32.5 ( 9.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 7 7 12 4 6 3 11 54
        Male
    		 6 4 13 10 7 12 3 8 63
    Ethnicity (NIH/ OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 2 0 1 1 1 1 6
        Not Hispanic or Latino
    		 10 11 18 22 10 17 5 18 111
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 1 0 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0 0 2 2
        White
    		 10 11 20 22 11 16 6 17 113
        More than one race
    		 0 0 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 1 0 0 1
    Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
    Units: Subjects
        <40 percent
    		 2 0 1 2 0 1 0 2 8
        >=40 to <70 percent
    		 6 9 13 13 8 12 5 13 79
        >=70 to <=90 percent
    		 2 2 6 7 3 5 1 4 30
        >90 percent
    		 0 0 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 Subjects received placebo matched to VX-659/TEZ/IVA in TC treatment period for 4 weeks and placebo matched to TEZ/IVA in washout period for 4 days.

    Reporting group title
    Part 1: VX-659/TEZ/IVA TC - Low Dose
    Reporting group description
    		 Subjects received VX-659 80 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.

    Reporting group title
    Part 1: VX-659/TEZ/IVA TC - Medium Dose
    Reporting group description
    		 Subjects received VX-659 240 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.

    Reporting group title
    Part 1: VX-659/TEZ/IVA TC - High Dose
    Reporting group description
    		 Subjects received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.

    Reporting group title
    Part 2: TEZ/IVA
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks.

    Reporting group title
    Part 2: VX-659/TEZ/IVA TC
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks.

    Reporting group title
    Part 3: Placebo
    Reporting group description
    		 Subjects received placebo matched to VX-659/TEZ/VX-561 in TC treatment period for 4 weeks.

    Reporting group title
    Part 3: VX-659/TEZ/VX-561 TC
    Reporting group description
    		 Subjects received VX-659 400 mg qd/TEZ 100 mg qd/VX-561 200 mg qd in TC treatment period for 4 weeks.

    Primary: Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [1]
    End point description
    Safety Set included all subjects who received at least 1 dose of study drug in TC treatment period.
    End point type
    Primary
    End point timeframe
    Day 1 Through Safety Follow-up (up to Day 61 for Part 1, Day 85 for Part 2 and Day 57 for Part 3)
    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 1: Placebo Part 1: VX-659/TEZ/IVA TC - Low Dose Part 1: VX-659/TEZ/IVA TC - Medium Dose Part 1: VX-659/TEZ/IVA TC - High Dose Part 2: TEZ/IVA Part 2: VX-659/TEZ/IVA TC Part 3: Placebo Part 3: VX-659/TEZ/VX-561 TC
    Number of subjects analysed
    10
    11
    20
    22
    11
    18
    6
    19
    Units: subjects
        Subjects with TEAEs
    9
    10
    15
    17
    9
    15
    6
    18
        Subjects with SAEs
    3
    1
    4
    1
    2
    1
    3
    2
    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
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Full Analysis Set (FAS) included all randomized subjects with an eligible cystic fibrosis transmembrane conductance regulator protein (CFTR) genotype and received at least 1 dose of study drug.
    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 is not designed to perform between treatment group comparisons.
    End point values
    		 Part 1: Placebo Part 1: VX-659/TEZ/IVA TC - Low Dose Part 1: VX-659/TEZ/IVA TC - Medium Dose Part 1: VX-659/TEZ/IVA TC - High Dose Part 2: TEZ/IVA Part 2: VX-659/TEZ/IVA TC Part 3: Placebo Part 3: VX-659/TEZ/VX-561 TC
    Number of subjects analysed
    10
    11
    20
    22
    11
    18
    6
    19
    Units: percentage points
        least squares mean (confidence interval 95%)
    0.4 (-5.3 to 6.1)
    10.2 (4.8 to 15.5)
    12.0 (8.0 to 16.0)
    13.3 (9.5 to 17.1)
    0.0 (-3.9 to 3.9)
    9.7 (6.6 to 12.7)
    -5.0 (-12.2 to 2.1)
    12.2 (8.3 to 16.2)
    No statistical analyses for this end point

    Secondary: Absolute Change in Sweat Chloride Concentrations

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    End point title
    		 Absolute Change in Sweat Chloride Concentrations
    End point description
    Sweat samples were collected using an approved collection device. FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline Through Day 29
    End point values
    		 Part 1: Placebo Part 1: VX-659/TEZ/IVA TC - Low Dose Part 1: VX-659/TEZ/IVA TC - Medium Dose Part 1: VX-659/TEZ/IVA TC - High Dose Part 2: TEZ/IVA Part 2: VX-659/TEZ/IVA TC Part 3: Placebo Part 3: VX-659/TEZ/VX-561 TC
    Number of subjects analysed
    10
    11
    20
    22
    11
    18
    6
    19
    Units: millimole per liter (mmol/L)
        least squares mean (confidence interval 95%)
    2.9 (-6.3 to 12.2)
    -45.7 (-54.4 to -37.0)
    -43.8 (-50.7 to -37.0)
    -51.4 (-57.8 to -44.9)
    3.0 (-2.8 to 8.9)
    -42.2 (-46.8 to -37.7)
    -1.3 (-12.4 to 9.8)
    -38.1 (-44.4 to -31.8)
    No statistical analyses for this end point

    Secondary: Relative Change in ppFEV1

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    End point title
    		 Relative Change in ppFEV1
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline Through Day 29
    End point values
    		 Part 1: Placebo Part 1: VX-659/TEZ/IVA TC - Low Dose Part 1: VX-659/TEZ/IVA TC - Medium Dose Part 1: VX-659/TEZ/IVA TC - High Dose Part 2: TEZ/IVA Part 2: VX-659/TEZ/IVA TC Part 3: Placebo Part 3: VX-659/TEZ/VX-561 TC
    Number of subjects analysed
    10
    11
    20
    22
    11
    18
    6
    19
    Units: percent change
        least squares mean (confidence interval 95%)
    0.0 (-10.5 to 10.4)
    18.8 (8.9 to 28.7)
    21.1 (13.8 to 28.5)
    24.6 (17.6 to 31.6)
    0.1 (-7.1 to 7.3)
    17.3 (11.7 to 23.0)
    -11.3 (-23.7 to 1.1)
    21.5 (14.6 to 28.4)
    No statistical analyses for this end point

    Secondary: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score

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    End point title
    		 Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score
    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, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline at Day 29
    End point values
    		 Part 1: Placebo Part 1: VX-659/TEZ/IVA TC - Low Dose Part 1: VX-659/TEZ/IVA TC - Medium Dose Part 1: VX-659/TEZ/IVA TC - High Dose Part 2: TEZ/IVA Part 2: VX-659/TEZ/IVA TC Part 3: Placebo Part 3: VX-659/TEZ/VX-561 TC
    Number of subjects analysed
    10
    11
    20
    22
    11
    18
    6
    19
    Units: units on a scale
        least squares mean (confidence interval 95%)
    4.7 (-7.5 to 16.8)
    24.6 (13.0 to 36.2)
    19.8 (11.0 to 28.6)
    21.8 (13.6 to 30.0)
    2.9 (-5.2 to 11.1)
    19.5 (13.1 to 25.9)
    -4.1 (-17.8 to 9.6)
    14.7 (7.1 to 22.4)
    No statistical analyses for this end point

    Secondary: Observed Pre-dose Concentration (Ctrough) of VX-659, TEZ, M1-TEZ, IVA, M1-IVA, and VX-561

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    End point title
    		 Observed Pre-dose Concentration (Ctrough) of VX-659, TEZ, M1-TEZ, IVA, M1-IVA, and VX-561 [3]
    End point description
    Pharmacokinetic Set (PK) included all subjects who have received at least 1 dose of study drug in TC treatment period. Here "n" signifies those subjects who were evaluable at specified time points and "99999" represents "not applicable" for particular category for Ctrough assessments. VX-659 category was not applicable for Part 2: TEZ/IVA group. VX-561 category was applicable for Part 3: TC group only. IVA and M1-IVA categories were not applicable for Part 3: TC group.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Day 15 and Day 29
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts 1 and 3: Placebo arms were not applicable for this endpoint.
    End point values
    		 Part 1: VX-659/TEZ/IVA TC - Low Dose Part 1: VX-659/TEZ/IVA TC - Medium Dose Part 1: VX-659/TEZ/IVA TC - High Dose Part 2: TEZ/IVA Part 2: VX-659/TEZ/IVA TC Part 3: VX-659/TEZ/VX-561 TC
    Number of subjects analysed
    11
    20
    22
    11
    18
    19
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        VX-659: Day 15 (n=10, 16, 19, 0, 17, 17)
    393 ( 604 )
    622 ( 429 )
    1100 ( 731 )
    99999 ( 99999 )
    835 ( 474 )
    1140 ( 646 )
        VX-659: Day 29 (n=11, 19, 22, 0, 18, 19)
    566 ( 861 )
    699 ( 489 )
    1080 ( 582 )
    99999 ( 99999 )
    1070 ( 914 )
    923 ( 582 )
        TEZ: Day 15 (n=10, 16, 19, 7, 17, 17)
    1910 ( 1360 )
    1250 ( 907 )
    1110 ( 455 )
    1050 ( 473 )
    1350 ( 1440 )
    1000 ( 305 )
        TEZ: Day 29 (n=11, 19, 22, 11, 18, 19)
    1910 ( 1230 )
    1050 ( 553 )
    1010 ( 479 )
    1150 ( 480 )
    955 ( 422 )
    776 ( 321 )
        M1-TEZ: Day 15 (n=10, 16, 19, 7, 17, 19)
    4390 ( 949 )
    3710 ( 1230 )
    4280 ( 1190 )
    4160 ( 1260 )
    4010 ( 1210 )
    4060 ( 660 )
        M1-TEZ: Day 29 (n=11, 19, 22, 11, 18, 19)
    4300 ( 774 )
    3650 ( 1280 )
    3870 ( 1020 )
    3790 ( 1080 )
    3810 ( 1120 )
    3660 ( 1190 )
        IVA: Day 15 (n=10, 16, 19, 7, 17, 0)
    824 ( 781 )
    522 ( 567 )
    423 ( 261 )
    458 ( 239 )
    313 ( 158 )
    99999 ( 99999 )
        IVA: Day 29 (n=11, 19, 22, 11, 18, 0)
    719 ( 604 )
    443 ( 398 )
    371 ( 220 )
    490 ( 179 )
    296 ( 175 )
    99999 ( 99999 )
        M1-IVA: Day 15 (n=10, 16, 19, 7, 17, 0)
    1200 ( 711 )
    1050 ( 852 )
    1170 ( 674 )
    1310 ( 684 )
    844 ( 622 )
    99999 ( 99999 )
        M1-IVA Day 29 (n=11, 19, 22, 11, 18, 0)
    1130 ( 682 )
    1140 ( 950 )
    1030 ( 460 )
    1240 ( 321 )
    866 ( 691 )
    99999 ( 99999 )
        VX-561: Day 15 (n=0, 0, 0, 0, 0, 17)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    380 ( 240 )
        VX-561: Day 15 (n=0, 0, 0, 0, 0, 19)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    288 ( 165 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 Through Safety Follow-up (up to Day 61 for Part 1, Day 85 for Part 2 and Day 57 for Part 3)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 Subjects received placebo matched to VX-659/TEZ/IVA in TC treatment period for 4 weeks and placebo matched to TEZ/IVA in washout period for 4 days.

    Reporting group title
    Part 1: VX-659/TEZ/IVA TC - Low Dose
    Reporting group description
    		 Subjects received VX-659 80 mg qd/TEZ 100 mg qd/IVA 150 mg every 12 q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.

    Reporting group title
    Part 1: VX-659/TEZ/IVA TC - Medium Dose
    Reporting group description
    		 Subjects received VX-659 240 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.

    Reporting group title
    Part 1: VX-659/TEZ/IVA TC - High Dose
    Reporting group description
    		 Subjects received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 days.

    Reporting group title
    Part 2: TEZ/IVA
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks.

    Reporting group title
    Part 2: VX-659/TEZ/IVA TC
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received VX-659 400 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in TC treatment period for 4 weeks and TEZ 100 mg qd/IVA 150 mg q12h in washout period for 4 weeks.

    Reporting group title
    Part 3: Placebo
    Reporting group description
    		 Subjects received placebo matched to VX-659/TEZ/VX-561 in TC treatment period for 4 weeks.

    Reporting group title
    Part 3: VX-659/TEZ/VX-561 TC
    Reporting group description
    		 Subjects received VX-659 400 mg qd/TEZ 100 mg qd/VX-561 200 mg qd in TC treatment period for 4 weeks.

    Serious adverse events
    		 Part 1: Placebo Part 1: VX-659/TEZ/IVA TC - Low Dose Part 1: VX-659/TEZ/IVA TC - Medium Dose Part 1: VX-659/TEZ/IVA TC - High Dose Part 2: TEZ/IVA Part 2: VX-659/TEZ/IVA TC Part 3: Placebo Part 3: VX-659/TEZ/VX-561 TC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 11 (9.09%)
    4 / 20 (20.00%)
    1 / 22 (4.55%)
    2 / 11 (18.18%)
    1 / 18 (5.56%)
    3 / 6 (50.00%)
    2 / 19 (10.53%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 11 (9.09%)
    2 / 20 (10.00%)
    1 / 22 (4.55%)
    2 / 11 (18.18%)
    1 / 18 (5.56%)
    3 / 6 (50.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 1
    0 / 2
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (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 tract infection viral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (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
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: Placebo Part 1: VX-659/TEZ/IVA TC - Low Dose Part 1: VX-659/TEZ/IVA TC - Medium Dose Part 1: VX-659/TEZ/IVA TC - High Dose Part 2: TEZ/IVA Part 2: VX-659/TEZ/IVA TC Part 3: Placebo Part 3: VX-659/TEZ/VX-561 TC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    10 / 11 (90.91%)
    15 / 20 (75.00%)
    17 / 22 (77.27%)
    8 / 11 (72.73%)
    15 / 18 (83.33%)
    5 / 6 (83.33%)
    18 / 19 (94.74%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 11 (9.09%)
    1 / 20 (5.00%)
    1 / 22 (4.55%)
    1 / 11 (9.09%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    1
    1
    1
    1
    1
    2
    0
    3
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 11 (18.18%)
    2 / 20 (10.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    2
    0
    1
    0
    1
    0
    Pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    2
    Application site rash
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Asthenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Vaginal discharge
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 11 (27.27%)
    6 / 20 (30.00%)
    4 / 22 (18.18%)
    2 / 11 (18.18%)
    4 / 18 (22.22%)
    2 / 6 (33.33%)
    4 / 19 (21.05%)
         occurrences all number
    1
    3
    6
    5
    2
    4
    2
    5
    Sputum increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 11 (18.18%)
    1 / 20 (5.00%)
    3 / 22 (13.64%)
    1 / 11 (9.09%)
    3 / 18 (16.67%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    1
    4
    2
    3
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    3 / 20 (15.00%)
    4 / 22 (18.18%)
    0 / 11 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    3
    4
    0
    2
    0
    2
    Haemoptysis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 11 (18.18%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    1
    0
    1
    1
    1
    0
    Respiration abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    1 / 20 (5.00%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    1
    3
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    4 / 18 (22.22%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    4
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    2 / 22 (9.09%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    2
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 11 (9.09%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    1
    0
    1
    0
    0
    0
    Lower respiratory tract congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 11 (18.18%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    1
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    3 / 20 (15.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    Paranasal sinus discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Rales
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    2 / 6 (33.33%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Sinus pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Sputum discoloured
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Bronchospasm
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Nasal discharge discolouration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Throat tightness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    1 / 20 (5.00%)
    3 / 22 (13.64%)
    2 / 11 (18.18%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    1
    3
    3
    1
    0
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    1
    1
    0
    Bacterial test positive
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    0
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    1
    Weight increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    0
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Blood glucose decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Blood chloride decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Blood creatinine decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Blood glucose fluctuation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Body temperature increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Coronavirus test positive
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Crystal urine present
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Glucose urine present
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Monocyte count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Red blood cells urine positive
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Urinary sediment present
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Wound
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    4 / 20 (20.00%)
    4 / 22 (18.18%)
    0 / 11 (0.00%)
    3 / 18 (16.67%)
    1 / 6 (16.67%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    4
    4
    0
    3
    1
    1
    Dizziness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Lethargy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Migraine
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Sinus headache
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    2
    Ear congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Motion sickness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    3 / 22 (13.64%)
    2 / 11 (18.18%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    3
    2
    2
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    2 / 11 (18.18%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    2
    2
    0
    2
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    3
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Faeces discoloured
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Food poisoning
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Pancreatic failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Parotid gland enlargement
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    2
    Acne
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Skin disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 11 (18.18%)
    1 / 20 (5.00%)
    3 / 22 (13.64%)
    1 / 11 (9.09%)
    4 / 18 (22.22%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    2
    1
    3
    1
    4
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 11 (18.18%)
    1 / 20 (5.00%)
    3 / 22 (13.64%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    2
    2
    3
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    2 / 22 (9.09%)
    0 / 11 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    2
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    1
    Influenza
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Cellulitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Chronic sinusitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 11 (9.09%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Genital infection fungal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Abnormal loss of weight
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Increased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 11 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jun 2017
    Added study drug doses, revised elements of the study design including treatment arms, sample size, and study duration, and revised inclusion/exclusion criteria.
    01 Sep 2017
    Added Part 3 to evaluate VX-659 in triple combination with TEZ/VX-561.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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