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    Clinical Trial Results:
    A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in Subjects Aged 18 Years and Older With Cystic Fibrosis

    Summary
    EudraCT number
    		 2018-002496-18
    Trial protocol
    		 DE   GB   PT   NL  
    Global end of trial date
    10 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Apr 2023
    First version publication date
    14 Apr 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    VX18-121-101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03912233
    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, +1 617 341 6777, medicalinfo@vrtx.com
    Scientific contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617 341 6777, medicalinfo@vrtx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2019
    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-121 combination therapy in subjects with cystic fibrosis (CF).
    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
    30 Apr 2019
    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: 34
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Germany: 19
    Worldwide total number of subjects
    87
    EEA total number of subjects
    53
    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)
    87
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Three parts were planned for this study, only Parts 1 (subjects heterozygous for F508del and a minimal function mutation [F/MF genotypes]) and 2 (subjects homozygous for F508del [F/F genotypes]) were conducted. Part 3 was optional and not conducted at sponsor’s discretion.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: Placebo (matched to VX-121/TEZ/VX-561)
    Arm description
    		 Subjects received placebo matched to VX-121/TEZ/VX-561 triple combination (TC) for 4 weeks in the treatment period and placebo matched to TEZ/VX-561 for 18 days in the washout period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (matched to VX-121)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to VX-121 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 1: VX-121/TEZ/VX-561 TC - Low Dose
    Arm description
    		 Subjects received VX-121 5 milligram (mg) once daily (qd)/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-121
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-121 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
    CTP-656
    Other name
    Deuterated IVA (D-IVA)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-561 once daily.

    Arm title
    		 Part 1: VX-121/TEZ/VX-561 TC - Medium Dose
    Arm description
    		 Subjects received VX-121 10 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-121
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-121 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
    CTP-656
    Other name
    D-IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-561 once daily.

    Arm title
    		 Part 1: VX-121/TEZ/VX-561 TC - High Dose
    Arm description
    		 Subjects received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-121
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-121 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
    CTP-656
    Other name
    D-IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-561 once daily.

    Arm title
    		 Part 2: TEZ/IVA
    Arm description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) for 4 weeks, subjects received TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the treatment period and TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the washout period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ/IVA fixed dose combination 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-121/TEZ/VX-561 TC - High Dose
    Arm description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the washout period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-121
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-121 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
    CTP-656
    Other name
    D-IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-561 once daily.

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

    Number of subjects in period 1 [1]
    		Part 1: Placebo (matched to VX-121/TEZ/VX-561) Part 1: VX-121/TEZ/VX-561 TC - Low Dose Part 1: VX-121/TEZ/VX-561 TC - Medium Dose Part 1: VX-121/TEZ/VX-561 TC - High Dose Part 2: TEZ/IVA Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Started
    10
    9
    19
    20
    10
    18
    Completed
    8
    9
    19
    20
    3
    6
    Not completed
    2
    0
    0
    0
    7
    12
         Physician decision
    1
    -
    -
    -
    -
    -
         Adverse Event
    1
    -
    -
    -
    -
    -
         Other
    -
    -
    -
    -
    7
    12
    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: Out of 87 subjects enrolled in the study (58 subjects in Part 1 and 29 subjects in Part 2 run-in Period), 1 subject in Part 2 run-in period discontinued from study and was not randomized in the treatment period. Therefore, only 86 subjects are included in the above subject disposition table and baseline characteristics section for the treatment period.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Placebo (matched to VX-121/TEZ/VX-561)
    Reporting group description
    		 Subjects received placebo matched to VX-121/TEZ/VX-561 triple combination (TC) for 4 weeks in the treatment period and placebo matched to TEZ/VX-561 for 18 days in the washout period.

    Reporting group title
    Part 1: VX-121/TEZ/VX-561 TC - Low Dose
    Reporting group description
    		 Subjects received VX-121 5 milligram (mg) once daily (qd)/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.

    Reporting group title
    Part 1: VX-121/TEZ/VX-561 TC - Medium Dose
    Reporting group description
    		 Subjects received VX-121 10 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.

    Reporting group title
    Part 1: VX-121/TEZ/VX-561 TC - High Dose
    Reporting group description
    		 Subjects received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.

    Reporting group title
    Part 2: TEZ/IVA
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) for 4 weeks, subjects received TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the treatment period and TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the washout period.

    Reporting group title
    Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the washout period.

    Reporting group values
    		 Part 1: Placebo (matched to VX-121/TEZ/VX-561) Part 1: VX-121/TEZ/VX-561 TC - Low Dose Part 1: VX-121/TEZ/VX-561 TC - Medium Dose Part 1: VX-121/TEZ/VX-561 TC - High Dose Part 2: TEZ/IVA Part 2: VX-121/TEZ/VX-561 TC - High Dose Total
    Number of subjects
    		 10 9 19 20 10 18 86
    Age categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0 0 0 0
        Between 18 and 65 years
    		 10 9 19 20 10 18 86
        >=65 years
    		 0 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 4 3 9 2 7 27
        Male
    		 8 5 16 11 8 11 59
    Ethnicity (NIH/ OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 2 1 0 3
        Not Hispanic or Latino
    		 10 8 19 17 8 18 80
        Unknown or Not Reported
    		 0 1 0 1 1 0 3
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0
        Black or African American
    		 0 0 1 0 0 0 1
        White
    		 9 8 18 17 9 18 79
        More than one race
    		 1 0 0 0 0 0 1
        Unknown or Not Reported
    		 0 1 0 3 1 0 5
    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
    		 1 1 1 0 1 2 6
        >=40 to <70 percent
    		 9 6 14 17 6 11 63
        >=70 to <=90 percent
    		 0 2 4 3 3 5 17

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Placebo (matched to VX-121/TEZ/VX-561)
    Reporting group description
    		 Subjects received placebo matched to VX-121/TEZ/VX-561 triple combination (TC) for 4 weeks in the treatment period and placebo matched to TEZ/VX-561 for 18 days in the washout period.

    Reporting group title
    Part 1: VX-121/TEZ/VX-561 TC - Low Dose
    Reporting group description
    		 Subjects received VX-121 5 milligram (mg) once daily (qd)/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.

    Reporting group title
    Part 1: VX-121/TEZ/VX-561 TC - Medium Dose
    Reporting group description
    		 Subjects received VX-121 10 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.

    Reporting group title
    Part 1: VX-121/TEZ/VX-561 TC - High Dose
    Reporting group description
    		 Subjects received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.

    Reporting group title
    Part 2: TEZ/IVA
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) for 4 weeks, subjects received TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the treatment period and TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the washout period.

    Reporting group title
    Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, subjects received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the washout period.

    Subject analysis set title
    Part 1: VX-121/TEZ/VX-561 TC - Combined
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who either received VX-121 5 mg, 10 mg or 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.

    Subject analysis set title
    Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, participants received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the washout period.

    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 the treatment period.
    End point type
    Primary
    End point timeframe
    From Day 1 Through Safety Follow-up (up to Day 75 for Part 1 and up to Day 85 for Part 2)
    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 analyses were planned for the primary safety end point. No statistical comparisons were planned.
    End point values
    		 Part 1: Placebo (matched to VX-121/TEZ/VX-561) Part 1: VX-121/TEZ/VX-561 TC - Low Dose Part 1: VX-121/TEZ/VX-561 TC - Medium Dose Part 1: VX-121/TEZ/VX-561 TC - High Dose Part 2: TEZ/IVA Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Number of subjects analysed
    10
    9
    19
    20
    10
    18
    Units: Subjects
        Subjects with TEAEs
    9
    8
    16
    20
    8
    16
        Subjects with SAEs
    2
    1
    1
    0
    0
    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
    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 who carry the intended cystic fibrosis transmembrane conductance regulator gene (CFTR) allele mutation(s) and received at least 1 dose of study drug in the 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: Only within treatment group comparisons were planned for this endpoint. Therefore, no between groups comparisons are reported.
    End point values
    		 Part 1: Placebo (matched to VX-121/TEZ/VX-561) Part 1: VX-121/TEZ/VX-561 TC - Low Dose Part 1: VX-121/TEZ/VX-561 TC - Medium Dose Part 1: VX-121/TEZ/VX-561 TC - High Dose Part 2: TEZ/IVA Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Number of subjects analysed
    10
    9
    19
    20
    10
    18
    Units: percentage points
        least squares mean (confidence interval 95%)
    1.9 (-4.1 to 8.0)
    4.6 (-1.3 to 10.6)
    14.2 (10.0 to 18.4)
    9.8 (5.7 to 13.8)
    -0.1 (-6.4 to 6.1)
    15.9 (11.3 to 20.6)
    No statistical analyses for this end point

    Secondary: Absolute Change in Sweat Chloride (SwCl) Concentrations

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    End point title
    		 Absolute Change in Sweat Chloride (SwCl) 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 (matched to VX-121/TEZ/VX-561) Part 1: VX-121/TEZ/VX-561 TC - Low Dose Part 1: VX-121/TEZ/VX-561 TC - Medium Dose Part 1: VX-121/TEZ/VX-561 TC - High Dose Part 2: TEZ/IVA Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Number of subjects analysed
    10
    9
    19
    20
    10
    18
    Units: millimole per liter (mmol/L)
        least squares mean (confidence interval 95%)
    2.3 (-7.0 to 11.6)
    -42.8 (-51.7 to -34.0)
    -45.8 (-51.9 to -39.7)
    -49.5 (-55.9 to -43.1)
    -2.6 (-8.2 to 3.1)
    -45.5 (-49.7 to -41.3)
    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 (matched to VX-121/TEZ/VX-561) Part 1: VX-121/TEZ/VX-561 TC - Low Dose Part 1: VX-121/TEZ/VX-561 TC - Medium Dose Part 1: VX-121/TEZ/VX-561 TC - High Dose Part 2: TEZ/IVA Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Number of subjects analysed
    10
    9
    19
    20
    10
    18
    Units: units on a scale
        least squares mean (confidence interval 95%)
    3.3 (-10.1 to 16.6)
    17.6 (3.5 to 31.6)
    21.2 (11.9 to 30.6)
    29.8 (21.0 to 38.7)
    -5.0 (-16.9 to 7.0)
    19.4 (10.5 to 28.3)
    No statistical analyses for this end point

    Secondary: Observed Pre-dose Plasma Concentration (Ctrough) of VX-121, TEZ and Its Metabolite (M1-TEZ) and, VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561)

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    End point title
    		 Observed Pre-dose Plasma Concentration (Ctrough) of VX-121, TEZ and Its Metabolite (M1-TEZ) and, VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561)
    End point description
    Pharmacokinetic (PK) set included all subjects who received at least 1 dose study drug in the treatment period and for whom the PK data are considered sufficient and interpretable. Subjects who received VX-121/TEZ/VX-561 TC in Parts 1 or 2 were to be analyzed for Ctrough. Overall subjects in Part 1 were assessed for Ctrough, therefore data are reported in single Part 1: TC combined arm. The "n" signifies subjects who were evaluable at specified time point for respective reporting arm. Here, "99999" represents "not applicable" category for respective Ctrough assessment.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Day 15 and Day 29
    End point values
    		 Part 1: VX-121/TEZ/VX-561 TC - Combined Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Number of subjects analysed
    48
    18
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 15: VX-121 5 mg (n=8, 0)
    317 ± 119
    99999 ± 99999
        Day 29: VX-121 5 mg (n=7, 0)
    366 ± 130
    99999 ± 99999
        Day 15: VX-121 10 mg (n=18, 0)
    520 ± 214
    99999 ± 99999
        Day 29: VX-121 10 mg (n=14, 0)
    582 ± 342
    99999 ± 99999
        Day 15: VX-121 20 mg (n=20, 17)
    974 ± 500
    1050 ± 414
        Day 29: VX-121 20 mg (n=18, 16)
    1160 ± 592
    1030 ± 371
        Day 15: TEZ (n=46, 17)
    1890 ± 925
    1870 ± 675
        Day 29: TEZ (n=46, 16)
    1920 ± 994
    2070 ± 1340
        Day 15: M1-TEZ (n=46, 17)
    4500 ± 1290
    4550 ± 1200
        Day 29: M1-TEZ (n=46, 16)
    4640 ± 1730
    4440 ± 1680
        Day 15: VX-561 (n=46, 17)
    475 ± 247
    457 ± 264
        Day 29: VX-561 (n=46, 16)
    510 ± 285
    434 ± 257
        Day 15: M1-VX-561 (n=46, 17)
    311 ± 141
    326 ± 175
        Day 29: M1-VX-561 (n=46, 16)
    336 ± 173
    316 ± 188
        Day 15: M6-VX-561 (n=46, 17)
    148 ± 98.0
    174 ± 128
        Day 29: M6-VX-561 (n=46, 16)
    163 ± 128
    159 ± 94.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 Through Safety Follow-up (up to Day 75 for Part 1 and up to Day 85 for Part 2)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Part 1: Placebo (matched to VX-121/TEZ/VX-561)
    Reporting group description
    		 Subjects received placebo matched to VX-121/TEZ/VX-561 TC for 4 weeks in the treatment period and placebo matched to TEZ/VX-561 for 18 days in the washout period.

    Reporting group title
    Part 1: VX-121/TEZ/VX-561 TC - Low Dose
    Reporting group description
    		 Subjects received VX-121 5 qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.

    Reporting group title
    Part 1: VX-121/TEZ/VX-561 TC - Medium Dose
    Reporting group description
    		 Subjects received VX-121 10 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.

    Reporting group title
    Part 1: VX-121/TEZ/VX-561 TC - High Dose
    Reporting group description
    		 Subjects received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/VX-561 150 mg qd for 18 days in the washout period.

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

    Reporting group title
    Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Reporting group description
    		 Following run-in period with TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks, participants received VX-121 20 mg qd/TEZ 100 mg qd/VX-561 150 mg qd TC for 4 weeks in the treatment period and TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the washout period.

    Serious adverse events
    		 Part 1: Placebo (matched to VX-121/TEZ/VX-561) Part 1: VX-121/TEZ/VX-561 TC - Low Dose Part 1: VX-121/TEZ/VX-561 TC - Medium Dose Part 1: VX-121/TEZ/VX-561 TC - High Dose Part 2: TEZ/IVA Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: Placebo (matched to VX-121/TEZ/VX-561) Part 1: VX-121/TEZ/VX-561 TC - Low Dose Part 1: VX-121/TEZ/VX-561 TC - Medium Dose Part 1: VX-121/TEZ/VX-561 TC - High Dose Part 2: TEZ/IVA Part 2: VX-121/TEZ/VX-561 TC - High Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 10 (90.00%)
    8 / 9 (88.89%)
    16 / 19 (84.21%)
    20 / 20 (100.00%)
    8 / 10 (80.00%)
    16 / 18 (88.89%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    3 / 10 (30.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 9 (22.22%)
    5 / 19 (26.32%)
    2 / 20 (10.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    5
    2
    3
    0
    Feeling abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Malaise
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    1
    2
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 10 (50.00%)
    4 / 9 (44.44%)
    5 / 19 (26.32%)
    9 / 20 (45.00%)
    7 / 10 (70.00%)
    5 / 18 (27.78%)
         occurrences all number
    7
    4
    5
    13
    9
    6
    Dysphonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    2 / 19 (10.53%)
    3 / 20 (15.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    2
    3
    3
    0
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Haemoptysis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    0
    2
    1
    0
    Lower respiratory tract congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    3 / 20 (15.00%)
    2 / 10 (20.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    3
    2
    1
    Nasal obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 9 (22.22%)
    3 / 19 (15.79%)
    2 / 20 (10.00%)
    0 / 10 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    2
    3
    2
    0
    3
    Painful respiration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Paranasal sinus hypersecretion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pleuritic pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Productive cough
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 9 (0.00%)
    2 / 19 (10.53%)
    3 / 20 (15.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    4
    3
    0
    0
    Rales
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Respiration abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    1
    3
    2
    0
    Sneezing
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Sputum increased
         subjects affected / exposed
    3 / 10 (30.00%)
    6 / 9 (66.67%)
    3 / 19 (15.79%)
    4 / 20 (20.00%)
    3 / 10 (30.00%)
    5 / 18 (27.78%)
         occurrences all number
    5
    8
    3
    7
    3
    5
    Throat clearing
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Mood swings
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Panic attack
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Somnambulism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    3 / 19 (15.79%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    1
    4
    1
    0
    2
    Blood glucose increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood potassium increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood sodium decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Crystal urine present
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Glucose urine present
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Contusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    2
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 9 (22.22%)
    4 / 19 (21.05%)
    6 / 20 (30.00%)
    1 / 10 (10.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    3
    5
    9
    1
    2
    Paraesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Eye disorders
    Swelling of eyelid
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    2
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    1
    3
    0
    0
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    4 / 19 (21.05%)
    5 / 20 (25.00%)
    1 / 10 (10.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    6
    6
    1
    2
    Dyspepsia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Post-tussive vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Salivary hypersecretion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Exfoliative rash
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Night sweats
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    1
    1
    0
    1
    0
    3
    Rash pruritic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    Neck pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tendon pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Infections and infestations
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    4 / 10 (40.00%)
    3 / 9 (33.33%)
    0 / 19 (0.00%)
    3 / 20 (15.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    5
    3
    0
    4
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 9 (22.22%)
    2 / 19 (10.53%)
    2 / 20 (10.00%)
    2 / 10 (20.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    2
    2
    3
    2
    Oral candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Sinusitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    Viral rash
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    3 / 19 (15.79%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    2 / 19 (10.53%)
    1 / 20 (5.00%)
    2 / 10 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    1
    2
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    Polydipsia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    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
    12 Nov 2018
    Amended to include study drug doses and dosing regimen.
    04 Mar 2019
    Amended to include clarification on PK sampling and study conduct.
    09 May 2019
    Amended to update acceptable methods of contraception.

    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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    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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