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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-659 Combination Therapy in Subjects With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)

    Summary
    EudraCT number
    2017-004132-11
    Trial protocol
    GB   DE   DK   IE   ES   PL  
    Global end of trial date
    05 Feb 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    05 Jun 2020
    First version publication date
    20 Nov 2019
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Updating secondary endpoints

    Trial information

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    Trial identification
    Sponsor protocol code
    VX17-659-102
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03447249
    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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002191-PIP02-17
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of VX-659 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are heterozygous for the F508del and a minimal function mutation (F/MF subjects).
    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
    07 Mar 2018
    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
    Spain: 14
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    United States: 203
    Country: Number of subjects enrolled
    Australia: 35
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Germany: 51
    Country: Number of subjects enrolled
    Ireland: 16
    Country: Number of subjects enrolled
    Israel: 19
    Country: Number of subjects enrolled
    Poland: 2
    Worldwide total number of subjects
    385
    EEA total number of subjects
    112
    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)
    94
    Adults (18-64 years)
    291
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This study was conducted in subjects with cystic fibrosis (CF) aged 12 years or older.

    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
    Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects who received placebo matched to VX-659/TEZ/IVA for 24 weeks in the TC treatment period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to VX-659/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 VX-659/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
    VX-659/TEZ/IVA TC
    Arm description
    Subjects who received VX-659/TEZ/IVA for 24 weeks in the TC treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    VX-659/TEZ/IVA
    Investigational medicinal product code
    VX-659/VX-661/VX-770
    Other name
    VX-659/Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-659/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.

    Number of subjects in period 1 [1]
    Placebo VX-659/TEZ/IVA TC
    Started
    190
    192
    Completed
    185
    192
    Not completed
    5
    0
         Other
    3
    -
         Adverse event
    1
    -
         Withdrawal of consent (not due to AE)
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In the above disposition summary, data are presented for 382 subjects who were randomized and dosed in the TC treatment period. Three subjects were enrolled into the study and randomized but were not dosed in the TC treatment period. Therefore, the total number of enrolled subjects is 385 but the number of subjects reported in subject disposition and baseline is 382.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects who received placebo matched to VX-659/TEZ/IVA for 24 weeks in the TC treatment period.

    Reporting group title
    VX-659/TEZ/IVA TC
    Reporting group description
    Subjects who received VX-659/TEZ/IVA for 24 weeks in the TC treatment period.

    Reporting group values
    Placebo VX-659/TEZ/IVA TC Total
    Number of subjects
    190 192 382
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    27.1 ± 10.0 26.7 ± 9.8 -
    Gender categorical
    Units: Subjects
        Female
    83 85 168
        Male
    107 107 214
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    7 6 13
        Not Hispanic or Latino
    181 184 365
        Unknown or Not Reported
    2 2 4
    Race
    Units: Subjects
        White
    187 188 375
        Black or African American
    1 2 3
        Both White and Black/African American
    2 2 4
    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. All randomized subjects who carried the intended CF transmembrane conductance regulator gene (CFTR) allele mutation and received at least 1 dose of study drug in the TC Treatment Period.
    Units: Percentage points
        arithmetic mean (standard deviation)
    60.4 ± 14.5 60.7 ± 15.4 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects who received placebo matched to VX-659/TEZ/IVA for 24 weeks in the TC treatment period.

    Reporting group title
    VX-659/TEZ/IVA TC
    Reporting group description
    Subjects who received VX-659/TEZ/IVA for 24 weeks in the TC treatment period.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who received placebo matched to VX-659/TEZ/IVA in the morning and placebo matched to IVA in the evening for 24 weeks in the TC treatment period.

    Subject analysis set title
    VX-659/TEZ/IVA TC
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 24 weeks in the TC treatment period.

    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)
    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 carried the intended CFTR allele mutation and received at least 1 dose of study drug in the TC Treatment Period.
    End point type
    Primary
    End point timeframe
    From Baseline through Week 24
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    190
    192
    Units: percentage points
        least squares mean (standard error)
    -0.8 ± 0.6
    13.4 ± 0.6
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    VX-659/TEZ/IVA TC v Placebo
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed-effects model for repeated measure
    Parameter type
    LS Mean Difference
    Point estimate
    14.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.6
         upper limit
    15.7

    Secondary: 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)
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Analysis population included all subjects in the Full Analysis Set (all randomized subjects who carried the intended CFTR allele mutation and received at least 1 dose of study drug) who completed the Week 4 Visit or were randomized at least 28 days before the data cutoff date.
    End point type
    Secondary
    End point timeframe
    From Baseline at Week 4
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    190
    192
    Units: percentage points
        least squares mean (standard error)
    -1.0 ± 0.6
    13.0 ± 0.6
    Statistical analysis title
    Statistical Analysis
    Statistical analysis description
    The data presented for this endpoint was based on interim analysis at Week 4.
    Comparison groups
    VX-659/TEZ/IVA TC v Placebo
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed-effects model for repeated measure
    Parameter type
    LS Mean Difference
    Point estimate
    14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.4
         upper limit
    15.7

    Secondary: Number of Pulmonary Exacerbations (PEx)

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    End point title
    Number of Pulmonary Exacerbations (PEx)
    End point description
    Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline through Week 24
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    190
    192
    Units: pulmonary exacerbation events
    116
    17
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Negative binomial regression model
    Parameter type
    Rate ratio
    Point estimate
    0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.24

    Secondary: Absolute Change in Sweat Chloride (SwCl)

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    End point title
    Absolute Change in Sweat Chloride (SwCl)
    End point description
    Sweat samples were collected using an approved collection device. FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline through Week 24
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    190
    192
    Units: millimole per liter (mmol/L)
        least squares mean (standard error)
    -0.1 ± 1.0
    -44.6 ± 0.9
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed-effects model for repeated measure
    Parameter type
    LS Mean Difference
    Point estimate
    -44.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -47.2
         upper limit
    -41.9

    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 through Week 24
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    190
    192
    Units: units on a scale
        least squares mean (standard error)
    -1.5 ± 1.1
    18.6 ± 1.0
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed-effects model for repeated measure
    Parameter type
    LS Mean Difference
    Point estimate
    20.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.2
         upper limit
    23

    Secondary: Absolute Change in Body Mass Index (BMI)

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    End point title
    Absolute Change in Body Mass Index (BMI)
    End point description
    BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2). FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline at Week 24
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    190
    192
    Units: kilogram per meter square (kg/m^2)
        least squares mean (standard error)
    -0.05 ± 0.07
    1.06 ± 0.07
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed-effects model for repeated measure
    Parameter type
    LS Mean Difference
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    1.31

    Secondary: Absolute Change in Sweat Chloride

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    End point title
    Absolute Change in Sweat Chloride
    End point description
    Sweat samples were collected using an approved collection device. FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline at Week 4
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    190
    192
    Units: mmol/L
        least squares mean (standard error)
    0.0 ± 1.0
    -43.3 ± 1.0
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed-effects model for repeated measure
    Parameter type
    LS Mean Difference
    Point estimate
    -43.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -46.3
         upper limit
    -40.5

    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 Week 4
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    190
    192
    Units: units on a scale
        least squares mean (standard error)
    0.1 ± 1.2
    18.0 ± 1.2
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed-effects model for repeated measure
    Parameter type
    LS Mean Difference
    Point estimate
    17.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.5
         upper limit
    21.3

    Secondary: Time-to-first Pulmonary Exacerbation (PEx)

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    End point title
    Time-to-first Pulmonary Exacerbation (PEx)
    End point description
    Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. FAS. Here 99999 represents that Median and 95% confidence interval could not be estimated because less than 50% of subjects had events.
    End point type
    Secondary
    End point timeframe
    From Baseline through Week 24
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    190
    192
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Absolute Change in BMI Z-score for Subjects <=20 Years of Age at Baseline

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    End point title
    Absolute Change in BMI Z-score for Subjects <=20 Years of Age at Baseline
    End point description
    BMI was defined as weight in kg divided by height in m^2. z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher BMI. FAS. Here "Overall Number of Subjects Analyzed" signifies those subjects who were <=20 years of age at Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline at Week 24
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    59
    58
    Units: kg/m^2
        least squares mean (standard error)
    -0.08 ± 0.05
    0.31 ± 0.05
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.24
         upper limit
    0.54

    Secondary: Absolute Change in Body Weight

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    End point title
    Absolute Change in Body Weight
    End point description
    FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline at Week 24
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    190
    192
    Units: kg
        least squares mean (standard error)
    0.1 ± 0.2
    3.3 ± 0.2
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v VX-659/TEZ/IVA TC
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    3.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.7
         upper limit
    3.8

    Secondary: Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (AEs) 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 (AEs) and Serious Adverse Events (SAEs)
    End point description
    Adverse events are presented as per Safety Set. Group assignments for subjects in the Safety Set were based on actual treatment received, such that 1 subject assigned to Placebo group who inadvertently received one or more doses of VX-659/TEZ/IVA TC regimen was included in VX-659/TEZ/IVA TC group for the purpose of safety analysis.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to 28 weeks)
    End point values
    Placebo VX-659/TEZ/IVA TC
    Number of subjects analysed
    189
    193
    Units: subjects
        Subjects with TEAEs
    175
    173
        Subjects with Serious TEAEs
    58
    11
    No statistical analyses for this end point

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

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    End point title
    Observed Pre-dose Concentration (Ctrough) of VX-659, TEZ, M1-TEZ, and IVA [1]
    End point description
    Pharmacokinetic (PK) set included all randomized subjects who carried the intended CFTR allele mutation and received at least 1 dose of study drug in the TC Treatment Period. Here “n” signifies those subjects who were evaluable for this outcome measure at specified time points.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Week 4, 8, 12, and 16
    Notes
    [1] - 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: Observed Pre-dose Concentration was calculated only for triple combination (TC) arm.
    End point values
    VX-659/TEZ/IVA TC
    Number of subjects analysed
    192
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        VX-659: Week 4 (n = 150)
    662 ± 528
        VX-659: Week 8 (n = 148)
    764 ± 1520
        VX-659: Week 12 (n = 144)
    614 ± 519
        VX-659: Week 16 (n = 162)
    638 ± 521
        TEZ: Week 4 (n = 150)
    1220 ± 645
        TEZ: Week 8 (n = 148)
    1390 ± 1250
        TEZ: Week 12 (n = 142)
    1290 ± 766
        TEZ: Week 16 (n = 161)
    1220 ± 654
        M1-TEZ: Week 4 (n = 150)
    4380 ± 1560
        M1-TEZ: Week 8 (n = 148)
    4580 ± 1480
        M1-TEZ: Week 12 (n = 142)
    4580 ± 1530
        M1-TEZ: Week 16 (n = 161)
    4420 ± 1520
        IVA: Week 4 (n = 150)
    442 ± 277
        IVA: Week 8 (n = 148)
    548 ± 1100
        IVA: Week 12 (n = 142)
    429 ± 327
        IVA: Week 16 (n = 161)
    416 ± 303
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to 28 weeks)
    Adverse event reporting additional description
    Adverse events are presented as per Safety Set. Treatment assignments for subjects in the Safety Set are based on actual treatment received, such that all subjects who received at least 1 dose of VX-659/TEZ/IVA TC were included in the VX-659/TEZ/IVA TC group for the safety analysis, even if they were assigned to the placebo group.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects who received placebo matched to VX-659/TEZ/IVA for 24 weeks in the TC treatment period.

    Reporting group title
    VX-659/TEZ/IVA TC
    Reporting group description
    Subjects who received VX-659/TEZ/IVA for 24 weeks in the TC treatment period.

    Serious adverse events
    Placebo VX-659/TEZ/IVA TC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    58 / 189 (30.69%)
    11 / 193 (5.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Psychiatric disorders
    Intentional self-injury
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Forced expiratory volume decreased
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis related diabetes
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right-to-left cardiac shunt
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    3 / 189 (1.59%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    2 / 189 (1.06%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash pruritic
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device damage
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Axillary mass
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    45 / 189 (23.81%)
    3 / 193 (1.55%)
         occurrences causally related to treatment / all
    1 / 55
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    2 / 189 (1.06%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysentery
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo VX-659/TEZ/IVA TC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    166 / 189 (87.83%)
    141 / 193 (73.06%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 189 (1.06%)
    17 / 193 (8.81%)
         occurrences all number
    3
    20
    Blood creatine phosphokinase increased
         subjects affected / exposed
    7 / 189 (3.70%)
    13 / 193 (6.74%)
         occurrences all number
    7
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 189 (2.12%)
    16 / 193 (8.29%)
         occurrences all number
    5
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    68 / 189 (35.98%)
    34 / 193 (17.62%)
         occurrences all number
    100
    42
    Oropharyngeal pain
         subjects affected / exposed
    13 / 189 (6.88%)
    20 / 193 (10.36%)
         occurrences all number
    14
    24
    Sputum increased
         subjects affected / exposed
    38 / 189 (20.11%)
    28 / 193 (14.51%)
         occurrences all number
    43
    32
    Haemoptysis
         subjects affected / exposed
    19 / 189 (10.05%)
    6 / 193 (3.11%)
         occurrences all number
    21
    6
    Nasal congestion
         subjects affected / exposed
    11 / 189 (5.82%)
    11 / 193 (5.70%)
         occurrences all number
    11
    11
    Respiration abnormal
         subjects affected / exposed
    14 / 189 (7.41%)
    7 / 193 (3.63%)
         occurrences all number
    16
    9
    Productive cough
         subjects affected / exposed
    14 / 189 (7.41%)
    3 / 193 (1.55%)
         occurrences all number
    22
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    31 / 189 (16.40%)
    26 / 193 (13.47%)
         occurrences all number
    37
    30
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    15 / 189 (7.94%)
    13 / 193 (6.74%)
         occurrences all number
    16
    13
    Fatigue
         subjects affected / exposed
    19 / 189 (10.05%)
    9 / 193 (4.66%)
         occurrences all number
    19
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    16 / 189 (8.47%)
    17 / 193 (8.81%)
         occurrences all number
    21
    20
    Nausea
         subjects affected / exposed
    24 / 189 (12.70%)
    8 / 193 (4.15%)
         occurrences all number
    31
    11
    Abdominal pain upper
         subjects affected / exposed
    10 / 189 (5.29%)
    3 / 193 (1.55%)
         occurrences all number
    14
    3
    Vomiting
         subjects affected / exposed
    11 / 189 (5.82%)
    7 / 193 (3.63%)
         occurrences all number
    11
    7
    Constipation
         subjects affected / exposed
    5 / 189 (2.65%)
    11 / 193 (5.70%)
         occurrences all number
    5
    11
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    10 / 189 (5.29%)
    10 / 193 (5.18%)
         occurrences all number
    16
    12
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    79 / 189 (41.80%)
    21 / 193 (10.88%)
         occurrences all number
    103
    23
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 189 (3.70%)
    35 / 193 (18.13%)
         occurrences all number
    7
    41
    Nasopharyngitis
         subjects affected / exposed
    16 / 189 (8.47%)
    26 / 193 (13.47%)
         occurrences all number
    19
    33

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2018
    Updated study drug regimen, dosing guidance, dose and population rationale
    27 Apr 2018
    Revised exclusion criteria
    01 Oct 2018
    A European-specific version of the protocol was created with a 24-week primary endpoint

    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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