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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)

    Summary
    EudraCT number
    		 2018-000183-28
    Trial protocol
    		 SE   DE   GB   CZ   BE   NL   AT   GR   FR   IT  
    Global end of trial date
    24 Apr 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Aug 2020
    First version publication date
    20 Nov 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of Secondary Endpoints

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    VX17-445-102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03525444
    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-002324-PIP01-17
    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
    14 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of VX-445 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
    15 Jun 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
    Canada: 24
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    United States: 216
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    Netherlands: 19
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Greece: 3
    Worldwide total number of subjects
    405
    EEA total number of subjects
    141
    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)
    116
    Adults (18-64 years)
    289
    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
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects who received placebo matched to VX-445/TEZ/IVA in the morning and placebo matched to IVA in the evening for 24 weeks in the TC treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (matched to VX-445/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-445/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-445/TEZ/IVA TC
    Arm description
    		 Subjects who received VX-445 200 mg/TEZ 100 mg/IVA150 mg as fixed-dose combination (FDC) tablets in the morning and IVA 150 mg as mono tablet in the evening for 24 weeks in the TC treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-445/TEZ/IVA
    Investigational medicinal product code
    VX-445/VX-661/VX-770
    Other name
    VX-445/Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-445/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-445/TEZ/IVA TC
    Started
    203
    200
    Completed
    203
    197
    Not completed
    0
    3
         Other
    -
    1
         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 403 subjects who were randomized and dosed in the TC treatment period. Two subjects were enrolled in to the study and randomized but were not dosed in the TC treatment period. Therefore, the total number of enrolled subjects is 405 but the number of subjects reported in subject disposition and baseline is 403.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who received placebo matched to VX-445/TEZ/IVA in the morning and placebo matched to IVA in the evening for 24 weeks in the TC treatment period.

    Reporting group title
    VX-445/TEZ/IVA TC
    Reporting group description
    		 Subjects who received VX-445 200 mg/TEZ 100 mg/IVA150 mg as fixed-dose combination (FDC) tablets in the morning and IVA 150 mg as mono tablet in the evening for 24 weeks in the TC treatment period.

    Reporting group values
    		 Placebo VX-445/TEZ/IVA TC Total
    Number of subjects
    		 203 200 403
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 26.8 ( 11.3 ) 25.6 ( 9.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 98 96 194
        Male
    		 105 104 209
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 12 4 16
        Not Hispanic or Latino
    		 175 187 362
        Unknown or Not Reported
    		 16 9 25
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Black or African American
    		 1 3 4
        Not Collected per Local Regulations
    		 16 9 25
        Australian Aboriginal
    		 0 1 1
        Not Otherwise Specified
    		 1 0 1
        Other- Unknown Mixed Heritage
    		 0 1 1
        White
    		 182 185 367
        White, Asian
    		 1 0 1
        White, Black or African American
    		 1 1 2
    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)
    		 61.3 ( 15.5 ) 61.6 ( 15.0 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who received placebo matched to VX-445/TEZ/IVA in the morning and placebo matched to IVA in the evening for 24 weeks in the TC treatment period.

    Reporting group title
    VX-445/TEZ/IVA TC
    Reporting group description
    		 Subjects who received VX-445 200 mg/TEZ 100 mg/IVA150 mg as fixed-dose combination (FDC) tablets in the morning and IVA 150 mg as mono tablet in the evening 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-445/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-445/TEZ/IVA TC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received VX-445 200 mg/TEZ 100 mg/IVA150 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-445/TEZ/IVA TC
    Number of subjects analysed
    203
    200
    Units: percentage points
        least squares mean (standard error)
    -0.4 ( 0.5 )
    13.9 ( 0.6 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    VX-445/TEZ/IVA TC v Placebo
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed-effects model for repeated measure
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    14.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.7
         upper limit
    		 15.8

    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-445/TEZ/IVA TC
    Number of subjects analysed
    203
    200
    Units: percentage points
        least squares mean (standard error)
    -0.2 ( 0.6 )
    13.6 ( 0.6 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    VX-445/TEZ/IVA TC v Placebo
    Number of subjects included in analysis
    403
    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
    13.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.1
         upper limit
    		 15.4

    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-445/TEZ/IVA TC
    Number of subjects analysed
    203
    200
    Units: pulmonary exacerbations events
    113
    41
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v VX-445/TEZ/IVA TC
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Negative binomial regression model
    Parameter type
    		 Rate ratio
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.55

    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-445/TEZ/IVA TC
    Number of subjects analysed
    203
    200
    Units: millimole per liter (mmol/L)
        least squares mean (standard error)
    -0.4 ( 0.9 )
    -42.2 ( 0.9 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v VX-445/TEZ/IVA TC
    Number of subjects included in analysis
    403
    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
    -41.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.4
         upper limit
    		 -39.3

    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-445/TEZ/IVA TC
    Number of subjects analysed
    203
    200
    Units: units on a scale
        least squares mean (standard error)
    -2.7 ( 1.0 )
    17.5 ( 1.0 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v VX-445/TEZ/IVA TC
    Number of subjects included in analysis
    403
    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
    20.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 17.5
         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-445/TEZ/IVA TC
    Number of subjects analysed
    203
    200
    Units: kilogram per meter square (kg/m^2)
        least squares mean (standard error)
    0.09 ( 0.07 )
    1.13 ( 0.07 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v VX-445/TEZ/IVA TC
    Number of subjects included in analysis
    403
    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
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.23

    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-445/TEZ/IVA TC
    Number of subjects analysed
    203
    200
    Units: mmol/L
        least squares mean (standard error)
    0.1 ( 1.0 )
    -41.2 ( 1.0 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    VX-445/TEZ/IVA TC v Placebo
    Number of subjects included in analysis
    403
    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
    -41.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44
         upper limit
    		 -38.5

    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-445/TEZ/IVA TC
    Number of subjects analysed
    203
    200
    Units: units on a scale
        least squares mean (standard error)
    -1.9 ( 1.1 )
    18.1 ( 1.1 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v VX-445/TEZ/IVA TC
    Number of subjects included in analysis
    403
    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
    		 16.9
         upper limit
    		 23.2

    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 indicates "Not Applicable" as 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-445/TEZ/IVA TC
    Number of subjects analysed
    203
    200
    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-445/TEZ/IVA TC
    Number of subjects analysed
    74
    71
    Units: z-score
        least squares mean (standard error)
    0.04 ( 0.05 )
    0.34 ( 0.05 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v VX-445/TEZ/IVA TC
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.43

    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-445/TEZ/IVA TC
    Number of subjects analysed
    203
    200
    Units: kg
        least squares mean (standard error)
    0.5 ( 0.2 )
    3.4 ( 0.2 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo v VX-445/TEZ/IVA TC
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.3
         upper limit
    		 3.4

    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 2 subjects assigned to Placebo group who inadvertently received one or more doses of VX-445/TEZ/IVA TC regimen were included in VX-445/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-445/TEZ/IVA TC
    Number of subjects analysed
    201
    202
    Units: Subjects
        Subjects with TEAEs
    193
    188
        Subjects with Serious TEAEs
    42
    28
    No statistical analyses for this end point

    Secondary: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA

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    End point title
    		 Observed Pre-dose Concentration (Ctrough) of VX-445, 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: Ctrough was only applicable for VX-445/TEZ/IVA TC arm.
    End point values
    		 VX-445/TEZ/IVA TC
    Number of subjects analysed
    200
    Units: microgram per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        VX-445 Week 4 (n=198)
    5.02 ( 2.68 )
        VX-445 Week 8 (n=192)
    4.90 ( 2.75 )
        VX-445 Week 12 (n=195)
    4.99 ( 3.11 )
        VX-445 Week 16 (n=196)
    4.75 ( 2.58 )
        TEZ Week 4 (n=198)
    2.16 ( 1.05 )
        TEZ Week 8 (n=193)
    2.14 ( 1.14 )
        TEZ Week 12 (n=196)
    2.22 ( 1.48 )
        TEZ Week 16 (n=196)
    2.32 ( 1.46 )
        M1-TEZ Week 4 (n=198)
    5.18 ( 2.01 )
        M1-TEZ Week 8 (n=193)
    5.09 ( 1.95 )
        M1-TEZ Week 12 (n=196)
    5.06 ( 1.92 )
        M1-TEZ Week 16 (n=196)
    5.29 ( 1.95 )
        IVA Week 4 (n=197)
    0.748 ( 0.471 )
        IVA Week 8 (n=193)
    0.738 ( 0.484 )
        IVA Week 12 (n=196)
    0.758 ( 0.572 )
        IVA Week 16 (n=196)
    0.778 ( 0.516 )
    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. Group assignments for subjects in the Safety Set were based on actual treatment received, such that 2 subjects assigned to Placebo group who inadvertently received one or more doses of VX-445/TEZ/IVA TC regimen were included in VX-445/TEZ/IVA TC group for the purpose of safety analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who received placebo matched to VX-445/TEZ/IVA in the morning and placebo matched to IVA in the evening for 24 weeks in the TC treatment period.

    Reporting group title
    VX-445/TEZ/IVA TC
    Reporting group description
    		 Subjects who received VX-445 200 mg/TEZ 100 mg/IVA150 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.

    Serious adverse events
    		 Placebo VX-445/TEZ/IVA TC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 201 (20.90%)
    28 / 202 (13.86%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Axonal neuropathy
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental impairment
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroglycopenia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device site inflammation
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         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
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    3 / 201 (1.49%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic paralysis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Painful respiration
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (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 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder enlargement
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal hypertension
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 201 (0.50%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity vasculitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash pruritic
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (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
    Back pain
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    33 / 201 (16.42%)
    11 / 202 (5.45%)
         occurrences causally related to treatment / all
    0 / 44
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 201 (0.00%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical mycobacterial lower respiratory tract infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coccidioidomycosis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital herpes simplex
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         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 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral sinusitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 202 (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-445/TEZ/IVA TC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    180 / 201 (89.55%)
    168 / 202 (83.17%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 201 (3.48%)
    20 / 202 (9.90%)
         occurrences all number
    8
    22
    Blood creatine phosphokinase increased
         subjects affected / exposed
    9 / 201 (4.48%)
    19 / 202 (9.41%)
         occurrences all number
    9
    20
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 201 (1.99%)
    19 / 202 (9.41%)
         occurrences all number
    4
    21
    Bacterial test positive
         subjects affected / exposed
    10 / 201 (4.98%)
    5 / 202 (2.48%)
         occurrences all number
    13
    5
    Blood bilirubin increased
         subjects affected / exposed
    2 / 201 (1.00%)
    10 / 202 (4.95%)
         occurrences all number
    2
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    30 / 201 (14.93%)
    35 / 202 (17.33%)
         occurrences all number
    42
    49
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    19 / 201 (9.45%)
    17 / 202 (8.42%)
         occurrences all number
    25
    18
    Fatigue
         subjects affected / exposed
    20 / 201 (9.95%)
    9 / 202 (4.46%)
         occurrences all number
    22
    9
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    14 / 201 (6.97%)
    26 / 202 (12.87%)
         occurrences all number
    23
    32
    Abdominal pain
         subjects affected / exposed
    12 / 201 (5.97%)
    20 / 202 (9.90%)
         occurrences all number
    20
    24
    Nausea
         subjects affected / exposed
    14 / 201 (6.97%)
    16 / 202 (7.92%)
         occurrences all number
    17
    16
    Vomiting
         subjects affected / exposed
    10 / 201 (4.98%)
    12 / 202 (5.94%)
         occurrences all number
    13
    14
    Constipation
         subjects affected / exposed
    12 / 201 (5.97%)
    6 / 202 (2.97%)
         occurrences all number
    12
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    77 / 201 (38.31%)
    34 / 202 (16.83%)
         occurrences all number
    113
    39
    Sputum increased
         subjects affected / exposed
    39 / 201 (19.40%)
    40 / 202 (19.80%)
         occurrences all number
    47
    47
    Oropharyngeal pain
         subjects affected / exposed
    25 / 201 (12.44%)
    20 / 202 (9.90%)
         occurrences all number
    26
    27
    Haemoptysis
         subjects affected / exposed
    27 / 201 (13.43%)
    9 / 202 (4.46%)
         occurrences all number
    39
    10
    Nasal congestion
         subjects affected / exposed
    15 / 201 (7.46%)
    19 / 202 (9.41%)
         occurrences all number
    18
    21
    Productive cough
         subjects affected / exposed
    16 / 201 (7.96%)
    12 / 202 (5.94%)
         occurrences all number
    17
    12
    Rhinorrhoea
         subjects affected / exposed
    6 / 201 (2.99%)
    17 / 202 (8.42%)
         occurrences all number
    7
    19
    Dyspnoea
         subjects affected / exposed
    13 / 201 (6.47%)
    5 / 202 (2.48%)
         occurrences all number
    15
    5
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    9 / 201 (4.48%)
    17 / 202 (8.42%)
         occurrences all number
    11
    20
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    83 / 201 (41.29%)
    41 / 202 (20.30%)
         occurrences all number
    137
    53
    Nasopharyngitis
         subjects affected / exposed
    26 / 201 (12.94%)
    22 / 202 (10.89%)
         occurrences all number
    34
    30
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 201 (10.95%)
    24 / 202 (11.88%)
         occurrences all number
    26
    30
    Rhinitis
         subjects affected / exposed
    11 / 201 (5.47%)
    15 / 202 (7.43%)
         occurrences all number
    14
    18
    Sinusitis
         subjects affected / exposed
    8 / 201 (3.98%)
    11 / 202 (5.45%)
         occurrences all number
    8
    15
    Influenza
         subjects affected / exposed
    3 / 201 (1.49%)
    12 / 202 (5.94%)
         occurrences all number
    3
    13

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Apr 2018
    Updated study drug regimen, dosing guidance, dose and population rationale
    19 Jul 2018
    Revised exclusion criteria
    30 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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    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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