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    Clinical Trial Results:
    A Phase 4, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Study of the Effect of Lumacaftor/Ivacaftor Combination Therapy on Exercise Tolerance in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation.

    Summary
    EudraCT number
    2016-000066-34
    Trial protocol
    GB  
    Global end of trial date
    23 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Feb 2019
    First version publication date
    02 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX15-809-112
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02875366
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States, 02210-1862
    Public contact
    Clinical Trials and Medical Info, Medical Monitor, Vertex Pharmaceuticals Incorporated, 001 617-341-6777, medicalinfo@vrtx.com
    Scientific contact
    Clinical Trials and Medical Info, Medical Monitor, Vertex Pharmaceuticals Incorporated, 001 617-341-6777, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of LUM/IVA on exercise tolerance in subjects with CF, homozygous for the F508del-CFTR mutation.
    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
    01 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 67
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    70
    EEA total number of subjects
    3
    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)
    22
    Adults (18-64 years)
    48
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects were randomized at 13 sites in Australia and the UK.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received placebo matched to lumacaftor (LUM)/ivacaftor (IVA) fixed-dose combination every 12 hours (q12h) for 24 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to LUM/IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to LUM/IVA fixed-dose combination q12h for 24 weeks.

    Arm title
    LUM/IVA
    Arm description
    Subjects received LUM 400 mg/IVA 250 mg fixed-dose combination q12h for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    LUM/IVA
    Investigational medicinal product code
    VX-809/VX-770
    Other name
    Lumacaftor/Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LUM 400 mg/IVA 250 mg fixed-dose combination q12h for 24 weeks.

    Number of subjects in period 1
    Placebo LUM/IVA
    Started
    36
    34
    Completed
    36
    31
    Not completed
    0
    3
         Noncompliance
    -
    1
         Adverse Event
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo matched to lumacaftor (LUM)/ivacaftor (IVA) fixed-dose combination every 12 hours (q12h) for 24 weeks.

    Reporting group title
    LUM/IVA
    Reporting group description
    Subjects received LUM 400 mg/IVA 250 mg fixed-dose combination q12h for 24 weeks.

    Reporting group values
    Placebo LUM/IVA Total
    Number of subjects
    36 34 70
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    26.1 ± 10.58 24.9 ± 10.17 -
    Gender categorical
    Units: Subjects
        Female
    18 13 31
        Male
    18 21 39
    Ethinicity
    Units: Subjects
        Hispanic or Latino
    0 0 0
        Not Hispanic or Latino
    36 34 70
        Unknown or Not Reported
    0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 0 0
        White
    36 34 70
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo matched to lumacaftor (LUM)/ivacaftor (IVA) fixed-dose combination every 12 hours (q12h) for 24 weeks.

    Reporting group title
    LUM/IVA
    Reporting group description
    Subjects received LUM 400 mg/IVA 250 mg fixed-dose combination q12h for 24 weeks.

    Primary: Relative (Percent) Change From Baseline in Maximal Oxygen Consumption (VO2max) During Cardiopulmonary Exercise Testing (CPET) at Week 24

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    End point title
    Relative (Percent) Change From Baseline in Maximal Oxygen Consumption (VO2max) During Cardiopulmonary Exercise Testing (CPET) at Week 24
    End point description
    CPET was used to assess change in exercise tolerance, as measured by VO2max. The Full Analysis Set (FAS) included all randomized subjects who received any amount of study drug. Here “Number of subjects analysed” signifies those subjects who were evaluated for this end point.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    32
    26
    Units: percent change
        least squares mean (confidence interval 95%)
    -3.5 (-7.7 to 0.8)
    -6.6 (-11.3 to -2.0)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3021
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least squares mean difference
    Point estimate
    -3.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.2
         upper limit
    2.9

    Secondary: Relative (Percent) Change From Baseline in Exercise Duration During CPET at Week 24

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    End point title
    Relative (Percent) Change From Baseline in Exercise Duration During CPET at Week 24
    End point description
    Exercise duration is defined as the time at the termination of CPET exercise minus the corresponding time when CPET starts for each CPET exercise. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    32
    26
    Units: percent change
        least squares mean (confidence interval 95%)
    0.4 (-3.0 to 3.8)
    -2.8 (-6.5 to 1.0)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1894
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -3.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8
         upper limit
    1.6

    Secondary: Absolute Change From Baseline in Exercise Duration During CPET at Week 24

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    End point title
    Absolute Change From Baseline in Exercise Duration During CPET at Week 24
    End point description
    Exercise duration is defined as the time at the termination of CPET exercise minus the corresponding time when CPET starts for each CPET exercise. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    32
    26
    Units: seconds
        least squares mean (confidence interval 95%)
    -2.1 (-20.0 to 15.9)
    -17.4 (-37.2 to 2.4)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    LUM/IVA v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2328
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -15.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.8
         upper limit
    10.1

    Secondary: Absolute Change From Baseline in VO2max During CPET at Week 24

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    End point title
    Absolute Change From Baseline in VO2max During CPET at Week 24
    End point description
    CPET was used to assess change in exercise tolerance, as measured by VO2max. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    32
    26
    Units: milliliter per kilogram per minute
        least squares mean (confidence interval 95%)
    -1.3 (-2.5 to -0.1)
    -2.7 (-4.0 to -1.3)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1203
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.1
         upper limit
    0.4

    Secondary: Absolute Change From Baseline in Oxygen Consumption (VO2) at Anaerobic Threshold at Week 24

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    End point title
    Absolute Change From Baseline in Oxygen Consumption (VO2) at Anaerobic Threshold at Week 24
    End point description
    Anaerobic threshold was defined as the exercise intensity at which lactate starts to accumulate. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    32
    25
    Units: milliliter per minute
        least squares mean (confidence interval 95%)
    94.6 (-5.8 to 195.0)
    -55.1 (-168.0 to 57.9)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0439
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -149.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -295
         upper limit
    -4.2

    Secondary: Relative (Percent) Change From Baseline in VO2 at Anaerobic Threshold at Week 24

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    End point title
    Relative (Percent) Change From Baseline in VO2 at Anaerobic Threshold at Week 24
    End point description
    Anaerobic threshold was defined as the exercise intensity at which lactate starts to accumulate. Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    32
    25
    Units: percent change
        least squares mean (confidence interval 95%)
    9.4 (0.9 to 17.8)
    1.8 (-7.7 to 11.3)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2237
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -7.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.8
         upper limit
    4.7

    Secondary: Absolute Change From Baseline in Functional VO2 Gain at Week 24

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    End point title
    Absolute Change From Baseline in Functional VO2 Gain at Week 24
    End point description
    Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    32
    26
    Units: milliliter per minute per watt
        least squares mean (confidence interval 95%)
    0.07 (-0.29 to 0.43)
    -0.53 (-0.93 to -0.14)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0226
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.12
         upper limit
    -0.09

    Secondary: Relative (Percent) Change From Baseline in Functional VO2 Gain at Week 24

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    End point title
    Relative (Percent) Change From Baseline in Functional VO2 Gain at Week 24
    End point description
    Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    32
    26
    Units: percent change
        least squares mean (confidence interval 95%)
    1.46 (-3.10 to 6.03)
    -4.85 (-9.93 to 0.22)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0613
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    -6.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.94
         upper limit
    0.31

    Secondary: Absolute Change From Baseline in Pulmonary Ventilation (VE) Versus Carbon Dioxide Production (VCO2) Slope at Week 24

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    End point title
    Absolute Change From Baseline in Pulmonary Ventilation (VE) Versus Carbon Dioxide Production (VCO2) Slope at Week 24
    End point description
    Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    31
    26
    Units: ratio
        least squares mean (confidence interval 95%)
    0.5 (-0.3 to 1.4)
    0.8 (-0.1 to 1.7)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6409
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    1.5

    Secondary: Relative (Percent) Change From Baseline in Pulmonary Ventilation (VE) Versus Carbon Dioxide Production (VCO2) Slope at Week 24

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    End point title
    Relative (Percent) Change From Baseline in Pulmonary Ventilation (VE) Versus Carbon Dioxide Production (VCO2) Slope at Week 24
    End point description
    Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    31
    26
    Units: percent change
        least squares mean (confidence interval 95%)
    2.0 (-0.7 to 4.6)
    3.0 (0.1 to 5.8)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Relative (Percent) Change From Baseline in Pulmonary Ventilation (VE) Versus Carbon Dioxide Production (VCO2) Slope at Week 24. Analysis was performed using MMRM model.
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5889
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.7
         upper limit
    4.7

    Secondary: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Week 24

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    End point title
    Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Week 24
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    32
    30
    Units: percentage of predicted FEV1
        least squares mean (confidence interval 95%)
    -4.0 (-7.3 to -0.7)
    -0.6 (-4.0 to 2.9)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.146
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    3.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    8.1

    Secondary: Relative (Percent) Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Week 24

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    End point title
    Relative (Percent) Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Week 24
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    32
    30
    Units: percent change
        least squares mean (confidence interval 95%)
    -5.4 (-10.3 to -0.5)
    -1.8 (-6.9 to 3.2)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3091
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.4
         upper limit
    10.4

    Secondary: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24

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    End point title
    Absolute Change From Baseline in Body Mass Index (BMI) at Week 24
    End point description
    BMI was defined as weight in kilograms (kg) divided by height in square meter (m^2). Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    33
    30
    Units: kg/m^2
        least squares mean (confidence interval 95%)
    0.3 (0.0 to 0.6)
    0.5 (0.1 to 0.8)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3961
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.6

    Secondary: Relative (Percent) Change From Baseline in BMI at Week 24

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    End point title
    Relative (Percent) Change From Baseline in BMI at Week 24
    End point description
    BMI was defined as weight in kg divided by height in m^2. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    33
    30
    Units: percent change
        least squares mean (confidence interval 95%)
    1.5 (0.0 to 3.1)
    2.5 (0.9 to 4.1)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    LUM/IVA v Placebo
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3905
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    3.1

    Secondary: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24

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    End point title
    Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24
    End point description
    The CFQ-R assessed respiratory symptoms on a scale with scores ranging from 0 to 100; where higher scores indicated fewer symptoms and better health-related quality of life. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    33
    30
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -6.1 (-11.7 to -0.5)
    0.1 (-5.9 to 6.1)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Placebo v LUM/IVA
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.1257
    Method
    Mixed effects model for repeated measure
    Parameter type
    Least Squares Mean Difference
    Point estimate
    6.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    14.1
    Notes
    [1] - Analysis was performed using MMRM model.

    Secondary: Number of Subjects in Each Severity Category of Patient Health Questionnaire (PHQ-8)

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    End point title
    Number of Subjects in Each Severity Category of Patient Health Questionnaire (PHQ-8)
    End point description
    The PHQ-8 is an eight item self-reported measure of depression. Each item is rated on a scale ranging from 0 (not at all) to 3 (nearly every day). Total score is the sum of individual eight items and ranges from 0 to 24, with higher scores indicating more severe depression symptoms. Total score of 0 to 5 indicates none to minimal depression, 6 to 10 indicates mild depression, 11 to 15 indicates moderate depression, 16 to 20 indicates moderately severe depression and 21 to 24 indicates severe depression. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    36
    34
    Units: subjects
    number (not applicable)
        Baseline: None to minimal (n=36,34)
    27
    28
        Baseline: Mild (n= 36,34)
    8
    5
        Baseline: Moderate (n=36,34)
    0
    1
        Baseline: Moderately severe (n=36,34)
    1
    0
        Baseline: Severe (n=36,34)
    0
    0
        Week 24: None to minimal (n=33,30)
    23
    24
        Week 24: Mild (n=33,30)
    8
    3
        Week 24: Moderate (n=33,30)
    1
    3
        Week 24: Moderately severe (n=33,30)
    1
    0
        Week 24: Severe (n=33,30)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects in Each Severity Category of Generalized Anxiety Disorder (GAD-7) Scores

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    End point title
    Number of Subjects in Each Severity Category of Generalized Anxiety Disorder (GAD-7) Scores
    End point description
    The GAD-7 is a seven item, self-reported measurement of GAD severity. Each item is rated on a scale ranging from 0 (not at all) to 3 (nearly every day). Total score is the sum of individual seven items and ranges from 0 to 21, with higher scores indicating more severe anxiety symptoms. Total score of 0 to 5 indicates none to minimal anxiety, 6 to 10 indicates mild anxiety, 11 to 15 indicates moderate anxiety, 16 to 21 indicates severe anxiety. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    36
    34
    Units: subjects
    number (not applicable)
        Baseline: None to minimal (n=36,34)
    31
    29
        Baseline: Mild (n=36,34)
    5
    5
        Baseline: Moderate (n=36,34)
    0
    0
        Baseline: Severe (n=36,34)
    0
    0
        Week 24: None to minimal (n=33,30)
    26
    26
        Week 24: Mild (n=33,30)
    6
    3
        Week 24: Moderate (n=33,30)
    1
    1
        Week 24: Severe (n=33,30)
    0
    0
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Physical Activity as Determined by Actigraphy at Week 24

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    End point title
    Absolute Change From Baseline in Physical Activity as Determined by Actigraphy at Week 24
    End point description
    Subjects were provided with a wrist-worn actigraphy device which continuously collected data about daily physical activities. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    19
    20
    Units: physical activity counts
        arithmetic mean (standard deviation)
    -23239 ± 73936.4
    -22409 ± 52450.1
    No statistical analyses for this end point

    Secondary: Relative (Percent) Change From Baseline in Physical Activity as Determined by Actigraphy at Week 24

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    End point title
    Relative (Percent) Change From Baseline in Physical Activity as Determined by Actigraphy at Week 24
    End point description
    Subjects were provided with a wrist-worn actigraphy device which continuously collected data about daily physical activities. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    19
    20
    Units: percent change
        arithmetic mean (standard deviation)
    -5 ± 26.9
    -7 ± 24.3
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Duration of Sleep Time at Week 24

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    End point title
    Absolute Change From Baseline in Duration of Sleep Time at Week 24
    End point description
    Subjects were provided with a wrist-worn actigraphy device which continuously collected data about sleep duration and quality. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    18
    18
    Units: hours
        arithmetic mean (standard deviation)
    -0.4 ± 0.88
    0.1 ± 0.74
    No statistical analyses for this end point

    Secondary: Relative (Percent) Change From Baseline in Duration of Sleep Time at Week 24

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    End point title
    Relative (Percent) Change From Baseline in Duration of Sleep Time at Week 24
    End point description
    Subjects were provided with a wrist-worn actigraphy device which continuously collected data about sleep duration and quality. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    18
    18
    Units: percent change
        arithmetic mean (standard deviation)
    -5.7 ± 12.30
    1.5 ± 9.79
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Time Above Sedentary Duration at Week 24

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    End point title
    Absolute Change From Baseline in Time Above Sedentary Duration at Week 24
    End point description
    Subjects were provided with a wrist-worn actigraphy device which continuously collected data about daily activities and sleep duration and quality. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    15
    21
    Units: hours
        arithmetic mean (standard deviation)
    -0.7 ± 1.48
    -0.7 ± 2.09
    No statistical analyses for this end point

    Secondary: Relative (Percent) Change From Baseline in Time Above Sedentary Duration at Week 24

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    End point title
    Relative (Percent) Change From Baseline in Time Above Sedentary Duration at Week 24
    End point description
    Subjects were provided with a wrist-worn actigraphy device which continuously collected data about daily activities and sleep duration and quality. Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    15
    21
    Units: percent change
        arithmetic mean (standard deviation)
    0.2 ± 64.7
    2.3 ± 77.18
    No statistical analyses for this end point

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

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    End point title
    Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    Analysis was performed on FAS. Here, "Number of subjects analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo LUM/IVA
    Number of subjects analysed
    36
    34
    Units: subjects
    number (not applicable)
        Subjects With AEs
    35
    30
        Subjects With SAEs
    9
    15
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 28
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo matched to LUM/IVA fixed-dose combination tablet orally q12h for 24 weeks.

    Reporting group title
    LUM/IVA
    Reporting group description
    Participants received LUM 400 mg/IVA 250 mg fixed-dose combination tablet orally q12h for 24 weeks.

    Serious adverse events
    Placebo LUM/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 36 (25.00%)
    15 / 34 (44.12%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 34 (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
    Fatigue
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular torsion
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    6 / 36 (16.67%)
    8 / 34 (23.53%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo LUM/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 36 (75.00%)
    19 / 34 (55.88%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    Bacterial test positive
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Blood iron decreased
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    Fungal test positive
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 36 (22.22%)
    5 / 34 (14.71%)
         occurrences all number
    10
    5
    Dyspnoea
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    Haemoptysis
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 34 (8.82%)
         occurrences all number
    4
    3
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    3
    Oropharyngeal pain
         subjects affected / exposed
    4 / 36 (11.11%)
    1 / 34 (2.94%)
         occurrences all number
    4
    1
    Productive cough
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    4
    1
    Respiration abnormal
         subjects affected / exposed
    9 / 36 (25.00%)
    5 / 34 (14.71%)
         occurrences all number
    9
    7
    Sputum increased
         subjects affected / exposed
    5 / 36 (13.89%)
    2 / 34 (5.88%)
         occurrences all number
    6
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    3
    Nausea
         subjects affected / exposed
    5 / 36 (13.89%)
    3 / 34 (8.82%)
         occurrences all number
    6
    3
    Toothache
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Diarrhoea
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 34 (2.94%)
         occurrences all number
    4
    1
    Constipation
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Rash
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    6 / 36 (16.67%)
    8 / 34 (23.53%)
         occurrences all number
    7
    10
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 36 (11.11%)
    4 / 34 (11.76%)
         occurrences all number
    5
    4
    Nasopharyngitis
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 34 (8.82%)
         occurrences all number
    3
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    2
    1
    Sinusitis
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 34 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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