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    Clinical Trial Results:
    A Phase 3, Open-label Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Lumacaftor in Combination With Ivacaftor in Subjects 6 Through 11 Years of Age With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

    Summary
    EudraCT number
    2017-001078-41
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    28 Oct 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Jun 2017
    First version publication date
    19 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX13-809-011
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01897233
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States, 022101862
    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-001582-PIP01-13
    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 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part A: To evaluate the pharmacokinetics (PK) of multiple doses of lumacaftor (LUM, VX-809) in combination with ivacaftor (IVA, VX-770); Part B: To evaluate the safety and tolerability of LUM in combination with IVA through Week 24.
    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
    12 Jul 2013
    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
    United States: 58
    Country: Number of subjects enrolled
    Canada: 4
    Worldwide total number of subjects
    62
    EEA total number of subjects
    0
    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)
    62
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study was conducted in 2 parts – Part A and Part B. Part A consisted of 2 cohorts, in which subjects aged 6 to 8 years were enrolled in Cohort 1 and subjects aged 9 to 11 years were enrolled in Cohort 2. Part B consisted of a single cohort. Subjects from Part A may have also participated in Part B of the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Part A Cohort 1: LUM/IVA
    Arm description
    Subjects aged 6 through 8 years received LUM 200 milligram (mg) in fixed-dose combination with IVA 250 mg orally every 12 hours (q12h) for 14 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    VX-809+VX-770
    Other name
    LUM+IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 200 mg in combination with IVA 250 mg as fixed-dose combination tablet orally q12h for 14 days.

    Arm title
    Part A Cohort 2: LUM/IVA
    Arm description
    Subjects aged 9 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    VX-809+VX-770
    Other name
    LUM+IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 200 mg in combination with IVA 250 mg as fixed-dose combination tablet orally q12h for 14 days.

    Arm title
    Part B: LUM/IVA
    Arm description
    Subjects aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    VX-809+VX-770
    Other name
    LUM+IVA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 200 mg in combination with IVA 250 mg as fixed-dose combination tablet orally q12h for 24 weeks.

    Number of subjects in period 1
    Part A Cohort 1: LUM/IVA Part A Cohort 2: LUM/IVA Part B: LUM/IVA
    Started
    5
    5
    58
    Completed
    5
    5
    54
    Not completed
    0
    0
    4
         Physician decision
    -
    -
    1
         Consent withdrawn by subject
    -
    -
    2
         Adverse Event
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A Cohort 1: LUM/IVA
    Reporting group description
    Subjects aged 6 through 8 years received LUM 200 milligram (mg) in fixed-dose combination with IVA 250 mg orally every 12 hours (q12h) for 14 days.

    Reporting group title
    Part A Cohort 2: LUM/IVA
    Reporting group description
    Subjects aged 9 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.

    Reporting group title
    Part B: LUM/IVA
    Reporting group description
    Subjects aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.

    Reporting group values
    Part A Cohort 1: LUM/IVA Part A Cohort 2: LUM/IVA Part B: LUM/IVA Total
    Number of subjects
    5 5 58
    Age categorical
    Units: Subjects
    Age continuous
    Data was planned to be reported separately for Part A and Part B of the study.
    Units: years
        arithmetic mean (standard deviation)
    6.6 ± 0.89 9.6 ± 0.89 9.1 ± 1.53 -
    Gender categorical
    Data was planned to be reported separately for Part A and Part B of the study.
    Units: Subjects
        Female
    1 1 31 33
        Male
    4 4 27 35

    End points

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    End points reporting groups
    Reporting group title
    Part A Cohort 1: LUM/IVA
    Reporting group description
    Subjects aged 6 through 8 years received LUM 200 milligram (mg) in fixed-dose combination with IVA 250 mg orally every 12 hours (q12h) for 14 days.

    Reporting group title
    Part A Cohort 2: LUM/IVA
    Reporting group description
    Subjects aged 9 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.

    Reporting group title
    Part B: LUM/IVA
    Reporting group description
    Subjects aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.

    Subject analysis set title
    Part A Overall Arm: LUM/IVA
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects aged 6 through 11 years who received LUM 200 mg in fixed-­dose combination with IVA 250 mg orally q12h for 14 days.

    Primary: Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 1

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    End point title
    Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 1 [1]
    End point description
    The Pharmacokinetic (PK) Set included all enrolled subjects who received the study drug and for whom the primary PK data were considered to be sufficient and interpretable.
    End point type
    Primary
    End point timeframe
    4 hours post-morning dose on Day 1
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were reported, inferential statistics were not planned for this primary endpoint.
    End point values
    Part A Overall Arm: LUM/IVA
    Number of subjects analysed
    10
    Units: Nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        LUM
    15200 ± 6740
        IVA
    1920 ± 727
    No statistical analyses for this end point

    Primary: Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 14

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    End point title
    Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 14 [2]
    End point description
    The PK Set included all enrolled subjects who received the study drug and for whom the primary PK data were considered to be sufficient and interpretable.
    End point type
    Primary
    End point timeframe
    4 hours post-morning dose on Day 14
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were reported, inferential statistics were not planned for this primary endpoint.
    End point values
    Part A Overall Arm: LUM/IVA
    Number of subjects analysed
    10
    Units: ng/mL
    arithmetic mean (standard deviation)
        LUM
    24500 ± 10400
        IVA
    622 ± 322
    No statistical analyses for this end point

    Primary: Part A: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Lumacaftor (LUM) and Ivacaftor (IVA)

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    End point title
    Part A: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Lumacaftor (LUM) and Ivacaftor (IVA) [3]
    End point description
    The AUCtau is the area under the concentration versus time curve from time 0 to time tau, where tau is the time at the end of dosing interval. The PK Set included all enrolled subjects who received the study drug and for whom the primary PK data were considered to be sufficient and interpretable.
    End point type
    Primary
    End point timeframe
    Day 14 (pre-morning dose, 4, 6, 12, and 24 hours post-morning dose for LUM; pre-morning dose, 2, 4, 6, 12 hours post-morning dose for IVA)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were reported, inferential statistics were not planned for this primary endpoint.
    End point values
    Part A Overall Arm: LUM/IVA
    Number of subjects analysed
    10
    Units: ng*hr/mL
    median (full range (min-max))
        LUM
    387600 (280700 to 640800)
        IVA
    6838 (2689 to 12100)
    No statistical analyses for this end point

    Primary: Part B: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Part B: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [4] [5]
    End point description
    AE: any untoward medical occurrence in a subject during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. AEs with start date or increased severity on or after the first study drug dose to Week 26 were considered treatment-emergent. The Safety Set included all subjects who received any amount of Part B study drug.
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 26
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [5] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    58
    Units: Subjects
        AEs
    55
        SAEs
    4
    No statistical analyses for this end point

    Secondary: Part A: Observed Plasma Concentration of Lumacaftor Metabolite (M28-LUM) and Ivacaftor Metabolites (M1-IVA and M6-IVA) at Hour 4 Post-dose (C4h) on Day 1 and 14

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    End point title
    Part A: Observed Plasma Concentration of Lumacaftor Metabolite (M28-LUM) and Ivacaftor Metabolites (M1-IVA and M6-IVA) at Hour 4 Post-dose (C4h) on Day 1 and 14
    End point description
    The PK Set included all enrolled subjects who received the study drug and for whom the primary PK data were considered to be sufficient and interpretable.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose, 2, 4, 6 and 12 hours post-morning dose); Day 14 (pre-dose, 4, 6, 12, and anytime between 24 to 96 hours post-morning dose)
    End point values
    Part A Overall Arm: LUM/IVA
    Number of subjects analysed
    10
    Units: ng/mL
    arithmetic mean (standard deviation)
        M28-LUM (Day 1)
    176 ± 79
        M1-IVA (Day 1)
    3940 ± 1380
        M6-IVA (Day 1)
    1810 ± 981
        M28-LUM (Day 14)
    2040 ± 1230
        M1-IVA (Day 14)
    2380 ± 1360
        M6-IVA (Day 14)
    4240 ± 1990
    No statistical analyses for this end point

    Secondary: Part A: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Part A: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [6]
    End point description
    AE: any untoward medical occurrence in a subject during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event.AEs with start date or increased severity on or after the first study drug dose through the end of Part A were considered treatment-emergent. Safety Set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 28
    Notes
    [6] - 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: Only arms which are applicable to the endpoint are reported.
    End point values
    Part A Cohort 1: LUM/IVA Part A Cohort 2: LUM/IVA
    Number of subjects analysed
    5
    5
    Units: Subjects
        AEs
    4
    3
        SAEs
    0
    0
    No statistical analyses for this end point

    Secondary: Part B: Average Absolute Change From Baseline in Sweat Chloride at Day 15 and at Week 4

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    End point title
    Part B: Average Absolute Change From Baseline in Sweat Chloride at Day 15 and at Week 4 [7]
    End point description
    Sweat samples were collected using an approved collection device. Baseline was defined as the average of the measurements at screening and on Day 1 pre-dose. Average of Day 15 and Week 4 measurements was taken and change was calculated as: Average (Day 15 and Week 4 measurement) minus Baseline measurement. The Full Analysis Set (FAS) included all Part B enrolled subjects who were exposed to any amount of Part B study drug. Here “Number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15 and Week 4
    Notes
    [7] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    57
    Units: Millimole per liter (mmol/L)
        least squares mean (confidence interval 95%)
    -19.7 (-23.2 to -16.3)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26

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    End point title
    Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26 [8]
    End point description
    Sweat samples were collected using an approved collection device. Change = Week 26 minus Week 24. The FAS included all Part B enrolled subjects who were exposed to any amount of Part B study drug. Here “Number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 24, Week 26
    Notes
    [8] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    47
    Units: mmol/L
        least squares mean (confidence interval 95%)
    21.3 (18.6 to 24)
    No statistical analyses for this end point

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

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    End point title
    Part B: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24 [9]
    End point description
    BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2). The FAS included all Part B enrolled subjects who were exposed to any amount of Part B study drug. Here “Number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [9] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    56
    Units: Kilogram per square meter (kg/m^2)
        least squares mean (confidence interval 95%)
    0.64 (0.46 to 0.83)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change From Baseline in BMI-for-age Z-score at Week 24

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    End point title
    Part B: Absolute Change From Baseline in BMI-for-age Z-score at Week 24 [10]
    End point description
    BMI was defined as weight in kg divided by height*height in m^2. z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from -infinity to +infinity; where 0: same mean, greater than (>) 0: a greater mean, and lesser than (<) 0: a lesser mean than the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score (BMI z-score). The BMI-for-age z-scores were calculated using National Center for Health Statistics growth charts. The FAS included all Part B enrolled subjects who were exposed to any amount of Part B study drug. Here “Number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [10] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    56
    Units: Z-score
        least squares mean (confidence interval 95%)
    0.15 (0.08 to 0.22)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change From Baseline in Weight at Week 24

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    End point title
    Part B: Absolute Change From Baseline in Weight at Week 24 [11]
    End point description
    The FAS included all Part B enrolled subjects who were exposed to any amount of Part B study drug. Here “Number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [11] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    56
    Units: Kilograms (kg)
        least squares mean (confidence interval 95%)
    2.6 (2.2 to 3)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change From Baseline in Weight-for-age Z-score at Week 24

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    End point title
    Part B: Absolute Change From Baseline in Weight-for-age Z-score at Week 24 [12]
    End point description
    Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from -infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. Weight, adjusted for age and sex, was analyzed as weight-for-age z-score (weight z-score). The weight-for-age z-scores were calculated using National Center for Health Statistics growth charts. The FAS included all Part B enrolled subjects who were exposed to any amount of Part B study drug. Here “Number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [12] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    56
    Units: Z-score
        least squares mean (confidence interval 95%)
    0.13 (0.07 to 0.19)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change From Baseline in Height at Week 24

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    End point title
    Part B: Absolute Change From Baseline in Height at Week 24 [13]
    End point description
    The FAS included all Part B enrolled subjects who were exposed to any amount of Part B study drug. Here “Number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [13] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    56
    Units: Centimeter (cm)
        least squares mean (confidence interval 95%)
    2.9 (2.6 to 3.2)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change From Baseline in Height-for-age Z-score at Week 24

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    End point title
    Part B: Absolute Change From Baseline in Height-for-age Z-score at Week 24 [14]
    End point description
    Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from -infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. Height, adjusted for age and sex, was analyzed as height-for-age z-score (height z-score). The height-for-age z-scores were calculated using National Center for Health Statistics growth charts. The FAS included all Part B enrolled subjects who were exposed to any amount of Part B study drug. Here “Number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [14] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    56
    Units: Z-score
        least squares mean (confidence interval 95%)
    0.03 (-0.02 to 0.09)
    No statistical analyses for this end point

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

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    End point title
    Part B: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24 [15]
    End point description
    The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. The FAS included all Part B enrolled subjects who were exposed to any amount of Part B study drug. Here “Number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [15] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    56
    Units: Units on a scale
        least squares mean (confidence interval 95%)
    5.4 (1.4 to 9.4)
    No statistical analyses for this end point

    Secondary: Part B: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains at Week 24

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    End point title
    Part B: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains at Week 24 [16]
    End point description
    The TSQM is a 14-item self-administered questionnaire which measures subject's experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction. The FAS included all Part B enrolled subjects who were exposed to any amount of Part B study drug. Here “Number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [16] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    50
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        Change at Week 24: Effectiveness
    9.2 (4.3 to 14.1)
        Change at Week 24: Side Effects
    -0.3 (-1.4 to 0.8)
        Change at Week 24: Convenience
    11.1 (7.1 to 15.1)
        Change at Week 24: Global Score
    3.6 (-2 to 9.1)
    No statistical analyses for this end point

    Secondary: Part B: Pre-dose Concentration (Ctrough) and 3 to 6 Hours Post-dose Concentration (C3-6hr) of Lumacaftor, Lumacaftor Metabolite (M28-LUM), Ivacaftor and Ivacaftor Metabolites (M1-IVA and M6-IVA)

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    End point title
    Part B: Pre-dose Concentration (Ctrough) and 3 to 6 Hours Post-dose Concentration (C3-6hr) of Lumacaftor, Lumacaftor Metabolite (M28-LUM), Ivacaftor and Ivacaftor Metabolites (M1-IVA and M6-IVA) [17]
    End point description
    Ctrough and C3-6hr for lumacaftor, M28 lumacaftor (lumacaftor metabolite), ivacaftor, M1 ivacaftor (ivacaftor metabolite), and M6 ivacaftor (ivacaftor metabolite) were calculated. Ctrough was observed pre-dose concentration. C3-6hr was observed concentration at 3 to 6 hours post- dose. The PK Set included all enrolled subjects who received the study drug and for whom the primary PK data were considered to be sufficient and interpretable. Here “n” signifies those subjects who were evaluable at the specified time point for the given category.
    End point type
    Secondary
    End point timeframe
    For Ctrough: pre-morning dose on Week 4, Week 6 and Week 24; For C3-6hr: 3 to 6 hours post-morning dose on Day 1, 15 and Week 4
    Notes
    [17] - 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: Only arm which is applicable to the endpoint is reported.
    End point values
    Part B: LUM/IVA
    Number of subjects analysed
    58
    Units: ng/mL
    arithmetic mean (standard deviation)
        C3-6h LUM (Day 1) (n=57)
    17100 ± 6260
        C3-6h IVA (Day 1) (n=57)
    1980 ± 850
        C3-6h M28-LUM (Day 1) (n=57)
    186 ± 96.3
        C3-6h M1-IVA (Day 1) (n=57)
    4170 ± 1940
        C3-6h M6-IVA (Day 1) (n=57)
    2040 ± 1650
        C3-6h LUM (Day 15) (n=55)
    21400 ± 6850
        C3-6h IVA (Day 15) (n=55)
    751 ± 433
        C3-6h M28-LUM (Day 15) (n=55)
    1660 ± 843
        C3-6h M1-IVA (Day 15) (n=55)
    2670 ± 1330
        C3-6h M6-IVA (Day 15) (n=55)
    4360 ± 2340
        C3-6h LUM (Week 4) (n=54)
    22000 ± 8470
        C3-6h IVA (Week 4) (n=54)
    779 ± 389
        C3-6h M28-LUM (Week 4) (n=54)
    1730 ± 884
        C3-6h M1-IVA (Week 4) (n=54)
    2800 ± 1410
        C3-6h M6-IVA (Week 4) (n=54)
    4690 ± 3360
        Ctrough LUM (Week 4) (n=53)
    12300 ± 6780
        Ctrough IVA (Week 4) (n=53)
    171 ± 228
        Ctrough M28-LUM (Week 4) (n=53)
    1780 ± 903
        Ctrough M1-IVA (Week 4) (n=53)
    684 ± 816
        Ctrough M6-IVA (Week 4) (n=53)
    2490 ± 2150
        Ctrough LUM (Week 16) (n=53)
    11500 ± 6020
        Ctrough IVA (Week 16) (n=52)
    153 ± 150
        Ctrough M28-LUM (Week 16) (n=53)
    1610 ± 859
        Ctrough M1-IVA (Week 16) (n=53)
    690 ± 627
        Ctrough M6-IVA (Week 16) (n=53)
    2360 ± 1570
        Ctrough LUM (Week 24) (n=51)
    11400 ± 5300
        Ctrough IVA (Week 24) (n=51)
    118 ± 87.2
        Ctrough M28-LUM (Week 24) (n=51)
    1710 ± 947
        Ctrough M1-IVA (Week 24) (n=51)
    493 ± 409
        Ctrough M6-IVA (Week 24) (n=51)
    1790 ± 1180
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Part A Cohort 1: LUM/IVA
    Reporting group description
    Subjects aged 6 through 8 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.

    Reporting group title
    Part A Cohort 2: LUM/IVA
    Reporting group description
    Subjects aged 9 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.

    Reporting group title
    Part B: LUM/IVA
    Reporting group description
    Subjects aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.

    Serious adverse events
    Part A Cohort 1: LUM/IVA Part A Cohort 2: LUM/IVA Part B: LUM/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    4 / 58 (6.90%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Part A Cohort 1: LUM/IVA Part A Cohort 2: LUM/IVA Part B: LUM/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    3 / 5 (60.00%)
    55 / 58 (94.83%)
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    House dust allergy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Mycotic allergy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    6 / 58 (10.34%)
         occurrences all number
    1
    0
    6
    Fatigue
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    6 / 58 (10.34%)
         occurrences all number
    0
    0
    6
    Asthenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Malaise
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Application site erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Application site urticaria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Application site vesicles
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Vessel puncture site reaction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Arthropod bite
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    2
    Foot fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Traumatic haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Sunburn
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Upper limb fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    6 / 58 (10.34%)
         occurrences all number
    0
    0
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Mean cell haemoglobin concentration decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Pseudomonas test positive
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    2
    Blood creatinine decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Crystal urine present
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    2
    Eosinophil count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Streptococcus test positive
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 58 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 5 (60.00%)
    29 / 58 (50.00%)
         occurrences all number
    1
    5
    44
    Nasal congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    12 / 58 (20.69%)
         occurrences all number
    0
    1
    16
    Sputum increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    8 / 58 (13.79%)
         occurrences all number
    0
    0
    11
    Haemoptysis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Lower respiratory tract congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    5 / 58 (8.62%)
         occurrences all number
    0
    0
    5
    Increased viscosity of upper respiratory secretion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Paranasal sinus hypersecretion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Pharyngeal erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Rales
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    Respiration abnormal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Sinus congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    3
    Sneezing
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Nasal polyps
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Rhonchi
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    Normochromic normocytic anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Lymphadenopathy
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    1
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 5 (20.00%)
    12 / 58 (20.69%)
         occurrences all number
    2
    1
    16
    Migraine
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Sinus headache
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    3
    Lethargy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Cataract
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    8 / 58 (13.79%)
         occurrences all number
    1
    0
    9
    Constipation
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    5 / 58 (8.62%)
         occurrences all number
    1
    0
    6
    Diarrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    1
    0
    5
    Abdominal discomfort
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    4
    Abdominal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    6 / 58 (10.34%)
         occurrences all number
    0
    0
    7
    Flatulence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    6 / 58 (10.34%)
         occurrences all number
    0
    0
    6
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    6 / 58 (10.34%)
         occurrences all number
    0
    0
    8
    Faeces soft
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Frequent bowel movements
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Faecal volume increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    0
    0
    4
    Dermatitis contact
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    Dandruff
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Urticaria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Muscle spasms
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Pain in extremity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    Increased appetite
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    11 / 58 (18.97%)
         occurrences all number
    0
    0
    13
    Gastroenteritis viral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Otitis media
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    4
    Sinusitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    Abscess limb
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Impetigo
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Otitis externa
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    0
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1
    Tinea infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2013
    Added Part B (a 24 week, open label Treatment Period).
    30 Sep 2014
    Added evaluation of sweat chloride and liver function to Part B.
    12 Mar 2015
    Added the PK evaluation of M28-LUM and M6-IVA to the secondary objectives and endpoints.

    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.
    Due to limited sampling and instances of missing data, C4h was reported instead of Cmax as an approximation of maximum concentration. Sparse PK sampling scheme was optimized around parent compounds which limited the estimation of AUC for metabolites.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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