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    Clinical Trial Results:
    A Phase 3, 2-Arm, Roll-Over Study to Evaluate the Long-term Safety and Pharmacodynamics of Ivacaftor Treatment in Pediatric Subjects With Cystic Fibrosis and a CFTR Gating Mutation

    Summary
    EudraCT number
    		 2012-000386-20
    Trial protocol
    		 GB  
    Global end of trial date
    17 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jul 2016
    First version publication date
    02 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    VX11-770-109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01946412
    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
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
    Scientific contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety of ivacaftor treatment.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    European Union: 8
    Worldwide total number of subjects
    33
    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)
    33
    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
    		 This was a Phase 3, multicenter, 2 arm study in subjects who received at least 1 dose of study drug in parent study VX11-770-108 (study 108) (2012-000204-15).

    Pre-assignment
    Screening details
    		 In study VX11-770-109 (study 109) (2012-000386-20), subjects were to be enrolled in either ivacaftor arm or observational arm. However, there were no subjects enrolled in the observational arm. A total of 33 subjects were enrolled in the ivacaftor arm.

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

    Arms
    Arm title
    		 Ivacaftor
    Arm description
    		 Subjects received ivacaftor 50 milligram (mg) or 75 mg or 150 mg based on body weight and age. Ivacaftor 50 mg administered every 12 hours (q12h) for subjects aged 2 to less than (<) 6 years and weighing <14 kilograms (kg), ivacaftor 75 mg q12h for subjects aged 2 to <6 years and weighing greater than or equal to (>=) 14 kg and ivacaftor 150 mg q12h for subjects >=6 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received either ivacaftor 50 mg or 75 mg or 150 mg orally q12h. Mini-tablets were used for 50 and 75 mg doses and tablet for 150 mg dose.

    Number of subjects in period 1
    		Ivacaftor
    Started
    33
    Completed
    28
    Not completed
    5
         Non-Compliance
    1
         Adverse Event
    1
         Difficulty in swallowing
    1
         Continued with commercial Kalydeco
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ivacaftor
    Reporting group description
    		 Subjects received ivacaftor 50 milligram (mg) or 75 mg or 150 mg based on body weight and age. Ivacaftor 50 mg administered every 12 hours (q12h) for subjects aged 2 to less than (<) 6 years and weighing <14 kilograms (kg), ivacaftor 75 mg q12h for subjects aged 2 to <6 years and weighing greater than or equal to (>=) 14 kg and ivacaftor 150 mg q12h for subjects >=6 years.

    Reporting group values
    		 Ivacaftor Total
    Number of subjects
    		 33 33
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.7 ( 1.04 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 27 27

    End points

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    End points reporting groups
    Reporting group title
    Ivacaftor
    Reporting group description
    		 Subjects received ivacaftor 50 milligram (mg) or 75 mg or 150 mg based on body weight and age. Ivacaftor 50 mg administered every 12 hours (q12h) for subjects aged 2 to less than (<) 6 years and weighing <14 kilograms (kg), ivacaftor 75 mg q12h for subjects aged 2 to <6 years and weighing greater than or equal to (>=) 14 kg and ivacaftor 150 mg q12h for subjects >=6 years.

    Subject analysis set title
    Ivacaftor 50 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received ivacaftor 50 mg q12h in parent study VX11-770-108 (2012-000204-15), received either ivacaftor 50 mg q12h for subjects aged 2 to <6 years and weighing <14 kg or ivacaftor 75 mg q12h for subjects aged 2 to <6 years and >=14 kg or ivacaftor 150 mg q12h for subjects >=6 years in this study (2012-000386-20).

    Subject analysis set title
    Ivacaftor 75 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received ivacaftor 75 mg q12h in parent study VX11-770-108 (2012-000204-15), received either ivacaftor 50 mg q12h for subjects aged 2 to <6 years and weighing <14 kg or ivacaftor 75 mg q12h for subjects aged 2 to <6 years and >=14 kg or ivacaftor 150 mg q12h for subjects >=6 years in this study (2012-000386-20).

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

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    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 dose of study drug through the end of study participation was considered treatment-emergent. Safety set included all subjects who received at least 1 dose of study drug in study 109 (2012-000386-20).
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 97 (for subjects who completed study drug dosing); Day 1 up to 24 weeks after the last dose of study drug (up to Week 108, for subjects who prematurely discontinued study drug dosing).
    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 primary endpoint.
    End point values
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Number of subjects analysed
    9 [2]
    24 [3]
    Units: Subjects
        Subjects with SAEs
    6
    5
        Subjects with AEs
    9
    24
    Notes
    [2] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    [3] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline of Parent Study in Sweat Chloride at Week 24, 48, 72 and 84

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    End point title
    		 Absolute Change From Baseline of Parent Study in Sweat Chloride at Week 24, 48, 72 and 84
    End point description
    Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Baseline was defined as the most recent measurement prior to intake of the first dose of study drug in study 108 Part B (2012-000204-15). Safety set included all subjects who received at least 1 dose of study drug in study 109 (2012-000386-20). Here “n” signifies those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (study 108), Week 24, 48, 72 and 84 (study 109)
    End point values
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Number of subjects analysed
    9 [4]
    24 [5]
    Units: millimole per liter (mmol/L)
    arithmetic mean (standard deviation)
        Baseline (n=7,22)
    93.1 ( 16.2 )
    99.6 ( 13.6 )
        Absolute Change at Week 24 (n=6,18)
    -62.1 ( 12.4 )
    -48.5 ( 18.4 )
        Absolute Change at Week 48 (n=6,15)
    -29.3 ( 37.8 )
    -51.8 ( 27.1 )
        Absolute Change at Week 72 (n=7,14)
    -46.4 ( 16 )
    -52.9 ( 26.7 )
        Absolute Change at Week 84 (n=6,14)
    -46.5 ( 31 )
    -58.1 ( 23.9 )
    Notes
    [4] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    [5] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline of Study 109 in Sweat Chloride at Week 24, 48, 72 and 84

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    End point title
    		 Absolute Change From Baseline of Study 109 in Sweat Chloride at Week 24, 48, 72 and 84
    End point description
    Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of >=15 microliter was required for determination of sweat chloride. Baseline is defined as the most recent measurement prior to intake of the first dose of study drug in study 109 (2012-000386-20). Safety set included all subjects who received at least 1 dose of study drug in study 109 (2012-000386-20). Here “n” signifies those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (study 109), Week 24, 48, 72 and 84 (study 109)
    End point values
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Number of subjects analysed
    9 [6]
    24 [7]
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline (n= 8,23)
    47.8 ( 23.3 )
    52.9 ( 23.1 )
        Absolute Change at Week 24 (n=7,18)
    -4.3 ( 31.6 )
    3.4 ( 15.9 )
        Absolute Change at Week 48 (n=7,17)
    18.1 ( 39.5 )
    -4.5 ( 22.6 )
        Absolute Change at Week 72 (n=8,15)
    -1.5 ( 24.3 )
    -6 ( 20.8 )
        Absolute Change at Week 84 (n=7,16)
    -2.4 ( 44.2 )
    -11.2 ( 25.4 )
    Notes
    [6] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    [7] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline of Parent Study in Weight at Week 12, 24, 36, 48, 60, 72 and 84

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    End point title
    		 Absolute Change From Baseline of Parent Study in Weight at Week 12, 24, 36, 48, 60, 72 and 84
    End point description
    Baseline was defined as the most recent measurement prior to intake of the first dose of study drug in study 108 Part B (2012-000204-15). Safety set included all subjects who received at least 1 dose of study drug in study 109 (2012-000386-20). Here “n” signifies those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (study 108), Week 12, 24, 36, 48, 60, 72 and 84 (study 109)
    End point values
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Number of subjects analysed
    9 [8]
    24 [9]
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        Baseline (n=9, 24)
    12.5 ( 1.1 )
    16.8 ( 1.8 )
        Absolute Change at Week 12 (n= 9, 23)
    1.3 ( 0.4 )
    1.9 ( 0.7 )
        Absolute Change at Week 24 (n=9, 23)
    2 ( 0.6 )
    2.5 ( 0.9 )
        Absolute Change at Week 36 (n=9, 23)
    2.4 ( 0.7 )
    3.1 ( 1 )
        Absolute Change at Week 48 (n=9, 22)
    2.6 ( 0.9 )
    3.4 ( 1.1 )
        Absolute Change at Week 60 (n=9, 22)
    3.2 ( 1 )
    4 ( 1.3 )
        Absolute Change at Week 72 (n=9, 20)
    3.4 ( 0.9 )
    4.8 ( 1.6 )
        Absolute Change at Week 84 (n=9, 19)
    4 ( 1.2 )
    5.7 ( 1.9 )
    Notes
    [8] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    [9] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline of Study 109 in Weight at Week 12, 24, 36, 48, 60, 72 and 84

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    End point title
    		 Absolute Change From Baseline of Study 109 in Weight at Week 12, 24, 36, 48, 60, 72 and 84
    End point description
    Baseline is defined as the most recent measurement prior to intake of the first dose of study drug in study 109 (2012-000386-20). Safety set included all subjects who received at least 1 dose of study drug in study 109 (2012-000386-20). Here “n” signifies those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (study 109), Week 12, 24, 36, 48, 60, 72 and 84 (study 109)
    End point values
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Number of subjects analysed
    9 [10]
    24 [11]
    Units: Kg
    arithmetic mean (standard deviation)
        Baseline (n= 9, 24)
    13.5 ( 1 )
    18.3 ( 2 )
        Absolute Change at Week 12 (n=9, 23)
    0.3 ( 0.4 )
    0.4 ( 0.5 )
        Absolute Change at Week 24 (n=9, 23)
    1 ( 0.5 )
    1 ( 0.7 )
        Absolute Change at Week 36 (n=9, 23)
    1.4 ( 0.6 )
    1.6 ( 0.8 )
        Absolute Change at Week 48 (n=9, 22)
    1.6 ( 0.7 )
    1.9 ( 0.8 )
        Absolute Change at Week 60 (n=9, 22)
    2.2 ( 0.8 )
    2.5 ( 1.1 )
        Absolute Change at Week 72 (n=9, 20)
    2.4 ( 0.7 )
    3.3 ( 1.4 )
        Absolute Change at Week 84 (n=9, 19)
    3 ( 1 )
    4.2 ( 1.7 )
    Notes
    [10] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    [11] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline of Parent Study in Stature at Week 12, 24, 36, 48, 60, 72 and 84

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    End point title
    		 Absolute Change From Baseline of Parent Study in Stature at Week 12, 24, 36, 48, 60, 72 and 84
    End point description
    Stature was measured as height if children could stand unassisted and follow directions; otherwise, stature was measured as length. Baseline was defined as the most recent measurement prior to intake of the first dose of study drug in study 108 Part B (2012-000204-15). Safety set included all subjects who received at least 1 dose of study drug in study 109 (2012-000386-20). Here “n” signifies those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (study 108), Week 12, 24, 36, 48, 60, 72 and 84 (study 109)
    End point values
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Number of subjects analysed
    9 [12]
    24 [13]
    Units: Centimeters (cm)
    arithmetic mean (standard deviation)
        Baseline (n=9, 24)
    89.1 ( 4.3 )
    102.3 ( 6.4 )
        Absolute Change in Week 12 (n=9, 23)
    4.6 ( 1.2 )
    5.4 ( 1.1 )
        Absolute Change in Week 24 (n=9, 23)
    6 ( 1.7 )
    7.7 ( 3.3 )
        Absolute Change in Week 36 (n=9, 23)
    7.8 ( 1.8 )
    8.8 ( 1.4 )
        Absolute Change in Week 48 (n=9, 21)
    9.7 ( 2 )
    10.4 ( 1.7 )
        Absolute Change in Week 60 (n=9, 22)
    11 ( 2.2 )
    11.6 ( 2 )
        Absolute Change in Week 72 (n=9, 20)
    12.5 ( 2.6 )
    13.4 ( 2 )
        Absolute Change in Week 84 (n=9, 19)
    13.6 ( 2.3 )
    15 ( 2.3 )
    Notes
    [12] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    [13] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline of Study 109 in Stature at Week 12, 24, 36, 48, 60, 72 and 84

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    End point title
    		 Absolute Change From Baseline of Study 109 in Stature at Week 12, 24, 36, 48, 60, 72 and 84
    End point description
    Stature was measured as height if children could stand unassisted and follow directions; otherwise, stature was measured as length. Baseline is defined as the most recent measurement prior to intake of the first dose of study drug in study 109 (2012-000386-20). Safety set included all subjects who received at least 1 dose of study drug in study 109 (2012-000386-20). Here “n” signifies those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (study 109), Week 12, 24, 36, 48, 60, 72 and 84 (study 109)
    End point values
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Number of subjects analysed
    9 [14]
    24 [15]
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n=9, 24)
    91.7 ( 4.3 )
    105.8 ( 6.6 )
        Absolute Change at Week 12 (n=9, 23)
    2 ( 1.1 )
    1.8 ( 0.9 )
        Absolute Change at Week 24 (n=9, 23)
    3.4 ( 1.2 )
    4.1 ( 3.2 )
        Absolute Change at Week 36 (n=9, 23)
    5.2 ( 1.5 )
    5.2 ( 1.1 )
        Absolute Change at Week 48 (n=9, 21)
    7.2 ( 1.3 )
    6.8 ( 1.3 )
        Absolute Change at Week 60 (n=9, 22)
    8.4 ( 1.4 )
    8 ( 1.5 )
        Absolute Change at Week 72 (n=9, 20)
    10 ( 2.1 )
    9.8 ( 1.6 )
        Absolute Change at Week 84 (n=9, 19)
    11.1 ( 1.7 )
    11.4 ( 1.9 )
    Notes
    [14] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    [15] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline of Parent Study in Body Mass Index (BMI) at Week 12, 24, 36, 48, 60, 72 and 84

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    End point title
    		 Absolute Change From Baseline of Parent Study in Body Mass Index (BMI) at Week 12, 24, 36, 48, 60, 72 and 84
    End point description
    BMI = (Weight [in kg]) divided by (Stature [in meters]) ^2. Baseline was defined as the most recent measurement prior to intake of the first dose of study drug in study 108 Part B (2012-000204-15). Safety set included all subjects who received at least 1 dose of study drug in study 109 (2012-000386-20). Here “n” signifies those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (study 108), Week 12, 24, 36, 48, 60, 72 and 84 (study 109)
    End point values
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Number of subjects analysed
    9 [16]
    24 [17]
    Units: Kilogram per square meter (kg/m^2)
    arithmetic mean (standard deviation)
        Baseline (n=9, 24)
    15.74 ( 0.69 )
    16.06 ( 1.15 )
        Absolute Change at Week 12 (n=9, 23)
    0.03 ( 0.4 )
    0.09 ( 0.6 )
        Absolute Change at Week 24 (n=9, 23)
    0.31 ( 0.57 )
    -0.12 ( 0.9 )
        Absolute Change at Week 36 (n=9, 23)
    0.15 ( 0.52 )
    0.09 ( 0.73 )
        Absolute Change at Week 48 (n=9, 22)
    -0.31 ( 0.6 )
    -0.13 ( 0.77 )
        Absolute Change at Week 60 (n=9, 22)
    -0.12 ( 0.7 )
    -0.06 ( 0.9 )
        Absolute Change at Week 72 (n=9, 20)
    -0.38 ( 0.68 )
    0.09 ( 0.97 )
        Absolute Change at Week 84 (n=9, 19)
    -0.16 ( 0.96 )
    0.28 ( 0.97 )
    Notes
    [16] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    [17] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline of Study 109 in Body Mass Index (BMI) at Week 12, 24, 36, 48, 60, 72 and 84

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    End point title
    		 Absolute Change From Baseline of Study 109 in Body Mass Index (BMI) at Week 12, 24, 36, 48, 60, 72 and 84
    End point description
    BMI = (Weight [in kg]) divided by (Stature [in meters]) ^2. Baseline is defined as the most recent measurement prior to intake of the first dose of study drug in study 109 (2012-000386-20). Safety set included all subjects who received at least 1 dose of study drug in study 109 (2012-000386-20). Here “n” signifies those subjects who were evaluable at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (study 109), Week 12, 24, 36, 48, 60, 72 and 84 (study 109)
    End point values
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Number of subjects analysed
    9 [18]
    24 [19]
    Units: kg/m^2
    arithmetic mean (standard deviation)
        Baseline (n= 9, 24)
    16.07 ( 0.55 )
    16.33 ( 1.12 )
        Absolute Change at Week 12 (n= 9, 23)
    -0.3 ( 0.6 )
    -0.16 ( 0.48 )
        Absolute Change at Week 24 (n= 9, 23)
    -0.02 ( 0.7 )
    -0.36 ( 1.03 )
        Absolute Change at Week 36 (n= 9, 23)
    -0.18 ( 0.83 )
    -0.16 ( 0.63 )
        Absolute Change at Week 48 (n= 9, 22)
    -0.64 ( 0.81 )
    -0.35 ( 0.57 )
        Absolute Change at Week 60 (n= 9, 22)
    -0.45 ( 0.82 )
    -0.29 ( 0.72 )
        Absolute Change at Week 72 (n= 9, 20)
    -0.71 ( 0.9 )
    -0.21 ( 0.78 )
        Absolute Change at Week 84 (n= 9, 19)
    -0.49 ( 1.09 )
    -0.01 ( 0.87 )
    Notes
    [18] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    [19] - Subjects were to be analyzed based on their dosing as per parent study VX11-770-108 (2012-000204-15)
    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 97 (for subjects who completed study drug dosing); Day 1 up to 24 weeks after the last dose (up to Week 108, for subjects who prematurely discontinued study drug dosing)
    Adverse event reporting additional description
    As per the planned analysis for this study, subjects were to be reported based on their dosing groups as per parent study VX11-770-108 (2012-000204-15).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Ivacaftor 50 mg
    Reporting group description
    		 Subjects who received ivacaftor 50 mg q12h in parent study VX11-770-108 (2012-000204-15), received either ivacaftor 50 mg q12h for subjects aged 2 to <6 years and weighing <14 kg or ivacaftor 75 mg q12h for subjects aged 2 to <6 years and >=14 kg or ivacaftor 150 mg q12h for subjects >=6 years in this study (2012-000386-20).

    Reporting group title
    Ivacaftor 75 mg
    Reporting group description
    		 Subjects who received ivacaftor 75 mg q12h in parent study VX11-770-108 (2012-000204-15), received either ivacaftor 50 mg q12h for subjects aged 2 to <6 years and weighing <14 kg or ivacaftor 75 mg q12h for subjects aged 2 to <6 years and >=14 kg or ivacaftor 150 mg q12h for subjects >=6 years in this study (2012-000386-20).

    Serious adverse events
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 9 (66.67%)
    5 / 24 (20.83%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenovirus test positive
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure anoxic
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    3 / 9 (33.33%)
    3 / 24 (12.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ivacaftor 50 mg Ivacaftor 75 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    24 / 24 (100.00%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 9 (77.78%)
    6 / 24 (25.00%)
         occurrences all number
    12
    10
    Fatigue
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 9 (88.89%)
    16 / 24 (66.67%)
         occurrences all number
    25
    45
    Nasal congestion
         subjects affected / exposed
    4 / 9 (44.44%)
    3 / 24 (12.50%)
         occurrences all number
    6
    3
    Rhinorrhoea
         subjects affected / exposed
    4 / 9 (44.44%)
    2 / 24 (8.33%)
         occurrences all number
    4
    3
    Productive cough
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Asthma
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Allergic sinusitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Respiratory tract congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    Paranasal sinus hypersecretion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Respiration abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Snoring
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Encopresis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Onychophagia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 24 (16.67%)
         occurrences all number
    1
    4
    Haemophilus test positive
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 24 (12.50%)
         occurrences all number
    1
    3
    Bacterial test positive
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Pseudomonas test positive
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Respiratory rate increased
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Adenovirus test positive
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Antibiotic resistant Staphylococcus test positive
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Influenza A virus test positive
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Lymph node palpable
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Respiratory syncytial virus test positive
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Staphylococcus test positive
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Arthropod bite
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Contusion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Eye injury
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Lethargy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Cerumen impaction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Amblyopia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Cataract cortical
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Eye pruritus
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    6 / 9 (66.67%)
    7 / 24 (29.17%)
         occurrences all number
    9
    11
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 24 (20.83%)
         occurrences all number
    0
    6
    Constipation
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 24 (8.33%)
         occurrences all number
    1
    5
    Abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Tooth discolouration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 24 (4.17%)
         occurrences all number
    4
    1
    Dry skin
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Eczema
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Nail disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Red man syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Micturition urgency
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 24 (16.67%)
         occurrences all number
    0
    10
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 24 (20.83%)
         occurrences all number
    0
    10
    Sinusitis
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 24 (12.50%)
         occurrences all number
    2
    7
    Otitis media
         subjects affected / exposed
    2 / 9 (22.22%)
    4 / 24 (16.67%)
         occurrences all number
    3
    5
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    1
    5
    Gastroenteritis viral
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 24 (16.67%)
         occurrences all number
    0
    4
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 24 (12.50%)
         occurrences all number
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Rhinitis
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Bronchitis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Ear infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Varicella
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Herpangina
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Lung infection pseudomonal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Molluscum contagiosum
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Myringitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Rhinovirus infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Streptococcal infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2014
    Changes to frequency of selected safety laboratory tests, study visit windows, and safety laboratory test panel.
    16 Jan 2015
    Changes to frequency of selected safety and efficacy laboratory tests, and changes to medical history data collection.

    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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