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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis who Have the R117H-CFTR Mutation

    Summary
    EudraCT number
    		 2012-000387-19
    Trial protocol
    		 GB  
    Global end of trial date
    25 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jun 2016
    First version publication date
    07 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX11-770-110
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01614457
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, MA, 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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000335-PIP01-08
    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 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy of ivacaftor in subjects (6 years of age and older) with cystic fibrosis (CF) with R117H-CF transmembrane conductance regulator (CFTR) mutation.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    		 Subjects remained on their stable CF medication regimens from 4 weeks before Day 1 through the Follow up Visit.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jul 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    United States: 54
    Worldwide total number of subjects
    69
    EEA total number of subjects
    15
    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)
    17
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    48
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 27 sites in the United States and the European Union.

    Pre-assignment
    Screening details
    		 A total of 70 subjects were randomized, of which 1 subject discontinued the study prior to study drug administration. A total of 69 subjects started treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ivacaftor
    Arm description
    		 Ivacaftor 150 milligram (mg) tablet orally twice daily for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ivacaftor 150 milligram (mg) tablet orally twice daily for 24 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to ivacaftor tablet orally twice daily for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to ivacaftor tablet orally twice daily for 24 weeks.

    Number of subjects in period 1
    		Ivacaftor Placebo
    Started
    34
    35
    Completed
    32
    35
    Not completed
    2
    0
         'Non-Compliance '
    1
    -
         'Pregnancy (Self or Partner) '
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ivacaftor
    Reporting group description
    		 Ivacaftor 150 milligram (mg) tablet orally twice daily for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to ivacaftor tablet orally twice daily for 24 weeks.

    Reporting group values
    		 Ivacaftor Placebo Total
    Number of subjects
    		 34 35 69
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 29.2 ( 16.57 ) 32.7 ( 17.43 ) -
    Gender categorical
    Units: Subjects
        Female
    		 19 20 39
        Male
    		 15 15 30

    End points

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    End points reporting groups
    Reporting group title
    Ivacaftor
    Reporting group description
    		 Ivacaftor 150 milligram (mg) tablet orally twice daily for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to ivacaftor tablet orally twice daily for 24 weeks.

    Primary: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24

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    End point title
    		 Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 6 to 17 years and for female subjects aged 6 to 15 years. The analysis was performed on Full Analysis Set (FAS) which included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo).
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Ivacaftor Placebo
    Number of subjects analysed
    34
    35
    Units: Percent predicted of FEV1
        least squares mean (standard error)
    2.5724 ( 1.1532 )
    0.4611 ( 1.1313 )
    Statistical analysis title
    		 Ivacaftor vs Placebo
    Statistical analysis description
    Analysis was based on mixed effects model for repeated measures (MMRM) with dependent variable absolute change from baseline, with treatment group, visit and treatment by visit interaction as fixed effects, subject as random effect, and with adjustment for the continuous baseline value of age and percent predicted FEV1, using compound symmetry covariance matrix.
    Comparison groups
    Ivacaftor v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1979
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least square (LS) Mean Difference
    Point estimate
    2.1114
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1305
         upper limit
    		 5.3532

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

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    End point title
    		 Change From Baseline in Body Mass Index (BMI) at Week 24
    End point description
    BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2). FAS included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Ivacaftor Placebo
    Number of subjects analysed
    34
    35
    Units: kg/m^2
        least squares mean (standard error)
    0.491 ( 0.6653 )
    0.2284 ( 0.6504 )
    Statistical analysis title
    		 Ivacaftor vs Placebo
    Statistical analysis description
    Analysis was based on linear mixed model with dependent variable BMI and treatment as a fixed effect, adjustment for baseline percent predicted FEV1, age and visit by treatment interaction was included as covariates and intercept, visit were included as random effects.
    Comparison groups
    Ivacaftor v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.778 [1]
    Method
    		 Linear Mixed Model
    Parameter type
    		 LS Mean difference
    Point estimate
    0.2626
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5698
         upper limit
    		 2.095
    Notes
    [1] - p-value for the treatment effect is from the slope of BMI versus time.

    Secondary: Change From Baseline in Sweat Chloride Through Week 24

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    End point title
    		 Change From Baseline in Sweat Chloride Through Week 24
    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. FAS included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo). Here, "Number of subjects analyzed" signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Ivacaftor Placebo
    Number of subjects analysed
    32
    35
    Units: millimole per liter (mmol/L
        least squares mean (standard error)
    -26.2771 ( 1.4584 )
    -2.3078 ( 1.3716 )
    Statistical analysis title
    		 Ivacaftor vs Placebo
    Statistical analysis description
    Analysis was based on MMRM with dependent variable absolute change from baseline, with treatment group, visit and treatment by visit interaction as fixed effects, subject as random effect, and with adjustment for the continuous baseline value of age and percent predicted FEV1, and sweat chloride, using a compound symmetry covariance matrix.
    Comparison groups
    Ivacaftor v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -23.9693
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.0094
         upper limit
    		 -19.9293

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

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    End point title
    		 Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24
    End point description
    The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. FAS included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo). Here, "Number of participants analyzed" signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Ivacaftor Placebo
    Number of subjects analysed
    33
    34
    Units: units on a scale
        least squares mean (standard error)
    7.5585 ( 2.2073 )
    -0.8289 ( 2.1569 )
    Statistical analysis title
    		 Ivacaftor vs Placebo
    Statistical analysis description
    Analysis was based on MMRM with dependent variable absolute change from baseline, with treatment group, visit and treatment by visit interaction as fixed effects, subject as random effect, and with adjustment for the continuous baseline value of age and percent predicted FEV1, and CFQ-R respiratory domain score, using compound symmetry covariance matrix.
    Comparison groups
    Ivacaftor v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0091
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 LS Mean difference
    Point estimate
    8.3874
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1658
         upper limit
    		 14.609

    Secondary: Time to First Pulmonary Exacerbation

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    End point title
    		 Time to First Pulmonary Exacerbation
    End point description
    Number of events (pulmonary exacerbation) during the pre-specified time intervals were reported. A subject without an exacerbation before withdrawal from the study was considered censored at the time of withdrawal, and a subject without an exacerbation who completes the study period was considered censored at the end of the analysis period. FAS included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo).
    End point type
    Secondary
    End point timeframe
    Day 0 to 15, Day 16 to 56, Day 57 to 112, Day 113 to 168
    End point values
    		 Ivacaftor Placebo
    Number of subjects analysed
    34
    35
    Units: Events
        Day 0 to 15
    3
    1
        Day 16 to 56
    4
    2
        Day 57 to 112
    2
    6
        Day 113 to 168
    1
    4
    Statistical analysis title
    		 Ivacaftor vs Placebo
    Comparison groups
    Ivacaftor v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8556
    Method
    		 Cox Proportional Hazard Regression
    Confidence interval

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

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    End point title
    		 Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    AE: any untoward medical occurrence, including clinically significant clinical laboratory assessments which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event. Safety Set included all subjects who received at least 1 dose of study drug (ivacaftor or placebo).
    End point type
    Secondary
    End point timeframe
    Baseline up to follow-up (3 to 4 weeks after last dose [last dose = Week 24])
    End point values
    		 Ivacaftor Placebo
    Number of subjects analysed
    34
    35
    Units: Subjects
        Subjects with any AEs
    32
    35
        Subjects with SAEs
    4
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to follow-up (3 to 4 weeks after last dose [last dose = Week 24])
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Ivacaftor
    Reporting group description
    		 Ivacaftor 150 mg tablet orally twice daily for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo-matched-to-ivacaftor tablet orally twice daily for 24 weeks.

    Serious adverse events
    		 Ivacaftor Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 34 (11.76%)
    6 / 35 (17.14%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    3 / 34 (8.82%)
    6 / 35 (17.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (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 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 34 (94.12%)
    35 / 35 (100.00%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 34 (5.88%)
    6 / 35 (17.14%)
         occurrences all number
    3
    9
    Fatigue
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    2
    2
    Influenza like illness
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Pain
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Chills
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Irritability
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 34 (29.41%)
    9 / 35 (25.71%)
         occurrences all number
    14
    12
    Sputum increased
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 35 (11.43%)
         occurrences all number
    6
    4
    Nasal congestion
         subjects affected / exposed
    5 / 34 (14.71%)
    2 / 35 (5.71%)
         occurrences all number
    7
    3
    Oropharyngeal pain
         subjects affected / exposed
    5 / 34 (14.71%)
    2 / 35 (5.71%)
         occurrences all number
    5
    4
    Haemoptysis
         subjects affected / exposed
    0 / 34 (0.00%)
    6 / 35 (17.14%)
         occurrences all number
    0
    10
    Rhinorrhoea
         subjects affected / exposed
    3 / 34 (8.82%)
    3 / 35 (8.57%)
         occurrences all number
    4
    3
    Dyspnoea
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 35 (5.71%)
         occurrences all number
    3
    2
    Wheezing
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 35 (2.86%)
         occurrences all number
    4
    1
    Nasal oedema
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Rales
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    4
    Upper-airway cough syndrome
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 35 (0.00%)
         occurrences all number
    3
    0
    Nasal mucosal disorder
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Paranasal sinus hypersecretion
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Sinus congestion
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Asthma
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    2
    Bronchospasm
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Nasal turbinate abnormality
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Pleurisy
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Pleuritic pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Respiration abnormal
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Respiratory tract congestion
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Tonsillolith
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Anxiety
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Investigations
    Forced expiratory volume decreased
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 35 (5.71%)
         occurrences all number
    4
    3
    Blood potassium increased
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    C-reactive protein increased
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Blood calcium decreased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Platelet count increased
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Urine leukocyte esterase positive
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    White blood cells urine positive
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Anal injury
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Animal bite
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Arthropod bite
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Hand fracture
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Muscle strain
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Periorbital haemorrhage
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Tendon rupture
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 34 (17.65%)
    5 / 35 (14.29%)
         occurrences all number
    9
    6
    Dizziness
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    3
    Lethargy
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Sinus headache
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    2
    Ear pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 35 (11.43%)
         occurrences all number
    6
    4
    Vomiting
         subjects affected / exposed
    3 / 34 (8.82%)
    4 / 35 (11.43%)
         occurrences all number
    3
    4
    Abdominal pain
         subjects affected / exposed
    4 / 34 (11.76%)
    0 / 35 (0.00%)
         occurrences all number
    5
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 35 (5.71%)
         occurrences all number
    5
    3
    Constipation
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    3
    Abdominal discomfort
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Abdominal tenderness
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Loose tooth
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Palatal oedema
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Drug eruption
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Eczema
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Ingrowing nail
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Pruritus generalised
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Rosacea
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 34 (0.00%)
    4 / 35 (11.43%)
         occurrences all number
    0
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Musculoskeletal pain
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Clubbing
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Exostosis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Joint swelling
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    11 / 34 (32.35%)
    13 / 35 (37.14%)
         occurrences all number
    14
    18
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 34 (8.82%)
    5 / 35 (14.29%)
         occurrences all number
    3
    6
    Sinusitis
         subjects affected / exposed
    2 / 34 (5.88%)
    5 / 35 (14.29%)
         occurrences all number
    4
    6
    Bacterial disease carrier
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 35 (2.86%)
         occurrences all number
    6
    1
    Influenza
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Acute sinusitis
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 35 (2.86%)
         occurrences all number
    1
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Bronchitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Candidiasis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Folliculitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Lip infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Oral fungal infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Otitis externa
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Scarlet fever
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Varicella
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Decreased appetite
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    1
    Iron deficiency
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Mar 2012
    An additional screening assessment of a comprehensive ophthalmologic examination was added for all subjects. Following feedback from Cystic Fibrosis Foundation Therapeutics, the number of electrocardiogram (ECG) assessments was reduced to shorten the duration of a study visit. -An inflammatory mediator assessment was added to the Follow-up Visit.
    15 Jun 2012
    Abstinence was removed as a highly effective method of contraception for a subject’s partner since this method would only be effective when practiced with a study subject who was also practicing abstinence.
    18 Dec 2012
    Collection of sweat chloride at Screening was required for subjects only if the value is not available in the subject’s medical records and the value was needed for the diagnosis of CF to fulfill inclusion criterion. Changed the timing of when the Follow-up Visit was to occur after the last dose of study drug from “4 weeks (±7 days)” to “3 to 4 weeks” in protocol -Ophthalmologic examinations were added as a safety endpoint for safety monitoring. Commercially available ivacaftor (Kalydeco™) was added to the list of prohibited medications. Clarified the statistical analysis was to be performed for the interim analysis. Requirement in protocol was changed to completing a case report form (CRF) for each subject screened in order to collect data for subjects who were screened but not enrolled.
    11 Jun 2013
    The exclusion of hypertonic saline use was removed. A recommendation was added that subjects should maintain their status of hypertonic saline use for the duration of the study and the final analysis was to be based on data from all enrolled subject assessments. Clarification was provided that, in the event of early study termination, subjects who had not had their Week 24 Visit were to be considered to have completed their assigned treatment duration.

    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.
    Enrollment was planned for a min of 40 & a max of approx. 80 subjects. Based upon power calculations & after exceeding min number of subjects defined in protocol, study was stopped by sponsor; however, the overall study status was completed.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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