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    Clinical Trial Results:
    A Phase 3 Efficacy and Safety Study of PTC124 as an Oral Treatment for Nonsense-Mutation-Mediated Cystic Fibrosis

    Summary
    EudraCT number
    		 2008-003924-52
    Trial protocol
    		 SE   NL   BE   ES   FR   GB   IT   DE  
    Global end of trial date
    12 Nov 2011

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Jun 2020
    First version publication date
    03 May 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    PTC124-GD-009-CF
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00803205
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PTC Therapeutics, Inc.
    Sponsor organisation address
    100 Corporate Court, South Plainfield, United States, NJ 07080
    Public contact
    Medical Information, PTC Therapeutics, Inc., +011 44 1-866-562-4620, medinfo@ptcbio.com
    Scientific contact
    Medical Information, PTC Therapeutics International Limited, +353 1-906-8700, medinfo@ptcbio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000115-PIP02-09
    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
    17 May 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Nov 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Nov 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the ability of ataluren to improve pulmonary function as assessed by forced expiratory volume in 1 second (FEV1).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Sep 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 84
    Country: Number of subjects enrolled
    France: 40
    Country: Number of subjects enrolled
    Israel: 34
    Country: Number of subjects enrolled
    Belgium: 25
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Canada: 1
    Worldwide total number of subjects
    238
    EEA total number of subjects
    119
    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)
    58
    Adults (18-64 years)
    163
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 299 male and female participants with nonsense-mutation-mediated cystic fibrosis (nmCF) aged ≥6 years (y) signed the informed consent form and were screened for eligibility, of which 61 did not meet entry criteria to participate in the study.

    Pre-assignment
    Screening details
    		 A total of 238 participants were randomized in a 1:1 ratio to either ataluren or placebo. Six participants (4 in the ataluren arm; 2 in the placebo arm) were excluded from the Intent-to-Treat (ITT) population because they did not have at least 1 post-Baseline (BL) forced expiratory volume (FEV1) assessment by Week 8.

    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
    		 Ataluren As-Treated
    Arm description
    		 Participants received ataluren 3 times daily (TID): 10 milligrams/kilogram (mg/kg) of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ataluren
    Investigational medicinal product code
    Other name
    PTC124, Translarna
    Pharmaceutical forms
    Granules for oral solution in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Ataluren was provided as a vanilla-flavored powder and was mixed with water. Participants received 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg).

    Arm title
    		 Placebo As-Treated
    Arm description
    		 Participants received placebo TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral solution in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching to ataluren was provided. Participants received 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg).

    Number of subjects in period 1
    		Ataluren As-Treated Placebo As-Treated
    Started
    120
    118
    Completed Week 16
    107
    113
    Completed Week 24
    103
    110
    As-Treated Population*
    120
    118
    Intent-to-Treat (ITT) Population
    116
    116
    Per Protocol Population
    100
    103 [1]
    Completed
    100
    104
    Not completed
    20
    14
         Medical Monitor Decision
    1
    -
         Consent withdrawn by subject
    9
    9
         Physician decision
    1
    -
         Acquired a Lung Infection
    -
    1
         Adverse event, non-fatal
    7
    2
         Sponsor Decision
    -
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    1
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: One participant did not contribute data for FEV1 at Week 48.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ataluren As-Treated
    Reporting group description
    		 Participants received ataluren 3 times daily (TID): 10 milligrams/kilogram (mg/kg) of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks.

    Reporting group title
    Placebo As-Treated
    Reporting group description
    		 Participants received placebo TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks.

    Reporting group values
    		 Ataluren As-Treated Placebo As-Treated Total
    Number of subjects
    		 120 118 238
    Age, Customized
    Units: Subjects
        Participants aged 6 (min) to 53 (max) years old
    		 120 118 238
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 23.0 ± 10.06 23.2 ± 9.24 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 58 59 117
        Male
    		 62 59 121
    Subject analysis sets

    Subject analysis set title
    Ataluren ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received ataluren TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks. The ITT population included randomized participants with FEV1 data at Baseline and at least 1 post-Baseline assessment by Week 8.

    Subject analysis set title
    Placebo ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received placebo TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks. The ITT population included randomized participants with FEV1 data at Baseline and at least 1 post-Baseline assessment by Week 8.

    Subject analysis sets values
    		 Ataluren ITT Placebo ITT
    Number of subjects
    116
    116
    Age, Customized
    Units: Subjects
        Participants aged 6 (min) to 53 (max) years old
    116
    116
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    22.8 ± 10.18
    23.2 ± 9.32
    Sex: Female, Male
    Units: Subjects
        Female
    56
    58
        Male
    60
    58

    End points

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    End points reporting groups
    Reporting group title
    Ataluren As-Treated
    Reporting group description
    		 Participants received ataluren 3 times daily (TID): 10 milligrams/kilogram (mg/kg) of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks.

    Reporting group title
    Placebo As-Treated
    Reporting group description
    		 Participants received placebo TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks.

    Subject analysis set title
    Ataluren ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received ataluren TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks. The ITT population included randomized participants with FEV1 data at Baseline and at least 1 post-Baseline assessment by Week 8.

    Subject analysis set title
    Placebo ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received placebo TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks. The ITT population included randomized participants with FEV1 data at Baseline and at least 1 post-Baseline assessment by Week 8.

    Primary: Percentage of Predicted Function (Percent-Predicted) of Forced Expiratory Volume in One Second (FEV1) at Baseline

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    End point title
    		 Percentage of Predicted Function (Percent-Predicted) of Forced Expiratory Volume in One Second (FEV1) at Baseline
    End point description
    Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FEV1 (the amount of air that can be exhaled in 1 second). Spirometry was assessed by using current guidelines of the American Thoracic Society (ATS) and European Respiratory Society (ERS). Baseline was the average of percent-predicted FEV1 at screening and randomization. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline (Week 1)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: percentage of predicted FEV1
        arithmetic mean (standard deviation)
    62.092 ± 13.6159
    60.232 ± 15.1437
    Statistical analysis title
    		 Ataluren, Placebo Baseline Analysis
    Comparison groups
    Ataluren ITT v Placebo ITT
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3264
    Method
    		 ANOVA
    Confidence interval

    Primary: Percentage Change From Baseline in Percent-Predicted of FEV1 at Week 48

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    End point title
    		 Percentage Change From Baseline in Percent-Predicted of FEV1 at Week 48
    End point description
    Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FEV1 (the amount of air that can be exhaled in 1 second). Spirometry was assessed by using current guidelines of the American Thoracic Society (ATS) and European Respiratory Society (ERS). The percentage of change in percent-predicted of FEV1 was calculated as follows: ([percent-predicted FEV1-Baseline percent-predicted FEV1]/Baseline percent-predicted FEV1)*100. Baseline was the average of percent-predicted FEV1 at screening and randomization. A negative change from Baseline indicates that percent-predicted of FEV1 decreased. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Primary
    End point timeframe
    End of Treatment (EOT) (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    100
    103
    Units: percent change
        arithmetic mean (standard deviation)
    -2.534 ± 13.2452
    -5.500 ± 12.5595
    Statistical analysis title
    		 Analysis of Percent-Predicted FEV1 At Week 48
    Statistical analysis description
    Least squares (LS) mean estimates based on mixed model for repeated measures (Weeks 8, 16, 24, 32, 40 and 48) of relative change in percent-predicted FEV1 as the dependent variable; independent variables including Baseline percent-predicted FEV1, treatment, visit, interactions between treatment and visit and between Baseline percent-predicted FEV1 and visit; and stratification factors of Baseline age, Baseline inhaled antibiotics, and Baseline percent-predicted FEV1.
    Comparison groups
    Ataluren ITT v Placebo ITT
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1235 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.754
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.756
         upper limit
    		 6.264
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.78124
    Notes
    [1] - The p-value is the LS-mean for the comparison between active treatment and placebo. The level of significance was 0.04998.

    Secondary: Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks

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    End point title
    		 Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks
    End point description
    A Respiratory Event Form, which collected data on various signs, symptoms, and effects for each event, was completed by the Investigator when informed by the participant of a respiratory event. Pulmonary exacerbations were assessed by using the modified Fuchs' criteria, which defines an exacerbation as a respiratory event requiring treatment with parenteral antibiotics for any 4 of the following 12 symptoms, with or without intravenous antibiotics: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue; temperature >38°C; anorexia; sinus pain; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10% or more from a previously recorded value; or radiographic changes indicative of pulmonary function. The 48-week exacerbation rate was determined by adding the weekly rates for each arm and dividing the sum by 48.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: exacerbations
        arithmetic mean (confidence interval 95%)
    1.42 (1.05 to 1.79)
    1.78 (1.38 to 2.17)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Awake Cough Hourly Rate at Week 48

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    End point title
    		 Change From Baseline in Awake Cough Hourly Rate at Week 48
    End point description
    The frequency of awake cough was measured using the LifeShirt, which incorporates motion-sensing transducers, electrodes, a microphone, and a 3-axis accelerometer into a lightweight vest. The rate was determined by dividing the total number of coughs by 24 (the number of hours of the observation period). Baseline was the latest, valid assessment prior to the treatment. A negative change from Baseline indicates that coughing decreased. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: coughs/hour
    arithmetic mean (standard deviation)
        Baseline (n=115, 114)
    28.218 ± 20.2726
    24.472 ± 16.7828
        Change From Baseline (n=97, 100)
    -0.595 ± 18.3221
    0.882 ± 14.3936
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48

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    End point title
    		 Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48
    End point description
    The CFQ-R consists of 44 items, including generic scales of physical functioning, role functioning, vitality, health perceptions, emotional functioning, and social functioning, and CF-specific scales of respiratory and digestive symptoms, body image, eating disturbances, and treatment burden. Each domain score ranges from 1 to 4. Scores were linearly transformed to a 0 to 100 scale, with higher scores indicating better health. Domain scores were calculated by using the following formula: 100 * (sum of responses - minimum possible sum)/ (maximum possible sum - minimum possible sum). The minimum possible sum = number of questions * 1; the maximum possible = the number of questions * 4. Baseline was the latest, valid assessment prior to the treatment. A negative change from Baseline indicates that health has worsened. Participants may have switched age groups during the study. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: units on a scale
    arithmetic mean (standard deviation)
        Aged 6-13 years, Baseline (n=18, 13)
    77.78 ± 11.070
    79.49 ± 16.879
        Aged 6-13 years, Change From Baseline (n=12, 7)
    -0.69 ± 12.028
    -3.57 ± 21.973
        Age ≥14 years, Baseline (n=95, 101)
    70.06 ± 15.678
    65.95 ± 16.771
        Age ≥14 years, Change From Baseline (n=81, 92)
    -2.81 ± 18.365
    -3.32 ± 16.245
    No statistical analyses for this end point

    Secondary: Percent-Predicted of Forced Vital Capacity (FVC) at Baseline

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    End point title
    		 Percent-Predicted of Forced Vital Capacity (FVC) at Baseline
    End point description
    Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FVC (the amount of air that can be exhaled after taking a deep breath). Spirometry was assessed by using current guidelines of the ATS and ERS. Baseline was the average of percent-predicted FVC at screening and randomization. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 1)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: percentage of predicted FVC
        arithmetic mean (standard deviation)
    78.332 ± 13.1825
    76.609 ± 13.3711
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Percent-Predicted of FVC at Week 48

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    End point title
    		 Percentage Change From Baseline in Percent-Predicted of FVC at Week 48
    End point description
    Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FVC (the amount of air that can be exhaled after taking a deep breath). Spirometry was assessed by using current guidelines of the ATS and ERS. The percentage of change in percent-predicted of FVC was calculated as follows: ((percent-predicted FVC-Baseline percent-predicted FVC)/Baseline percent-predicted FVC)*100. Baseline was the average of percent-predicted FVC at screening and randomization. A negative change from Baseline indicates that percent-predicted of FVC decreased. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    100
    103
    Units: percent change
        arithmetic mean (standard deviation)
    -2.139 ± 10.0463
    -3.484 ± 9.9304
    No statistical analyses for this end point

    Other pre-specified: Percentage of Participants With Treatment-Emergent Adverse Events (TEAE)

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    End point title
    		 Percentage of Participants With Treatment-Emergent Adverse Events (TEAE)
    End point description
    A TEAE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship that occurred or worsened in the period extending from first dose of study drug to 4 weeks after the last dose of study drug. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. AE severity was graded as follows: Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening; Grade 5: fatal. A TEAE was considered related if in the opinion of the Investigator it was possibly or probably caused by the study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the Adverse Events module.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 4 Weeks Post-Treatment (Week 52) or Premature Discontinuation (PD)
    End point values
    		 Ataluren As-Treated Placebo As-Treated
    Number of subjects analysed
    120
    118
    Units: percent of participants
    number (not applicable)
        At least 1 TEAE
    98.3
    97.5
        Grade 1 TEAE
    15.0
    16.9
        Grade 2 TEAE
    67.5
    55.1
        Grade 3 TEAE
    15.8
    25.4
        Grade 4 TEAE
    0
    0
        Grade 5 TEAE
    0
    0
        Unrelated TEAE
    25.0
    35.6
        Unlikely related TEAE
    32.5
    26.3
        Possibly related TEAE
    28.3
    29.7
        Probably related TEAE
    12.5
    5.9
        Discontinuation due to TEAE
    6.7
    2.5
        Serious TEAE
    37.5
    40.7
    No statistical analyses for this end point

    Other pre-specified: Rate of Study Drug Compliance by Drug Accountability

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    End point title
    		 Rate of Study Drug Compliance by Drug Accountability
    End point description
    Study drug compliance was assessed by using a Pharmacy Subject Study Drug Accountability Log (completed by the investigational site personnel). The rate of compliance was defined as 100 * (number of sachets taken/number of planned sachets) during the study. All calculations were based on the records of the first dose date to the last dose date. To differentiate dose strengths while maintaining the blind, each kit had a unique kit number and had prominent lettering “A” and “B.” Each kit contained 65 packets of 1 of the dose strengths (125, 250, or 1000 mg or matching placebo). Labeling for active drug and placebo was identical.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to EOT (Week 48)
    End point values
    		 Ataluren As-Treated Placebo As-Treated
    Number of subjects analysed
    120
    118
    Units: percent of doses taken
    median (full range (min-max))
        Drug Kit A
    90.149 (18.24 to 109.24)
    85.119 (28.36 to 125.79)
        Drug Kit B
    90.830 (13.27 to 116.67)
    86.614 (25.22 to 107.60)
    No statistical analyses for this end point

    Other pre-specified: Rate of Study Drug Compliance by Patient-Reported Data

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    End point title
    		 Rate of Study Drug Compliance by Patient-Reported Data
    End point description
    Patient-reported data were obtained from the participant’s electronic daily diary, which was completed by the participant or the caregiver. During study treatment, the electronic daily diary was to be completed by the participant or caregiver each day for each dose. For each participant, compliance is described in terms of the percentage of study drug actually taken. All calculations were based on the records of the first dose date to the last dose date. To differentiate dose strengths while maintaining the blind, each kit had a unique kit number and had prominent lettering “A” and “B.” Each kit contained 65 packets of 1 of the dose strengths (125, 250, or 1000 mg or matching placebo). Labeling for active drug and placebo was identical.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to EOT (Week 48)
    End point values
    		 Ataluren As-Treated Placebo As-Treated
    Number of subjects analysed
    120
    118
    Units: percent of doses taken
        median (full range (min-max))
    71.48 (0 to 98.5)
    69.27 (6.4 to 98.9)
    No statistical analyses for this end point

    Other pre-specified: Concentration of Ataluren

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    End point title
    		 Concentration of Ataluren [2]
    End point description
    Blood samples were drawn immediately before administration of the first daily dose (dose taken with breakfast) of study drug and 2 hours after the first daily dose. Whenever possible, the pre-dose sample was to be obtained within 15 minutes of drug administration. Participants in the Placebo arm did not receive Ataluren and are not included in this End Point. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Predose and 2 Hours Postdose at Week 1, Week 16, Week 32, EOT (Week 48)
    Notes
    [2] - 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: Participants in the Placebo arm did not receive Ataluren and are not included in this End Point.
    End point values
    		 Ataluren As-Treated
    Number of subjects analysed
    120
    Units: micrograms/milliliter (ug/mL)
    median (full range (min-max))
        Week 1 Predose (n=119)
    0 (0 to 0)
        Week 1 Postdose (n=117)
    14.100 (1.42 to 56.40)
        Week 16 Predose (n=103)
    4.350 (0 to 52.60)
        Week 16 Postdose (n=104)
    11.900 (0.80 to 41.90)
        Week 32 Predose (n=99)
    4.630 (0 to 29.20)
        Week 32 Postdose (n=97)
    13.400 (2.37 to 36.30)
        Week 48 Predose (n= 97)
    3.970 (0 to 27.00)
        Week 48 Postdose (n=96)
    10.500 (0 to 39.10)
    No statistical analyses for this end point

    Other pre-specified: Rate of Interventions for Respiratory Symptoms

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    End point title
    		 Rate of Interventions for Respiratory Symptoms
    End point description
    During treatment, any intervention including hospitalization or use of oral, inhaled, or intravenous antibiotics was documented if it was due to an exacerbation-like episode. Participants and caregivers recorded interventions in an electronic diary. The rate of interventions was defined as the total days with interventions divided by the total study duration.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: days with interventions during the study
    arithmetic mean (standard deviation)
        Hospitalization
    0.010 ± 0.0222
    0.021 ± 0.0469
        Use of Antibiotics
    0.220 ± 0.2284
    0.245 ± 0.2380
    No statistical analyses for this end point

    Other pre-specified: Rate of Disruptions in Activities of Daily Living Because of Pulmonary Symptoms

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    End point title
    		 Rate of Disruptions in Activities of Daily Living Because of Pulmonary Symptoms
    End point description
    During treatment, any disruption in the activities of daily living, such as missed school or work, was documented if it was due to an exacerbation-like episode. Participants and caregivers recorded all disruptions in an electronic diary. The rate of disruptions was defined as the total days with disruptions to daily living divided by the total study duration.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: days with disruption during the study
        arithmetic mean (standard deviation)
    0.037 ± 0.0550
    0.047 ± 0.0755
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Body Weight at Week 48

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    End point title
    		 Change From Baseline in Body Weight at Week 48
    End point description
    Participants were weighed, and the weight was recorded at Baseline and then every 8 weeks during the treatment period. Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that weight increased. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: kg
    arithmetic mean (standard deviation)
        Baseline (n=116, 116)
    53.46 ± 13.941
    56.01 ± 13.149
        Change From Baseline (n=100, 104)
    0.87 ± 3.342
    0.83 ± 3.101
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48

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    End point title
    		 Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48
    End point description
    Expression of IL-8 was measured in serum and in sputum. Sputum was spontaneously produced and tested by using standardized procedures developed by the Cystic Fibrosis Foundation Therapeutics, Inc. Therapeutics Development Network (CFFT-TDN). Baseline was the latest valid assessment prior to the treatment. A negative change from Baseline indicates that the concentration of IL-8 decreased. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: picograms/mL
    arithmetic mean (standard deviation)
        Serum, Baseline (n=115, 116)
    39.537 ± 14.1697
    55.845 ± 131.8505
        Serum, Change From Baseline (n=96, 103)
    -2.334 ± 13.2141
    -16.197 ± 138.3108
        Sputum, Baseline (n=94, 95)
    267629.93 ± 259089.569
    250170.95 ± 180581.976
        Sputum, Change From Baseline (n=73, 81)
    28882.79 ± 199160.845
    9957.24 ± 166348.660
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in the Concentration of Neutrophil Elastase in Sputum at Week 48

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    End point title
    		 Change From Baseline in the Concentration of Neutrophil Elastase in Sputum at Week 48
    End point description
    Expression of neutrophil elastase was measured in sputum. Sputum was spontaneously produced and tested by using standardized procedures developed by the CFFT-TDN. Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that the concentration of neutrophil elastase increased. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    94 [3]
    94 [4]
    Units: ug/mL
    arithmetic mean (standard deviation)
        Baseline (n=94, 94)
    183.64 ± 221.901
    227.35 ± 227.881
        Change From Baseline (n=73, 80)
    5.45 ± 232.824
    -8.67 ± 296.105
    Notes
    [3] - Twenty-two participants in the ataluren group were not evaluable.
    [4] - Twenty-two participants in the placebo group were not evaluable.
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in the Concentration of C-Reactive Protein (CRP) in Serum at Week 48

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    End point title
    		 Change From Baseline in the Concentration of C-Reactive Protein (CRP) in Serum at Week 48
    End point description
    Expression of CRP was measured in serum. Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that CRP concentration increased. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: mg/liter (L)
    arithmetic mean (standard deviation)
        Baseline (n=115, 116)
    6.899 ± 11.5869
    7.037 ± 8.4411
        Change From Baseline (n=96, 103)
    2.420 ± 10.5162
    2.031 ± 10.1202
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in the Total Lung Score as Assessed by Computed Tomography (CT) at Week 48

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    End point title
    		 Change From Baseline in the Total Lung Score as Assessed by Computed Tomography (CT) at Week 48
    End point description
    Lungs were imaged by using non-contrast, spiral CT. The total lung score for each CT scan was established by the sum of 5 characteristics from the Brody scoring system, with scores ranging from 0 to 40.5, with lower scores indicating better lung function. The characteristics scored were bronchiectasis (score range 0 – 12), mucus plugging (score range 0 – 6), peribronchial thickening (score range 0 – 9), parenchyma (score range 0 – 9), and hyperinflation (score range 0 – 4.5). Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that lung function worsened. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    105 [5]
    106 [6]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=105, 106)
    9.531 ± 3.7526
    9.619 ± 3.4244
        Change From Baseline (n=99, 104)
    0.282 ± 1.3441
    0.560 ± 1.5602
    Notes
    [5] - Eleven participants in the ataluren group were not evaluable.
    [6] - Ten participants in the placebo group were not evaluable.
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Total Nasal Chloride Transport as Assessed by Transepithelial Potential Difference (TEPD) at Week 48

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    End point title
    		 Change From Baseline in Total Nasal Chloride Transport as Assessed by Transepithelial Potential Difference (TEPD) at Week 48
    End point description
    TEPD was assessed in each nostril using standardized equipment, techniques, and solutions. Assessments were made on the nasal epithelium cells lining the inferior turbinate. Warmed solutions of Ringer’s solution, amiloride, chloride-free gluconate, isoproterenol, and adenosine triphosphate (ATP) were perfused for ≥3-minute sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed for each nostril. The total chloride transport values were calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol-amiloride). The average of the values for each nostril was computed. If the assessment was available in only 1 nostril, this value was used as if it were the average of both nostrils. A positive change from Baseline indicates that nasal chloride transport increased. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    116
    116
    Units: millivolts
    arithmetic mean (standard deviation)
        Baseline (n=116, 116)
    1.578 ± 3.8786
    1.950 ± 3.5462
        Change From Baseline (n=100, 104)
    0.312 ± 5.0574
    0.139 ± 5.8139
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Sweat Chloride Concentration at Week 48

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    End point title
    		 Change From Baseline in Sweat Chloride Concentration at Week 48
    End point description
    Sweat was collected, from each arm, by using pilocarpine iontophoresis. The chloride concentration in the sweat was quantified for each arm by using standard laboratory methods. Tests were also considered valid if the sweat collection time was ≤35 minutes; tests with longer collection times were also considered valid if extra time was needed to obtain sufficient volume (≥15uL) for analysis. For analysis purposes, the average of the values from each arm were computed. If the assessment was valid and/or available in only 1 arm, this value was used as if it were the average of both arms. The method used was consistent with the CFFT-TDN guidelines. Baseline was the latest, valid assessment prior to the treatment. A negative change from Baseline indicates that sweat chloride concentration decreased. Here, ‘Number analyzed' signifies participants evaluable for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, EOT (Week 48)
    End point values
    		 Ataluren ITT Placebo ITT
    Number of subjects analysed
    114 [7]
    111 [8]
    Units: millimoles/L
    arithmetic mean (standard deviation)
        Baseline (n=114, 111)
    100.140 ± 14.2170
    96.586 ± 15.9279
        Change From Baseline (n=97, 97)
    -1.325 ± 8.9431
    -0.619 ± 10.2657
    Notes
    [7] - Two participants in the ataluren group were not evaluable.
    [8] - Five participants in the placebo group were not evaluable.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 4 Weeks Post-Treatment (Week 52) or Premature Discontinuation (PD)
    Adverse event reporting additional description
    The As-Treated Population: all randomized participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks.

    Reporting group title
    Ataluren
    Reporting group description
    		 Participants received ataluren TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks.

    Serious adverse events
    		 Placebo Ataluren
    Total subjects affected by serious adverse events
         subjects affected / exposed
    50 / 118 (42.37%)
    46 / 120 (38.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 118 (0.85%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cystic fibrosis long
         subjects affected / exposed
    41 / 118 (34.75%)
    34 / 120 (28.33%)
         occurrences causally related to treatment / all
    0 / 66
    0 / 47
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 118 (2.54%)
    2 / 120 (1.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 118 (0.85%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 118 (0.00%)
    3 / 120 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 118 (0.00%)
    3 / 120 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Hypercreatinaemia
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 118 (0.00%)
    2 / 120 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterium abscessus infection
         subjects affected / exposed
    2 / 118 (1.69%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 118 (0.85%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Ataluren
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    115 / 118 (97.46%)
    118 / 120 (98.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 118 (11.86%)
    20 / 120 (16.67%)
         occurrences all number
    34
    38
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    22 / 118 (18.64%)
    17 / 120 (14.17%)
         occurrences all number
    30
    28
    Fatigue
         subjects affected / exposed
    11 / 118 (9.32%)
    11 / 120 (9.17%)
         occurrences all number
    12
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 118 (11.86%)
    20 / 120 (16.67%)
         occurrences all number
    20
    38
    Vomiting
         subjects affected / exposed
    11 / 118 (9.32%)
    14 / 120 (11.67%)
         occurrences all number
    13
    16
    Diarrhoea
         subjects affected / exposed
    21 / 118 (17.80%)
    13 / 120 (10.83%)
         occurrences all number
    27
    18
    Abdominal pain upper
         subjects affected / exposed
    7 / 118 (5.93%)
    11 / 120 (9.17%)
         occurrences all number
    22
    15
    Nausea
         subjects affected / exposed
    13 / 118 (11.02%)
    11 / 120 (9.17%)
         occurrences all number
    19
    13
    Constipation
         subjects affected / exposed
    9 / 118 (7.63%)
    7 / 120 (5.83%)
         occurrences all number
    10
    9
    Respiratory, thoracic and mediastinal disorders
    Cystic fibrosis lung
         subjects affected / exposed
    82 / 118 (69.49%)
    85 / 120 (70.83%)
         occurrences all number
    190
    168
    Cough
         subjects affected / exposed
    35 / 118 (29.66%)
    28 / 120 (23.33%)
         occurrences all number
    70
    47
    Productive cough
         subjects affected / exposed
    11 / 118 (9.32%)
    12 / 120 (10.00%)
         occurrences all number
    14
    16
    Haemoptysis
         subjects affected / exposed
    16 / 118 (13.56%)
    9 / 120 (7.50%)
         occurrences all number
    25
    18
    Rales
         subjects affected / exposed
    6 / 118 (5.08%)
    6 / 120 (5.00%)
         occurrences all number
    7
    8
    Respiratory tract congestion
         subjects affected / exposed
    8 / 118 (6.78%)
    5 / 120 (4.17%)
         occurrences all number
    10
    6
    Oropharyngeal pain
         subjects affected / exposed
    14 / 118 (11.86%)
    4 / 120 (3.33%)
         occurrences all number
    20
    5
    Bronchospasm
         subjects affected / exposed
    6 / 118 (5.08%)
    1 / 120 (0.83%)
         occurrences all number
    6
    1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    4 / 118 (3.39%)
    8 / 120 (6.67%)
         occurrences all number
    4
    9
    Dysuria
         subjects affected / exposed
    1 / 118 (0.85%)
    7 / 120 (5.83%)
         occurrences all number
    1
    8
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 118 (5.08%)
    8 / 120 (6.67%)
         occurrences all number
    6
    8
    Hypercreatinaemia
         subjects affected / exposed
    1 / 118 (0.85%)
    8 / 120 (6.67%)
         occurrences all number
    1
    13
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    32 / 118 (27.12%)
    21 / 120 (17.50%)
         occurrences all number
    37
    27
    Sinusitis
         subjects affected / exposed
    14 / 118 (11.86%)
    15 / 120 (12.50%)
         occurrences all number
    25
    18
    Rhinitis
         subjects affected / exposed
    13 / 118 (11.02%)
    12 / 120 (10.00%)
         occurrences all number
    16
    13
    Nasopharyngitis
         subjects affected / exposed
    8 / 118 (6.78%)
    10 / 120 (8.33%)
         occurrences all number
    12
    15
    Pharyngitis
         subjects affected / exposed
    4 / 118 (3.39%)
    7 / 120 (5.83%)
         occurrences all number
    4
    7
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 118 (10.17%)
    5 / 120 (4.17%)
         occurrences all number
    16
    6
    Metabolism and nutrition disorders
    Abnormal loss of weight
         subjects affected / exposed
    5 / 118 (4.24%)
    10 / 120 (8.33%)
         occurrences all number
    5
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2010
    This amendment introduced the following changes: * Updates of results of Phase 1 and Phase 2 clinical studies in the cystic fibrosis and Duchene/Becker muscular dystrophy populations. * Addition of endpoints related to the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) questionnaire. * Updates of eligibility criteria, frequency of laboratory assessment, treatment with concomitant medications, blood collection, and adverse events reporting. * Updates of procedures for subject enrollment. * Update to plans for statistical analyses and interim analyses, blinding, and unblinding. * Inclusion of summary of findings related to renal dysfunction in this study.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24836205
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