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    Clinical Trial Results:
    A Phase 3 Efficacy and Safety Study of Ataluren (PTC124®) in Patients with Nonsense Mutation Cystic Fibrosis

    Summary
    EudraCT number
    		 2013-004581-34
    Trial protocol
    		 IT   BE   DE   NL   ES   GB   BG   GR  
    Global end of trial date
    02 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Apr 2020
    First version publication date
    17 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PTC124-GD-021-CF
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02139306
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PTC Therapeutics, Inc.
    Sponsor organisation address
    100 Corporate Court, South Plainfield, United States, 07080
    Public contact
    Medical Information, PTC Therapeutics, Inc., +353 1-866-562-4620, medinfo@ptcbio.com
    Scientific contact
    Medical Information, PTC Therapeutics International Limited, +353 19068700, 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
    25 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the ability of ataluren to improve pulmonary function relative to placebo by analysing the absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) at Week 48, defined as the average between the change at Week 40 and that at Week 48.
    Protection of trial subjects
    The trial was conducted in accordance with Declaration of Helsinki (revised version of Edinburgh, Scotland, 2000) and in conformance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidance documents.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Aug 2014
    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
    Australia: 16
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    Italy: 40
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 85
    Worldwide total number of subjects
    279
    EEA total number of subjects
    147
    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)
    44
    Adolescents (12-17 years)
    71
    Adults (18-64 years)
    164
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted from 15 August 2014 to 02 November 2016.

    Pre-assignment
    Screening details
    		 A total of 449 participants were enrolled, of which 170 did not qualify for the study due to failure to meet entry criteria. A total of 279 participants were randomized and received study drugs.

    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
    		 Investigator, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ataluren
    Arm description
    		 Participants received ataluren as oral powder for suspension at the dosages of 10, 10, and 20 milligrams/kilograms (mg/kg) at morning, midday, and evening, respectively for 48 weeks of treatment duration or until treatment discontinuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ataluren (PTC124®)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Ataluren was administered as per the dose and schedule specified in the respective arms.

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo orally at morning, midday, and evening for 48 weeks of treatment duration or until treatment discontinuation.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to ataluren was administered as per the dose and schedule specified in the respective arms.

    Number of subjects in period 1
    		Ataluren Placebo
    Started
    140
    139
    Completed
    127
    125
    Not completed
    13
    14
         Consent withdrawn by subject
    4
    6
         Physician decision
    -
    1
         Adverse event, non-fatal
    3
    4
         Protocol deviation
    4
    -
         Other Unspecified
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ataluren
    Reporting group description
    		 Participants received ataluren as oral powder for suspension at the dosages of 10, 10, and 20 milligrams/kilograms (mg/kg) at morning, midday, and evening, respectively for 48 weeks of treatment duration or until treatment discontinuation.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo orally at morning, midday, and evening for 48 weeks of treatment duration or until treatment discontinuation.

    Reporting group values
    		 Ataluren Placebo Total
    Number of subjects
    		 140 139 279
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 25 19 44
        Adolescents (12-17 years)
    		 34 37 71
        Adults (18-64 years)
    		 81 83 164
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 22.0 ± 11.00 22.0 ± 10.44 -
    Gender Categorical
    Units: Subjects
        Female
    		 59 74 133
        Male
    		 81 65 146

    End points

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    End points reporting groups
    Reporting group title
    Ataluren
    Reporting group description
    		 Participants received ataluren as oral powder for suspension at the dosages of 10, 10, and 20 milligrams/kilograms (mg/kg) at morning, midday, and evening, respectively for 48 weeks of treatment duration or until treatment discontinuation.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo orally at morning, midday, and evening for 48 weeks of treatment duration or until treatment discontinuation.

    Primary: Absolute Change From Baseline in Percent-Predicted Forced Expiratory Volume in One Second (ppFEV1) at Week 48

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    End point title
    		 Absolute Change From Baseline in Percent-Predicted Forced Expiratory Volume in One Second (ppFEV1) at Week 48
    End point description
    The FEV1 is the volume of air forcibly exhaled in 1 second and is measured using forced expiratory air spirometry. Change in ppFEV1 at Week 48 was defined as the average between the change from baseline at Week 40 and that at Week 48. Baseline for ppFEV1 was defined as an average of ppFEV1 at Screening (Weeks -4 to -1) and Baseline (Day 1) visits. The intent-to-treat (ITT) population included all randomized participants who had FEV1 data available at Baseline and at least 1 post-baseline visit.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 48
    End point values
    		 Ataluren Placebo
    Number of subjects analysed
    138
    136
    Units: Percentage of predicted FEV1
        least squares mean (confidence interval 95%)
    -1.396 (-2.7735 to -0.0180)
    -1.992 (-3.3271 to -0.6576)
    Statistical analysis title
    		 Ataluren versus Placebo
    Comparison groups
    Ataluren v Placebo
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5336
    Method
    		 Mixed-model, repeated-measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.597
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2881
         upper limit
    		 2.4813
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.957

    Secondary: 48-Week Rate of Pulmonary Exacerbations

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    End point title
    		 48-Week Rate of Pulmonary Exacerbations
    End point description
    Pulmonary exacerbations were assessed using expanded Fuchs' criteria. The expanded Fuchs' exacerbation is defined as the presence of at least 4 of 12 Fuchs’ signs and symptoms requiring treatment with any form of antibiotic treatment (inhaled, oral, or intravenous). Fuchs’ signs and symptoms included increased cough; change in sputum volume, color, or consistency; new or increased hemoptysis; increased dyspnea during moderate or mild exertion, or at rest; sinus pain or tenderness; change in sinus discharge; malaise, fatigue, or lethargy; anorexia or weight loss; temperature above 38 degrees Celsius; change in findings on chest examination; relative 10% decrease in ppFEV1, and chest radiography results consistent with pulmonary infection. The 48-week rate was calculated as: 48-week rate = total number of events/treatment duration by Week 48. The ITT population included all randomized participants who had FEV1 data available at Baseline and at least 1 post-baseline visit.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Ataluren Placebo
    Number of subjects analysed
    138
    136
    Units: number of exacerbations per 48 weeks
        arithmetic mean (standard deviation)
    0.950 ± 1.4038
    1.127 ± 2.5241
    Statistical analysis title
    		 Ataluren versus Placebo
    Comparison groups
    Ataluren v Placebo
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4008
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.8567
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5973
         upper limit
    		 1.2288
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1577

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

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    End point title
    		 Change From Baseline in the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain at Week 48
    End point description
    The teen/adult CFQ-R was used for this study. It was developed specifically for participants with cystic fibrosis. It is a disease-specific instrument designed to measure impact on overall health, daily life, perceived well-being, and symptoms. The respiratory domain assessed respiratory symptoms like coughing, congestion, wheezing etc. Scaling of each item is done via 4-point Likert scales. Scores for each item are summed up to generate a domain score. Scores ranges from 0 to 100, with higher scores indicating better health and lower scores indicating worse health. The ITT population included all randomized participants who had FEV1 data available at Baseline and at least 1 post-baseline visit.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 48
    End point values
    		 Ataluren Placebo
    Number of subjects analysed
    138
    136
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -0.760 (-3.4566 to 1.9364)
    -1.032 (-3.7368 to 1.6728)
    Statistical analysis title
    		 Ataluren versus Placebo
    Comparison groups
    Ataluren v Placebo
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8881
    Method
    		 Mixed-model, repeated measures
    Parameter type
    		 Median difference (net)
    Point estimate
    0.272
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5292
         upper limit
    		 4.0731
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.93

    Secondary: Change From Baseline in Body Mass Index (BMI) at Week 48

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    End point title
    		 Change From Baseline in Body Mass Index (BMI) at Week 48
    End point description
    Malnutrition is common in participants with cystic fibrosis. The BMI is an important clinical measure of nutritional status. The ITT population included all randomized participants who had FEV1 data available at Baseline and at least 1 post-baseline visit.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 48
    End point values
    		 Ataluren Placebo
    Number of subjects analysed
    138
    136
    Units: kilogram per meter square (kg/m^2)
        least squares mean (confidence interval 95%)
    0.296 (0.1126 to 0.4789)
    0.361 (0.1759 to 0.5455)
    Statistical analysis title
    		 Ataluren versus Placebo
    Comparison groups
    Ataluren v Placebo
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6208
    Method
    		 Mixed-model, repeated measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.065
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3233
         upper limit
    		 0.1934
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1312

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)
    End point description
    Adverse Event (AE): any unfavourable/unintended sign, symptom or disease temporally associated with use of study drug, whether or not considered related to study treatment. TEAE: an AE that occurs or worsens in the period extending from first dose of study drug to 4 weeks after last dose of study drug. SAE: a TEAE, regardless of whether it is considered to be related to study drug resulting in 1 of following: death; inpatient hospitalization or prolongation of existing hospitalization; life-threatening; persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; any other medically important event; or a pregnancy resulting in spontaneous abortion, stillbirth, neonatal death or congenital anomaly. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module. As-treated population included all randomized participants who actually received any study treatment.
    End point type
    Secondary
    End point timeframe
    From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks)
    End point values
    		 Ataluren Placebo
    Number of subjects analysed
    140
    139
    Units: participants
        TEAEs
    133
    135
        SAEs
    40
    46
    No statistical analyses for this end point

    Secondary: Number of Participants with TEAEs by Severity and Relationship to Study Drugs

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    End point title
    		 Number of Participants with TEAEs by Severity and Relationship to Study Drugs
    End point description
    The relationship of TEAEs to the study drugs were assessed as: probable related, possibly related, unlikely related, and unrelated. The severity of TEAEs was graded using the Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal). A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. The as-treated population included all randomized participants who actually received any study treatment.
    End point type
    Secondary
    End point timeframe
    From study drug administration to 4-week post-treatment follow-up visit (approximately 52 weeks)
    End point values
    		 Ataluren Placebo
    Number of subjects analysed
    140
    139
    Units: participants
        Severity: Grade 1
    26
    18
        Severity: Grade 2
    88
    88
        Severity: Grade 3
    19
    29
        Severity: Grade 4
    0
    0
        Severity: Grade 5
    0
    0
        Relationship to study drug: Unrelated
    74
    72
        Relationship to study drug: Unlikely related
    37
    34
        Relationship to study drug: Possible related
    21
    25
        Relationship to study drug: Probable related
    1
    4
    No statistical analyses for this end point

    Secondary: Number of Participants with SAEs by Relationship and Severity to Study Drugs

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    End point title
    		 Number of Participants with SAEs by Relationship and Severity to Study Drugs
    End point description
    The relationship of SAEs to the study drugs was assessed as: probable related, possibly related, unlikely related, and unrelated. The severity of SAEs were graded using the CTCAE, Version 3.0 as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal). A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. The as-treated population included all randomized participants who actually received any study treatment.
    End point type
    Secondary
    End point timeframe
    From study drug administration to 4-week post-treatment follow-up visit (approximately 52 weeks)
    End point values
    		 Ataluren Placebo
    Number of subjects analysed
    140
    139
    Units: participants
        Severity: Grade 1
    2
    1
        Severity: Grade 2
    23
    20
        Severity: Grade 3
    15
    25
        Severity: Grade 4
    0
    0
        Severity: Grade 5
    0
    0
        Relationship to study drug: Unrelated
    26
    31
        Relationship to study drug: Unlikely related
    13
    15
        Relationship to study drug: Possible related
    1
    0
        Relationship to study drug: Probable related
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal Vital Signs Reported as TEAEs

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    End point title
    		 Number of Participants with Abnormal Vital Signs Reported as TEAEs
    End point description
    Vital signs included systolic and diastolic blood pressure, pulse rate, pulse oximetry, and body temperature. Participants with abnormal vital signs who required clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test), unless they are associated with an already reported clinical event, are reported. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. The as-treated population included all randomized participants who actually received any study treatment.
    End point type
    Secondary
    End point timeframe
    From study drug administration to 4-week post-treatment follow-up visit (approximately 52 weeks)
    End point values
    		 Ataluren Placebo
    Number of subjects analysed
    140
    139
    Units: participants
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal Clinical Laboratory Parameters Reported as TEAEs

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    End point title
    		 Number of Participants with Abnormal Clinical Laboratory Parameters Reported as TEAEs
    End point description
    Clinical laboratory tests included haematology, biochemistry, and urinalysis. Participants with abnormal laboratory parameters who required clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test), unless they are associated with an already reported clinical event, are reported. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. The as-treated population included all randomized participants who actually received any study treatment.
    End point type
    Secondary
    End point timeframe
    From study drug administration to 4-week post-treatment follow-up visit (approximately 52 weeks)
    End point values
    		 Ataluren Placebo
    Number of subjects analysed
    140
    139
    Units: participants
    32
    30
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal Electrocardiogram Reported as TEAEs

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    End point title
    		 Number of Participants with Abnormal Electrocardiogram Reported as TEAEs
    End point description
    Participants with abnormal electrocardiogram who required clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test), unless they are associated with an already reported clinical event, are reported. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. The as-treated population included all randomized participants who actually received any study treatment.
    End point type
    Secondary
    End point timeframe
    From study drug administration to 4-week post-treatment follow-up visit (approximately 52 weeks)
    End point values
    		 Ataluren Placebo
    Number of subjects analysed
    140
    139
    Units: participants
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From study drug administration to 4-week post-treatment follow-up visit (approximately 52 Weeks)
    Adverse event reporting additional description
    All randomized participants who actually received any study treatment were analysed for AEs and SAEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo orally at morning, midday, and evening for 48 weeks of treatment duration or until treatment discontinuation.

    Reporting group title
    Ataluren
    Reporting group description
    		 Participants received ataluren as oral powder for suspension at the dosages of 10, 10, and 20-mg/kg at morning, midday, and evening, respectively for 48 weeks of treatment duration or until treatment discontinuation.

    Serious adverse events
    		 Placebo Ataluren
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 139 (33.09%)
    40 / 140 (28.57%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Forced expiratory volume decreased
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pseudocholinesterase deficiency
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Thrombosis in device
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopneumopathy
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 139 (0.72%)
    4 / 140 (2.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Red man syndrome
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 139 (0.00%)
    3 / 140 (2.14%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         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
    Costochondritis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (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
    Aspergillus infection
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device-related sepsis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    34 / 139 (24.46%)
    25 / 140 (17.86%)
         occurrences causally related to treatment / all
    0 / 50
    2 / 36
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterium abscessus infection
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 139 (1.44%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection fungal
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Ataluren
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    120 / 139 (86.33%)
    123 / 140 (87.86%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 139 (11.51%)
    12 / 140 (8.57%)
         occurrences all number
    18
    23
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 139 (7.19%)
    9 / 140 (6.43%)
         occurrences all number
    12
    17
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 139 (3.60%)
    11 / 140 (7.86%)
         occurrences all number
    6
    15
    Diarrhoea
         subjects affected / exposed
    12 / 139 (8.63%)
    13 / 140 (9.29%)
         occurrences all number
    20
    15
    Nausea
         subjects affected / exposed
    10 / 139 (7.19%)
    11 / 140 (7.86%)
         occurrences all number
    12
    14
    Vomiting
         subjects affected / exposed
    4 / 139 (2.88%)
    8 / 140 (5.71%)
         occurrences all number
    7
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 139 (17.99%)
    25 / 140 (17.86%)
         occurrences all number
    31
    36
    Haemoptysis
         subjects affected / exposed
    10 / 139 (7.19%)
    12 / 140 (8.57%)
         occurrences all number
    22
    17
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 139 (2.16%)
    7 / 140 (5.00%)
         occurrences all number
    7
    7
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    78 / 139 (56.12%)
    75 / 140 (53.57%)
         occurrences all number
    145
    142
    Influenza
         subjects affected / exposed
    8 / 139 (5.76%)
    7 / 140 (5.00%)
         occurrences all number
    9
    7
    Nasopharyngitis
         subjects affected / exposed
    8 / 139 (5.76%)
    10 / 140 (7.14%)
         occurrences all number
    10
    13
    Pharyngitis
         subjects affected / exposed
    2 / 139 (1.44%)
    7 / 140 (5.00%)
         occurrences all number
    3
    8
    Pseudomonas infection
         subjects affected / exposed
    9 / 139 (6.47%)
    4 / 140 (2.86%)
         occurrences all number
    10
    4
    Rhinitis
         subjects affected / exposed
    8 / 139 (5.76%)
    10 / 140 (7.14%)
         occurrences all number
    9
    12
    Sinusitis
         subjects affected / exposed
    11 / 139 (7.91%)
    16 / 140 (11.43%)
         occurrences all number
    11
    20
    Staphylococcal infection
         subjects affected / exposed
    8 / 139 (5.76%)
    4 / 140 (2.86%)
         occurrences all number
    9
    4
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 139 (15.11%)
    21 / 140 (15.00%)
         occurrences all number
    26
    25
    Viral upper respiratory tract infection
         subjects affected / exposed
    21 / 139 (15.11%)
    27 / 140 (19.29%)
         occurrences all number
    25
    43

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Dec 2014
    • Updated the required screening laboratory values; the previous requirement of plasma adrenocorticotropic hormone (ACTH) ≤upper limit of normal (ULN) in the adrenal system has been removed. - The ACTH laboratory parameter, as an indicator of cortisol cycle and hypothalamus-pituitary-adrenal axis function, was found to be obsolete, and had been a legacy from earlier studies (in which no relevant change had been found). • Updated exclusion criteria for chronic use of inhaled or systemic tobramycin within 4 weeks prior to screening; change in acute therapy between screening and randomization; and evidence of pulmonary exacerbation between screening and randomization. - The previous, longer, 4-month exclusion of inhaled or systemic tobramycin, was found to be impractical, and an impediment to enrolment. - The 4-week exclusion of inhaled or systemic tobramycin allows for a more “lifelike, standard of care” approach, in which Investigators treat possible P.aeruginosa lung infection in the way they would in normal clinical routine. - A possible interference between tobramycin and ataluren regarding read through in nonsense mutations is believed to be fully washed out at 1-2 weeks (that is, less than 1 month). • Identified the type of medications that must be withheld for at least 4 hours prior to spirometric tests; explanation of the timing of restrictions on short- and long-acting beta agonists was added. - Short-acting beta agonists (SABA) are routinely withheld prior to lung function for 4 hours (long-acting beta agonists [LABA] are routinely withheld for 12 hours prior to lung function), and with the above clarification in the protocol, this was included in the participant materials.
    30 Sep 2016
    • Changed the primary endpoint from relative to absolute change in ppFEV1 and redefined the change at Week 48 as an average between the change at Weeks 40 and 48, as per feedback from regulatory authorities. • Updated the definition of pulmonary exacerbation to use the Expanded Fuchs’ criteria instead of the Modified Fuchs’ criteria based on the most current clinical information. • Revised BMI and CFQ-R respiratory domain as secondary endpoints (previously tertiary endpoints). • Added additional tertiary endpoints: - Time to pulmonary exacerbations. - Incidence of pulmonary exacerbations requiring hospitalization. - Change in weight and height. - Incidence and rate of disruptions to daily living (for example, missed school or work). - Incidence, rate, and duration (where possible) of interventions (for example, antibiotic use and hospitalization). - Adjusted sample size calculations based on the new primary endpoint, explained the hierarchical testing procedure for the secondary endpoints, and detailed the statistical analysis plan (SAP) for the newly added endpoints.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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