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    Clinical Trial Results:
    A Phase 3 Extension Study of Ataluren (PTC124) in Patients With Nonsense Mutation Dystrophinopathy

    Summary
    EudraCT number
    2013-005489-20
    Trial protocol
    SE   GB   BE   DE   IT   ES   CZ   FR   BG  
    Global end of trial date
    12 Jun 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Aug 2020
    First version publication date
    02 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PTC124-GD-020e-DMD
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02090959
    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
    PTC Trial Disclosure, PTC Therapeutics, Inc., +353 19068700, ptctrialdisclosure@ptcbio.com
    Scientific contact
    PTC Trial Disclosure, PTC Therapeutics, Inc., +353 19068700, ptctrialdisclosure@ptcbio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    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
    12 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this extension study was to obtain long-term safety data of ataluren administered 3 times a day at 10, 10, and 20 milligrams/kilogram (mg/kg) to augment the ataluren safety database.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki (revised version of Edinburgh, Scotland, 2000) and in conformance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidance documents.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Chile: 14
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Turkey: 14
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 63
    Worldwide total number of subjects
    218
    EEA total number of subjects
    95
    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)
    175
    Adolescents (12-17 years)
    43
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    All participants who successfully completed the double-blind, placebo-controlled Phase 3 study (PTC124-GD-020-DMD [NCT01826487]) were screened for this open-label extension study.

    Pre-assignment
    Screening details
    A total of 221 participants completed the double-blind Phase 3 Study PTC124-GD-020-DMD. Of the 221 participants who completed Study PTC124-GD-020-DMD, 219 participants were enrolled in this open-label extension study and 218 were treated.

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

    Arms
    Arm title
    Ataluren
    Arm description
    Participants received ataluren suspension orally 3 times a day (TID), 10 milligrams/kilogram (mg/kg) at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for up to 144 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Ataluren
    Investigational medicinal product code
    PTC124
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Ataluren will be administered per the dose and schedule specified in the arm.

    Number of subjects in period 1
    Ataluren
    Started
    218
    Completed
    68
    Not completed
    150
         Switched to commercial supply
    88
         Consent withdrawn by subject
    10
         Move to medical need program
    3
         Adverse event, non-fatal
    1
         Study termination
    6
         Investigator decision
    2
         Transfer for compassionate use medicine
    4
         Other than specified
    2
         Entered in to other study
    34

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ataluren
    Reporting group description
    Participants received ataluren suspension orally 3 times a day (TID), 10 milligrams/kilogram (mg/kg) at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for up to 144 weeks.

    Reporting group values
    Ataluren Total
    Number of subjects
    218 218
    Age categorical
    Units: Subjects
        Children (2-11 years)
    175 175
        Adolescents (12-17 years)
    43 43
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    9.9 ± 1.78 -
    Sex: Female, Male
    Units: Subjects
        Female
    0 0
        Male
    218 218
    Race/Ethnicity, Customized
    Units: Subjects
        White
    169 169
        Black
    2 2
        Asian
    13 13
        Hispanic
    12 12
        Other
    8 8
        Missing
    14 14
    6 Minute Walk Distance (6MWD)
    The 6MWD test was performed in a 30 meters long flat corridor, where the participant was instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Ambulation was assessed via the 6MWD test following standardized procedures by measuring the 6MWD in meters. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. Number of participants analyzed for this baseline measure are 198 (ambulatory participants).
    Units: meters
        arithmetic mean (standard deviation)
    349.885 ± 105.7913 -
    Time to Stand From Supine Position
    Number of participants analyzed for this baseline measure are 199.
    Units: seconds
        arithmetic mean (standard deviation)
    13.0 ± 10.34 -
    Time to Walk/Run 10 Meters
    Number of participants analyzed for this baseline measure are 215.
    Units: seconds
        arithmetic mean (standard deviation)
    9.31 ± 7.388 -
    Time to Climb 4 Stairs
    Number of participants analyzed for this baseline measure are 203.
    Units: seconds
        arithmetic mean (standard deviation)
    9.03 ± 8.939 -
    Time to Descend 4 Stairs
    Number of participants analyzed for this baseline measure are 204.
    Units: seconds
        arithmetic mean (standard deviation)
    7.52 ± 8.401 -
    North Star Ambulatory Assessment (NSAA) Total Score
    NSAA:tests of 17 abilities: ability to stand, rise from floor, get from lying to sitting, from sitting to standing, raise one’s head, stand on one’s heels, hop, jump, and run. For each activity, a score of 0,1, or 2 was recorded, with 0=“unable to achieve independently,” 1=“modified method but achieves goal independently,” or 2=“normal- achieves goal without any assistance.” Sum of these 17 scores was reported as ordinal total score, which can be transformed to a linear total score from 0(worst) to 100(best). Number of participants analyzed=195 (ambulatory participants with a baseline value).
    Units: units on a scale
        arithmetic mean (standard deviation)
    20.73 ± 8.513 -
    Performance Upper Limb (PUL) Total Score
    PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into shoulder level (4 items), elbow level (9 items), and distal level (8 items) dimensions. Scoring options per item may vary from 0-1 and 0-6, with higher values corresponding to better performance. Each dimension was scored separately with a maximum score of 16 for shoulder level, 34 for elbow level, and 24 for distal level. Total score was calculated by adding the 3 level scores (maximum global score of 74). Number of participants analyzed for this baseline measure are 210.
    Units: units on a scale
        arithmetic mean (standard deviation)
    68.7 ± 4.61 -
    Percent Predicted Forced Vital Capacity (FVC)
    FVC is a standard pulmonary function test. FVC was defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Percent predicted FVC (in %) = [(observed FVC)/(predicted FVC)]*100. Number of participants analyzed for this baseline measure are 210.
    Units: percent predicted FVC
        arithmetic mean (standard deviation)
    59.42 ± 13.843 -
    Percent Predicted Forced Expiratory Volume in 1 Second (FEV1)
    FEV1 is a standard pulmonary function test. FEV1 was defined as the volume of air that can forcibly be blown out in 1 second, after full inspiration in the upright position, measured in liters. Percent predicted FEV1 (in %) = [(observed FEV1)/(predicted FEV1)]*100. Number of participants analyzed for this baseline measure are 209.
    Units: percent predicted FEV1
        arithmetic mean (standard deviation)
    53.76 ± 12.870 -
    Peak Expiratory Flow (PEF)
    PEF was defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Number of participants analyzed for this baseline measure are 213.
    Units: liters/second (L/sec)
        arithmetic mean (standard deviation)
    3.36 ± 1.055 -
    Peak Cough Flow (PCF)
    PCF measures an individual's maximum speed of expiration during cough. Number of participants analyzed for this baseline measure are 194.
    Units: L/sec
        arithmetic mean (standard deviation)
    3.30 ± 1.139 -
    Pediatric Outcomes Data Collection Instrument (PODCI) Transfers/Basic Mobility Score
    PODCI includes a Global Functioning Scale and 5 core scales: Upper Extremity & Physical Function,Transfer/Basic Mobility, Sports/Physical Functioning, Pain/Comfort,and Happiness. Following PODCI domains were prespecified in protocol for analysis:Transfers/Basic Mobility domain assesses difficulty experienced in performing routine motor activities in daily life. Each domain was scored from 0 (poor outcome/worse health) to 100 (the highest level of functioning & least pain). Number of participants analyzed for this baseline measure are 216.
    Units: units on a scale
        arithmetic mean (standard deviation)
    74.6 ± 23.66 -
    Systolic blood pressure
    Number of participants analyzed for this baseline measure are 217.
    Units: millimeters of mercury (mm Hg)
        arithmetic mean (standard deviation)
    106.3 ± 10.72 -
    Diastolic blood pressure
    Number of participants analyzed for this baseline measure are 217.
    Units: mm Hg
        arithmetic mean (standard deviation)
    68.6 ± 11.01 -
    Pulse Rate
    Number of participants analyzed for this baseline measure are 217.
    Units: beats/minute
        arithmetic mean (standard deviation)
    97.0 ± 13.31 -
    Body Temperature
    Number of participants analyzed for this baseline measure are 217.
    Units: degrees centigrade
        arithmetic mean (standard deviation)
    36.47 ± 0.453 -

    End points

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    End points reporting groups
    Reporting group title
    Ataluren
    Reporting group description
    Participants received ataluren suspension orally 3 times a day (TID), 10 milligrams/kilogram (mg/kg) at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for up to 144 weeks.

    Primary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event (AE): any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of AEs: graded per Common Terminology Criteria for AEs (CTCAE), Version 3.0 as Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Drug-related AEs: AEs with possible, probable, unlikely relationship, or unrelated to study drug. Serious AEs (SAEs): death, a life-threatening AE, inpatient hospitalization or prolongation of hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that required medical intervention. TEAE: an AE that occurred from first dose of study drug in this study to 6 weeks after last dose. A summary of other non-serious AEs and all SAEs, regardless of causality is located in Reported AE section. As Treated (AT) population: all participants who received at least 1 dose of ataluren treatment in this study.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) up to 6 weeks post-treatment (Week 150)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Endpoint is safety in nature
    End point values
    Ataluren
    Number of subjects analysed
    218
    Units: participants
        Any AEs
    202
        SAEs
    24
        Drug-Related AEs
    44
        AEs Leading to Withdrawal From Study
    1
        Mild AEs
    87
        Moderate AEs
    71
        Severe AEs
    42
        Life-threatening AEs
    2
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormalities in Clinical Laboratory Parameters

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    End point title
    Number of Participants With Abnormalities in Clinical Laboratory Parameters [2]
    End point description
    Abnormalities in laboratory variables as pre-defined in protocol for safety-monitoring were: Hepatic (Serum alanine aminotransferase [ALT]: increase of greater than [>] 150 units/liter [U/L] with stable or decrease of creatinine kinese [CK]; Serum glutamyl amino transferase [GGT] [U/L]: Grade 2 [>2.5 - 5.0 * upper limit of normal {ULN}]), renal (Serum cystatin C miiligrams/liter [mg/L] >1.33 - 2.00 mg/L; Serum blood urea nitrogen [UREAN] [millimoles/liter {mmol/L}] greater than or equal to [≥]1.5 - 3.0 * ULN; Urine occult blood: 2+ [Small], 3+ [Moderate], 4+ [Large]), and electrolytes (Serum sodium: low [mmol/L], Grade 3-4 [less than {<}130 mmol/L]; serum potassium: high [mmol/L], Grade 3-4 [>6.0 mmol/L]; and Serum bicarbonate [mmol/L]: Grade 2 [<16 - 11 mmol/L]). AT population included all participants who received at least 1 dose of ataluren treatment in this extension study.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) up to 6 weeks post-treatment (Week 150)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Endpoint is safety in nature
    End point values
    Ataluren
    Number of subjects analysed
    218
    Units: participants
    29
    No statistical analyses for this end point

    Secondary: Change From Baseline in 6MWD at Week 144

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    End point title
    Change From Baseline in 6MWD at Week 144
    End point description
    The 6MWD test was performed in a 30 meters long flat corridor, where the participant was instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Ambulation was assessed via the 6MWD test following standardized procedures by measuring the 6MWD in meters. Participants were not permitted to use assistive devices (walker, long leg braces, or short leg braces) during the 6MWD test. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline 6MWD value at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    26
    Units: meters
        arithmetic mean (standard deviation)
    -98.18 ± 86.604
    No statistical analyses for this end point

    Secondary: Change From Baseline in Time to Stand From Supine Position at Week 144

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    End point title
    Change From Baseline in Time to Stand From Supine Position at Week 144
    End point description
    If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    19
    Units: seconds
        arithmetic mean (standard deviation)
    5.22 ± 5.104
    No statistical analyses for this end point

    Secondary: Change From Baseline in Time to Walk/Run 10 Meters at Week 144

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    End point title
    Change From Baseline in Time to Walk/Run 10 Meters at Week 144
    End point description
    If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    27
    Units: seconds
        arithmetic mean (standard deviation)
    2.29 ± 1.991
    No statistical analyses for this end point

    Secondary: Change From Baseline in Time to Climb 4 Stairs at Week 144

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    End point title
    Change From Baseline in Time to Climb 4 Stairs at Week 144
    End point description
    If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    22
    Units: seconds
        arithmetic mean (standard deviation)
    4.01 ± 7.260
    No statistical analyses for this end point

    Secondary: Change From Baseline in Time to Descend 4 Stairs at Week 144

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    End point title
    Change From Baseline in Time to Descend 4 Stairs at Week 144
    End point description
    If the time taken to perform this test exceeded 30 seconds or if a participant could not perform this test due to disease progression, a value of 30 seconds was used. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    22
    Units: seconds
        arithmetic mean (standard deviation)
    2.45 ± 5.853
    No statistical analyses for this end point

    Secondary: Change From Baseline in Physical Function Total Score as Measured by NSAA at Week 144

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    End point title
    Change From Baseline in Physical Function Total Score as Measured by NSAA at Week 144
    End point description
    NSAA comprised tests for 17 abilities of a participant, such as ability to stand, rise from floor, get from lying to sitting, get from sitting to standing, raise one’s head, stand on one’s heels, hop, jump, and run. For each activity, a score of 0, 1, or 2 was recorded, with 0 = “unable to achieve independently,” 1 = “modified method but achieves goal independently,” or 2 = “normal- achieves goal without any assistance.” Sum of these scores (except for 'raise one's head' activity score) was reported as the ordinal total score, which was transformed to a linear total score ranging from 0 (worst) to 100 (best). Participants with confirmed loss of ambulation at a particular visit were assigned a score of 0. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    40
    Units: units on a scale
        arithmetic mean (standard deviation)
    -7.95 ± 5.611
    No statistical analyses for this end point

    Secondary: Change From Baseline in PUL Total Score at Week 144

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    End point title
    Change From Baseline in PUL Total Score at Week 144
    End point description
    The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into shoulder level (4 items), elbow level (9 items), and distal level (8 items) dimensions. Scoring options per item may not be uniform and may vary from 0-1 and 0-6, according to the performance, with higher values corresponding to better performance. Each dimension was scored separately with a maximum score of 16 for shoulder level, 34 for elbow level, and 24 for distal level. Total score was calculated by adding the 3 level scores (maximum global score of 74). AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    44
    Units: units on a scale
        arithmetic mean (standard deviation)
    -4.0 ± 7.49
    No statistical analyses for this end point

    Secondary: Change From Baseline in Percent Predicted FVC as Measured by Spirometry at Week 144

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    End point title
    Change From Baseline in Percent Predicted FVC as Measured by Spirometry at Week 144
    End point description
    FVC is a standard pulmonary function test. FVC was defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Percent predicted FVC (in %) = [(observed FVC)/(predicted FVC)]*100. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    63
    Units: percent predicted FVC
        arithmetic mean (standard deviation)
    3.51 ± 14.253
    No statistical analyses for this end point

    Secondary: Change From Baseline in Percent Predicted FEV1 as Measured by Spirometry at Week 144

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    End point title
    Change From Baseline in Percent Predicted FEV1 as Measured by Spirometry at Week 144
    End point description
    FEV1 is a standard pulmonary function test. FEV1 was defined as the volume of air that can forcibly be blown out in 1 second, after full inspiration in the upright position, measured in liters. Percent predicted FEV1 (in %) = [(observed FEV1)/(predicted FEV1)]*100. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    63
    Units: percent predicted FEV1
        arithmetic mean (standard deviation)
    1.40 ± 15.319
    No statistical analyses for this end point

    Secondary: Change From Baseline in PEF as Measured by Spirometry at Week 144

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    End point title
    Change From Baseline in PEF as Measured by Spirometry at Week 144
    End point description
    PEF was defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    65
    Units: L/sec
        arithmetic mean (standard deviation)
    0.23 ± 1.099
    No statistical analyses for this end point

    Secondary: Change From Baseline in PCF as Measured by Spirometry at Week 144

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    End point title
    Change From Baseline in PCF as Measured by Spirometry at Week 144
    End point description
    PCF measures an individual's maximum speed of expiration during cough. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    57
    Units: L/sec
        arithmetic mean (standard deviation)
    0.53 ± 1.281
    No statistical analyses for this end point

    Secondary: Change From Baseline in PODCI Transfers/Basic Mobility Score at Week 144

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    End point title
    Change From Baseline in PODCI Transfers/Basic Mobility Score at Week 144
    End point description
    Changes in health-related quality of life (HRQL) were measured via the PODCI questionnaire that has been shown to correlate with disease progression and clinical outcome measures in DMD. PODCI includes a Global Functioning Scale and 5 core scales: Upper Extremity and Physical Function,Transfer/Basic Mobility, Sports/Physical Functioning, Pain/Comfort,and Happiness. The following PODCI domain was prespecified in the protocol for analysis:Transfers/Basic Mobility domain assesses difficulty experienced in performing routine motor activities in daily life. Each domain was scored from 0 to 100, with 0 representing a poor outcome/worse health, while 100 representing the highest level of functioning and least pain. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    65
    Units: units on a scale
        arithmetic mean (standard deviation)
    -29.3 ± 25.05
    No statistical analyses for this end point

    Secondary: Number of Participants With Change From Baseline in Activities of Daily Living and Disease Status at Week 144, as Assessed by a Standardized Survey Administered by Site Personnel

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    End point title
    Number of Participants With Change From Baseline in Activities of Daily Living and Disease Status at Week 144, as Assessed by a Standardized Survey Administered by Site Personnel
    End point description
    Changes in activities of daily living and disease symptoms were captured via a DMD-specific survey administered by Site personnel. At screening/baseline, participant and/or parent/caregiver were asked to identify any activities of daily living or symptoms that were affected by participant’s DMD. At post-baseline visit (Week 144), the same participant and/or parent/caregiver was asked to describe any changes from baseline in those activities of daily living/symptoms, within the following categories: physical functioning (PF); general energy level (GEL); cognition/school function (C/SF); emotional/social functioning (E/SF); and sleep. Changes from baseline were reported on a 5-point Likert scale: 1 (much better), 2 (slightly better), 3 (unchanged), 4 (slightly worse), or 5 (much worse). AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, ‘n‘signifies participants evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    218
    Units: participants
        PF- Walking: Much better (n=143)
    6
        PF- Walking: Slightly better (n=143)
    3
        PF- Walking: Unchanged (n=143)
    47
        PF- Walking: Slightly worse (n=143)
    32
        PF- Walking: Much worse (n=143)
    55
        PF- Climbing stairs: Much better (n=141)
    6
        PF- Climbing stairs: Slightly better (n=141)
    4
        PF- Climbing stairs: Unchanged (n=141)
    37
        PF- Climbing stairs: Slightly worse (n=141)
    29
        PF- Climbing stairs: Much worse (n=141)
    65
        PF- Upper Extremity Activity: Much better (n=119)
    5
        PF-Upper Extremity Activity:Slightly better(n=119)
    6
        PF- Upper Extremity Activity: Unchanged (n=119)
    75
        PF- Upper Extremity Activity:Slightly worse(n=119)
    21
        PF- Upper Extremity Activity: Much worse (n=119)
    12
        PF- Other: Much better (n=62)
    3
        PF- Other: Slightly better (n=62)
    2
        PF- Other: Unchanged (n=62)
    29
        PF- Other: Slightly worse (n=62)
    13
        PF- Other: Much worse (n=62)
    15
        E/SF: Much better (n=134)
    13
        E/SF: Slightly better (n=134)
    16
        E/SF: Unchanged (n=134)
    93
        E/SF: Slightly worse (n=134)
    7
        E/SF: Much worse (n=134)
    5
        C/SF: Much better (n=133)
    9
        C/SF: Slightly better (n=133)
    24
        C/SF: Unchanged (n=133)
    92
        C/SF: Sightly worse (n=133)
    8
        C/SF: Much worse (n=133)
    0
        GEL: Much better (n=127)
    8
        GEL: Slightly better (n=127)
    8
        GEL: Unchanged (n=127)
    82
        GEL: Slightly worse (n=127)
    21
        GEL: Much worse (n=127)
    8
        Sleep: Much better (n=128)
    11
        Sleep: Slightly better (n=128)
    11
        Sleep: Unchanged (n=128)
    95
        Sleep: Slightly worse (n=128)
    9
        Sleep: Much worse (n=128)
    2
        Other: Much better (n=31)
    2
        Other: Slightly better (n=31)
    2
        Other: Unchanged (n=31)
    12
        Other: Slightly worse (n=31)
    8
        Other: Much worse (n=31)
    7
    No statistical analyses for this end point

    Secondary: Ataluren Plasma Concentration

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    End point title
    Ataluren Plasma Concentration
    End point description
    Pre-dose ataluren plasma concentrations prior to morning ataluren administration at each clinic visit was assessed using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC/MS-MS) method. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'n' signifies participants evaluable for this outcome measure at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144
    End point values
    Ataluren
    Number of subjects analysed
    218
    Units: micrograms/milliliter (μg/mL)
    arithmetic mean (standard deviation)
        Week 12 (n=210)
    4.5231 ± 5.08583
        Week 24 (n=211)
    4.4817 ± 5.65883
        Week 36 (n=205)
    5.1551 ± 5.67555
        Week 48 (n=201)
    5.2221 ± 5.32846
        Week 60 (n=191)
    5.0396 ± 5.07812
        Week 72 (n=180)
    6.0677 ± 6.05912
        Week 84 (n=171)
    5.4673 ± 5.15083
        Week 96 (n=160)
    5.8870 ± 5.90954
        Week 108 (n=133)
    5.5905 ± 6.48016
        Week 120 (n=119)
    5.2406 ± 5.69648
        Week 132 (n=94)
    6.6729 ± 7.03882
        Week 144 (n=66)
    5.3898 ± 6.28487
    No statistical analyses for this end point

    Secondary: Change From Baseline in Systolic and Diastolic Blood Pressure at Week 144

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    End point title
    Change From Baseline in Systolic and Diastolic Blood Pressure at Week 144
    End point description
    Blood pressure determination was performed with the participant in a sitting position after a 5-minute rest. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'n' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    217
    Units: mmHg
    arithmetic mean (standard deviation)
        Systolic blood pressure (n=68)
    0.8 ± 11.86
        Diastolic blood pressure (n=63)
    1.3 ± 11.60
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pulse Rate at Week 144

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    End point title
    Change From Baseline in Pulse Rate at Week 144
    End point description
    Pulse rate determination was performed with the participant in a sitting position after a 5-minute rest. AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    68
    Units: beats/minute
        arithmetic mean (standard deviation)
    -0.9 ± 13.00
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Temperature at Week 144

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    End point title
    Change From Baseline in Body Temperature at Week 144
    End point description
    AT population included all participants who received at least 1 dose of ataluren treatment in this extension study. Here, 'Overall number of participants analyzed' = participants who had both baseline and post-baseline value of this parameter at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    End point values
    Ataluren
    Number of subjects analysed
    68
    Units: degrees centigrade
        arithmetic mean (standard deviation)
    0.05 ± 0.545
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) up to 6 weeks post-treatment (Week 150)
    Adverse event reporting additional description
    AT population included all participants who received at least 1 dose of ataluren treatment in this extension study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Ataluren
    Reporting group description
    Participants received ataluren suspension orally TID, 10 mg/kg at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for up to 144 weeks.

    Serious adverse events
    Ataluren
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 218 (11.01%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Exposure to communicable disease
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    5 / 218 (2.29%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Transposition of the great vessels
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular septal defect
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intussusception
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary artery stenosis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint contracture
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tendinous contracture
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Adenoiditis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ataluren
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    201 / 218 (92.20%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    48 / 218 (22.02%)
         occurrences all number
    76
    Ligament sprain
         subjects affected / exposed
    19 / 218 (8.72%)
         occurrences all number
    22
    Nervous system disorders
    Headache
         subjects affected / exposed
    42 / 218 (19.27%)
         occurrences all number
    116
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    56 / 218 (25.69%)
         occurrences all number
    56
    Pyrexia
         subjects affected / exposed
    26 / 218 (11.93%)
         occurrences all number
    33
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    18 / 218 (8.26%)
         occurrences all number
    20
    Diarrhoea
         subjects affected / exposed
    17 / 218 (7.80%)
         occurrences all number
    22
    Nausea
         subjects affected / exposed
    16 / 218 (7.34%)
         occurrences all number
    27
    Vomiting
         subjects affected / exposed
    37 / 218 (16.97%)
         occurrences all number
    71
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 218 (11.93%)
         occurrences all number
    40
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    20 / 218 (9.17%)
         occurrences all number
    26
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 218 (6.42%)
         occurrences all number
    20
    Back pain
         subjects affected / exposed
    27 / 218 (12.39%)
         occurrences all number
    29
    Pain in extremity
         subjects affected / exposed
    26 / 218 (11.93%)
         occurrences all number
    41
    Infections and infestations
    Ear infection
         subjects affected / exposed
    11 / 218 (5.05%)
         occurrences all number
    12
    Gastroenteritis
         subjects affected / exposed
    18 / 218 (8.26%)
         occurrences all number
    25
    Influenza
         subjects affected / exposed
    23 / 218 (10.55%)
         occurrences all number
    30
    Nasopharyngitis
         subjects affected / exposed
    57 / 218 (26.15%)
         occurrences all number
    99
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 218 (12.84%)
         occurrences all number
    62

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2015
    Changes to the conduct of the study included the following: ● Study treatment period was extended from 96 weeks to 144 weeks. ● Blood drawing requirements were updated to specify the number of tubes for blood trough PK would be 10 rather than 8 and the total blood volume drawn from screening to end of study would be 152 milliliters (mL). ● Language discouraging the use of cardiac drugs for prophylactic/treatment of congestive heart failure (CHF) was removed. ● Language regarding weight-based dosing assessments was simplified to specify assessments be made every 6 months. ● Exempted participants who terminated from study early due to a transition to commercial ataluren from the 6-week post treatment follow-up visit. ● Removed requirement for videotaping the 6MWT, timed function tests, NSAA, and PUL assessments.

    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.
    The study was terminated early per Sponsor decision due to commercial availability of ataluren.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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