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    Clinical Trial Results:
    A Phase 2 Open-label study to Evaluate the Safety of Aceneuramic Acid Extended Release (Ace-ER) Tablets in GNE Myopathy (GNEM) (also known as Hereditary Inclusion Body Myopathy (HIBM)) patients with Severe Ambulatory Impairment

    Summary
    EudraCT number
    2015-004553-41
    Trial protocol
    BG  
    Global end of trial date
    10 Jan 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    28 Mar 2019
    First version publication date
    23 Jan 2019
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Correction of unit of measure

    Trial information

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    Trial identification
    Sponsor protocol code
    UX001-CL203
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02731690
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ultragenyx Pharmaceutical Inc.
    Sponsor organisation address
    60 Leveroni Court, Novato, United States, California 94949
    Public contact
    Medical Information, Ultragenyx Pharmaceutical Inc., 1 888-756-8657, medinfo@ultragenyx.com
    Scientific contact
    Medical Information, Ultragenyx Pharmaceutical Inc., 1 888-756-8657, medinfo@ultragenyx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this Phase 2 study is to evaluate the safety of open-label 6 g/day Ace-ER in GNEM participants with severe ambulatory impairment.
    Protection of trial subjects
    The trial was designed, conducted, recorded, and reported in accordance with the principles established by the 18th World Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and clarifications adopted by the General Assemblies. The investigators made every effort to ensure that the study was conducted in full conformance with Helsinki principles, International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, current Food and Drug Administration (FDA) regulations, EU Clinical Trial Directive 2001/20/EC, and local ethical and regulatory requirements. Each investigator was thoroughly familiar with the appropriate administration and potential risks of administration of the study drug, as described in the protocol and Investigator’s Brochure, prior to the initiation of the study. The method of obtaining and documenting informed consent and the contents of the informed consent form (ICF) complied with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of Human Subjects,” the Health Insurance Portability and Accountability Act regulations, and all other applicable regulatory requirements. Investigators were responsible for preparing the ICF and submitting it to the Sponsor for approval prior to submission to the Institutional Review Board (IRB). All ICFs were written in regional language and contained the minimum elements for consent as mandated by the ICH guidelines. An IRB-approved ICF was provided by the Sponsor prior to initiation of the study. Investigators obtained signed written informed consent from each potential study subject prior to the conduct of any study procedures and after the methods, objectives, requirements, and potential risks of the study were fully explained to each potential subject. Consent for participation could be withdrawn at any time for any reason by the subject.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 17
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Canada: 3
    Worldwide total number of subjects
    42
    EEA total number of subjects
    17
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    38
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects were screened up to 28 days before the Baseline Visit.

    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
    UX001 6g/Day
    Arm description
    Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Aceneuramic Acid Extended-Release
    Investigational medicinal product code
    UX001
    Other name
    Ace-ER, Sialic Acid Extended Release
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.

    Number of subjects in period 1
    UX001 6g/Day
    Started
    42
    Completed
    12
    Not completed
    30
         Discontinuation of Study by Sponsor
    26
         Consent withdrawn by subject
    3
         Adverse Event
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    -

    Reporting group values
    Overall Study Total
    Number of subjects
    42 42
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    46.0 ± 13.97 -
    Gender categorical
    Units: Subjects
        Female
    25 25
        Male
    17 17
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 0
        Not Hispanic or Latino
    42 42
        Unknown or Not Reported
    0 0
    Race
    Units: Subjects
        White
    31 31
        Asian
    2 2
        Other (Not Specified)
    9 9
    Glucosamine (UDP-N-acetyl)-2-epimerase Myopathy Functional Activities Scale(GNEM-FAS) Mobility Score
    GNEM-FAS Expanded Version Mobility subscale scores have 13 items and range from 0 to 52 with higher scores representing greater mobility.
    Units: units on a scale
        arithmetic mean (standard deviation)
    ± -
    GNEM-FAS Upper Extremity Domain Score
    GNEM-FAS Expanded Version Upper Extremity subscale scores have 9 items and range from 0 to 36 with higher scores representing more skilled, independent use of the arms during functional activity performance.
    Units: units on a scale
        arithmetic mean (standard deviation)
    ± -
    GNEM-FAS Self-Care Domain Score
    GNEM-FAS Expanded Version Self-Care subscale scores have 8 items range from 0 to 32 with higher scores representing greater independence with functional care activities.
    Units: units on a scale
        arithmetic mean (standard deviation)
    ± -
    GNEM-FAS Total Score
    GNEM-FAS Expanded Version Total Score were calculated as the sum of the subscale Scores range from 0 to 120 with higher scores representing greater independence with functional activities.
    Units: units on a scale
        arithmetic mean (standard deviation)
    ± -
    Hand-Held Dynamometry (HHD) Raw Strength: Average Grip
    Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kilogram-force [kgf]) for each was recorded.
    Units: kgf
        arithmetic mean (standard deviation)
    ± -
    HHD Raw Strength: Average Shoulder Abduction
    Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.
    Units: kgf
        arithmetic mean (standard deviation)
    ± -
    HHD Raw Strength: Average Wrist Extension
    Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.
    Units: kgf
        arithmetic mean (standard deviation)
    ± -
    HHD Lower Extremity Muscle Strength: Average Knee Extension
    Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.
    Units: kgf
        arithmetic mean (standard deviation)
    ± -
    HHD Raw Strength: Key Pinch
    Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.
    Units: kgf
        arithmetic mean (standard deviation)
    ± -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    all subjects with a baseline measurement and at least 1 postbaseline measurement.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    all enrolled subjects who received at least 1 dose of study drug.

    Subject analysis sets values
    Full Analysis Set Safety Analysis Set
    Number of subjects
    41
    42
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male
    Ethnicity
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Race
    Units: Subjects
        White
        Asian
        Other (Not Specified)
    Glucosamine (UDP-N-acetyl)-2-epimerase Myopathy Functional Activities Scale(GNEM-FAS) Mobility Score
    GNEM-FAS Expanded Version Mobility subscale scores have 13 items and range from 0 to 52 with higher scores representing greater mobility.
    Units: units on a scale
        arithmetic mean (standard deviation)
    10.63 ± 7.816
    ±
    GNEM-FAS Upper Extremity Domain Score
    GNEM-FAS Expanded Version Upper Extremity subscale scores have 9 items and range from 0 to 36 with higher scores representing more skilled, independent use of the arms during functional activity performance.
    Units: units on a scale
        arithmetic mean (standard deviation)
    15.20 ± 8.897
    ±
    GNEM-FAS Self-Care Domain Score
    GNEM-FAS Expanded Version Self-Care subscale scores have 8 items range from 0 to 32 with higher scores representing greater independence with functional care activities.
    Units: units on a scale
        arithmetic mean (standard deviation)
    13.00 ± 7.413
    ±
    GNEM-FAS Total Score
    GNEM-FAS Expanded Version Total Score were calculated as the sum of the subscale Scores range from 0 to 120 with higher scores representing greater independence with functional activities.
    Units: units on a scale
        arithmetic mean (standard deviation)
    38.83 ± 23.116
    ±
    Hand-Held Dynamometry (HHD) Raw Strength: Average Grip
    Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kilogram-force [kgf]) for each was recorded.
    Units: kgf
        arithmetic mean (standard deviation)
    5.535 ± 7.6778
    ±
    HHD Raw Strength: Average Shoulder Abduction
    Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.
    Units: kgf
        arithmetic mean (standard deviation)
    3.880 ± 4.4583
    ±
    HHD Raw Strength: Average Wrist Extension
    Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.
    Units: kgf
        arithmetic mean (standard deviation)
    3.532 ± 3.5177
    ±
    HHD Lower Extremity Muscle Strength: Average Knee Extension
    Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.
    Units: kgf
        arithmetic mean (standard deviation)
    10.50 ± 8.001
    ±
    HHD Raw Strength: Key Pinch
    Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.
    Units: kgf
        arithmetic mean (standard deviation)
    1.790 ± 2.1614
    ±

    End points

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    End points reporting groups
    Reporting group title
    UX001 6g/Day
    Reporting group description
    Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    all subjects with a baseline measurement and at least 1 postbaseline measurement.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    all enrolled subjects who received at least 1 dose of study drug.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation [1]
    End point description
    An AE was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at any dose, in the view of either the Investigator or Ultragenyx, results in any of the following outcomes: death; a life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability (substantial disruption of the ability to conduct normal life functions); congenital anomaly/birth defect. TEAEs were defined as any AE that occurred after the first dose of study drug.
    End point type
    Primary
    End point timeframe
    48 Weeks (plus 30 [+5] days for participants not enrolling in extension study)
    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: Descriptive statistics are presented per protocol.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    42
    Units: subjects
        TEAEs
    30
        Treatment-Related TEAEs
    18
        Treatment-Related Serious TEAEs
    0
        Serious TEAEs
    1
        TEAEs Causing Study Drug Discontinuation
    1
        TEAEs Causing Study Discontinuation
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects Taking Prior and Concomitant Medications

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    End point title
    Number of Subjects Taking Prior and Concomitant Medications
    End point description
    Prior medications are any medications which started before the date of the first dose of investigational product. Concomitant medications are any medications that are taken on or after the date of the first dose of investigational product excluding concomitant medications started after the date of the last dose of investigational product.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Safety Analysis Set
    Number of subjects analysed
    42
    Units: subjects
        Prior Medications
    31
        Concomitant Medications
    33
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Changes From Baseline In Physical Examinations

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    End point title
    Number of Subjects With Clinically Significant Changes From Baseline In Physical Examinations
    End point description
    Complete physical examinations included assessments of general appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, lymphatic, respiratory, GI, musculoskeletal, and neurologic systems. The neurologic system examination included assessments of cognition, cranial nerves, motor function, coordination and gait, reflexes, and sensory function. Brief physical examinations included assessments of general appearance, cardiovascular and respiratory systems, and a focus on any presenting complaints.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Safety Analysis Set
    Number of subjects analysed
    42
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Changes From Baseline In Vital Signs

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    End point title
    Number of Subjects With Clinically Significant Changes From Baseline In Vital Signs
    End point description
    Vital signs included seated systolic blood pressure and diastolic blood pressure, heart rate, respiration rate, and temperature.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Safety Analysis Set
    Number of subjects analysed
    42
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Changes From Baseline In Clinical Laboratory Results

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    End point title
    Number of Subjects With Clinically Significant Changes From Baseline In Clinical Laboratory Results
    End point description
    The clinical laboratory evaluations performed included serum chemistry, complete blood count (hematology), and urinalysis.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Safety Analysis Set
    Number of subjects analysed
    42
    Units: subjects
        Hematology
    0
        Clinical Chemistry
    2
        Urinalysis
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Overall Suicidal Behaviors and/or Ideation at Baseline and Post-Baseline

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    End point title
    Number of Participants With Overall Suicidal Behaviors and/or Ideation at Baseline and Post-Baseline
    End point description
    As evaluated by the Columbia Suicide Severity Rating Scale (C-SSRS), a participant-rated questionnaire to assess suicidal ideation, suicidal behavior, actual attempts (yes or no responses).
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Safety Analysis Set
    Number of subjects analysed
    42
    Units: subjects
        Overall Suicidal Behaviors: Baseline
    1
        Overall Suicidal Behaviors: Post-Baseline
    0
        Non-Suicide Self-Injurious Behavior: Baseline
    0
        Non-Suicide Self-Injurious Behavior: Post-Baseline
    0
        Completed Suicide: Post-Baseline
    0
        Overall Suicidal Ideation: Baseline
    7
        Overall Suicidal Ideation: Post-Baseline
    1
    No statistical analyses for this end point

    Secondary: Change From Baseline in GNEM-FAS Expanded Version Mobility Domain Subscale Scores Over Time

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    End point title
    Change From Baseline in GNEM-FAS Expanded Version Mobility Domain Subscale Scores Over Time
    End point description
    GNEM-FAS Expanded Version Mobility subscale scores have 13 items and range from 0 to 52 with higher scores representing greater mobility. Analyzed using a repeated measure generalized estimation equation (GEE) model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 48
    End point values
    Full Analysis Set
    Number of subjects analysed
    41 [2]
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 12
    0.16 (-0.33 to 0.64)
        Week 24
    -0.65 (-1.56 to 0.27)
        Week 36
    -0.69 (-1.57 to 0.18)
        Week 48
    -1.03 (-2.15 to 0.09)
    Notes
    [2] - P-values: Week 12=0.5303; Week 24=0.1646; Week 36=0.1189; Week 48=0.0706
    No statistical analyses for this end point

    Secondary: Change From Baseline in GNEM-FAS Expanded Version Upper Extremity Domain Subscale Scores Over Time

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    End point title
    Change From Baseline in GNEM-FAS Expanded Version Upper Extremity Domain Subscale Scores Over Time
    End point description
    GNEM-FAS Expanded Version Upper Extremity subscale scores have 9 items and range from 0 to 36 with higher scores representing more skilled, independent use of the arms during functional activity performance. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 48
    End point values
    Full Analysis Set
    Number of subjects analysed
    41 [3]
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 12
    0.57 (-0.05 to 1.19)
        Week 24
    -0.62 (-1.50 to 0.26)
        Week 36
    -0.51 (-1.58 to 0.55)
        Week 48
    -1.91 (-3.93 to 0.11)
    Notes
    [3] - P-values: Week 12=0.0715; Week 24=0.1697; Week 36=0.3428; Week 48=0.0642
    No statistical analyses for this end point

    Secondary: Change From Baseline in GNEM-FAS Expanded Version Self-Care Domain Subscale Scores Over Time

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    End point title
    Change From Baseline in GNEM-FAS Expanded Version Self-Care Domain Subscale Scores Over Time
    End point description
    GNEM-FAS Expanded Version Self-Care subscale scores have 8 items range from 0 to 32 with higher scores representing greater independence with functional care activities. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 48
    End point values
    Full Analysis Set
    Number of subjects analysed
    41 [4]
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 12
    -0.39 (-0.79 to 0.01)
        Week 24
    -0.71 (-1.43 to 0.01)
        Week 36
    -0.83 (-1.64 to -0.02)
        Week 48
    -0.40 (-1.78 to 0.98)
    Notes
    [4] - P-values: Week 12=0.0568; Week 24=0.0533; Week 36=0.0459; Week 48=0.5678
    No statistical analyses for this end point

    Secondary: Change From Baseline in GNEM-FAS Expanded Version Total Scores Over Time

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    End point title
    Change From Baseline in GNEM-FAS Expanded Version Total Scores Over Time
    End point description
    GNEM-FAS Expanded Version Total Score were calculated as the sum of the subscale Scores range from 0 to 120 with higher scores representing greater independence with functional activities. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 48
    End point values
    Full Analysis Set
    Number of subjects analysed
    41 [5]
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 12
    0.35 (-0.89 to 1.58)
        Week 24
    -1.95 (-3.87 to -0.03)
        Week 36
    -2.02 (-4.46 to 0.42)
        Week 48
    -3.34 (-6.90 to 0.22)
    Notes
    [5] - P-values: Week 12=0.5810; Week 24=0.0465; Week 36=0.1047; Week 48=0.0661
    No statistical analyses for this end point

    Secondary: Change From Baseline in HHD Raw Strength (Grip) Over Time

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    End point title
    Change From Baseline in HHD Raw Strength (Grip) Over Time
    End point description
    The highest force value collected using hand held dynamometer for each muscle group was used for data analysis. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 48
    End point values
    Full Analysis Set
    Number of subjects analysed
    41
    Units: kgf
    least squares mean (confidence interval 95%)
        Week 12
    0.258 (-0.103 to 0.620)
        Week 24
    0.128 (-0.377 to 0.632)
        Week 36
    0.038 (-0.724 to 0.799)
        Week48
    -0.261 (-1.325 to 0.803)
    No statistical analyses for this end point

    Secondary: Change From Baseline in HHD Raw Strength (Shoulder Abductors) Over Time

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    End point title
    Change From Baseline in HHD Raw Strength (Shoulder Abductors) Over Time
    End point description
    The highest force value collected using hand held dynamometer for each muscle group was used for data analysis. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 48
    End point values
    Full Analysis Set
    Number of subjects analysed
    41
    Units: kgf
    least squares mean (confidence interval 95%)
        Week 12
    0.339 (0.085 to 0.592)
        Week 24
    0.379 (-0.228 to 0.987)
        Week 36
    0.437 (0.075 to 0.800)
        Week 48
    -0.277 (-0.698 to 0.144)
    No statistical analyses for this end point

    Secondary: Change From Baseline in HHD Raw Strength (Wrist Extensors) Over Time

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    End point title
    Change From Baseline in HHD Raw Strength (Wrist Extensors) Over Time
    End point description
    The highest force value collected using hand held dynamometer for each muscle group was used for data analysis. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 48
    End point values
    Full Analysis Set
    Number of subjects analysed
    41
    Units: kgf
    least squares mean (confidence interval 95%)
        Week 12
    0.235 (-0.024 to 0.495)
        Week 24
    0.152 (-0.486 to 0.791)
        Week 36
    0.358 (-0.228 to 0.943)
        Week 48
    -0.123 (-0.924 to 0.678)
    No statistical analyses for this end point

    Secondary: Change From Baseline in HHD Muscle Strength in Knee Extensors Over Time

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    End point title
    Change From Baseline in HHD Muscle Strength in Knee Extensors Over Time
    End point description
    The highest force value collected using hand held dynamometer for each muscle group was used for data analysis. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 48
    End point values
    Full Analysis Set
    Number of subjects analysed
    41
    Units: kgf
    least squares mean (confidence interval 95%)
        Week 12
    0.80 (-0.12 to 1.73)
        Week 24
    1.35 (0.36 to 2.33)
        Week 36
    2.05 (0.52 to 3.58)
        Week 48
    2.45 (0.01 to 4.88)
    No statistical analyses for this end point

    Secondary: Change From Baseline in HHD Raw Strength (Key Pinch) Over Time

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    End point title
    Change From Baseline in HHD Raw Strength (Key Pinch) Over Time
    End point description
    The highest force value collected using hand held dynamometer for each muscle group was used for data analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 48
    End point values
    Full Analysis Set
    Number of subjects analysed
    41
    Units: kgf
    arithmetic mean (standard deviation)
        Week 12; n=41
    0.110 ± 0.7083
        Week 24; n=30
    0.112 ± 0.6534
        Week 36; n=23
    0.049 ± 0.8090
        Week 48; n=11
    0.318 ± 0.9509
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    48 Weeks (plus 30 [+5] days for participants not enrolling in extension study)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Ace-ER 6 g/day
    Reporting group description
    PLACEHOLDER

    Serious adverse events
    Ace-ER 6 g/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 42 (2.38%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 42 (2.38%)
         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
    Ace-ER 6 g/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 42 (61.90%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 42 (9.52%)
         occurrences all number
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    7
    Oedema peripheral
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    4
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    7 / 42 (16.67%)
         occurrences all number
    9
    Abdominal pain upper
         subjects affected / exposed
    6 / 42 (14.29%)
         occurrences all number
    7
    Dysphagia
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Dyspepsia
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Flatulence
         subjects affected / exposed
    7 / 42 (16.67%)
         occurrences all number
    12
    Nausea
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    5
    Muscular weakness
         subjects affected / exposed
    4 / 42 (9.52%)
         occurrences all number
    4
    Back pain
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    6
    Pain in extremity
         subjects affected / exposed
    4 / 42 (9.52%)
         occurrences all number
    6
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 42 (16.67%)
         occurrences all number
    7
    Urinary tract infection
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2017
    The UX0001-CL203 Original Protocol (dated 04 December 2015) has been modified by Amendment 1 to: a) increase the planned number of enrolled subjects; b) clarify the timing and conduct of the Safety Follow-up Period for all subjects; c) clarify that study assessments for a subject should be performed in a consistent order at each visit; d) add urine microscopic examination if abnormal urinalysis results are observed; e) update information regarding safety laboratory blood and urine sample collection and the analytes to be assessed in the samples; f) instruct that the Short Form Health Survey-36 (SF-36) will only be completed for subjects when a validated version is available in the subject’s native language; g) remove the requirement for urine collection for assessment of sialic acid (SA), h) update the requirement for urine collection for N-acetyl-D-mannosamine (ManNAc); i) clarify safety reporting requirements; j) more clearly define the various study period/visits and the associated assessments; k) remove reference to the Study Reference Manual; l) clarify what will be done with leftover blood and urine samples from this study; m) correct the volume of blood to be drawn from subjects; n) correct inconsistencies between sections; o) update the retention requirement for subject identifiers, subject files, and other source data; p) update the Sponsor’s Responsible Medical Officer information; q) add the designated Coordinating Investigator.

    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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