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    Clinical Trial Results:
    A Phase 3b Open-label Extension Study to Evaluate the Safety and Efficacy of Aceneuramic Acid Extended-Release (Ace-ER) Tablets in Patients with GNE Myopathy (GNEM) or Hereditary Inclusion Body Myopathy (HIBM)

    Summary
    EudraCT number
    		 2016-000360-42
    Trial protocol
    		 GB   BG   IT  
    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-CL302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02736188
    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 objective of this study is to evaluate the long-term safety and efficacy of Ace-ER treatment in subjects with glucosamine (UDP-N-acetyl)-2-epimerase myopathy (GNEM).
    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
    02 May 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
    United States: 55
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Bulgaria: 10
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Canada: 9
    Worldwide total number of subjects
    143
    EEA total number of subjects
    49
    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)
    141
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 143 subjects were screened and enrolled across 14 total sites in the United States, Israel, United Kingdom, Italy, France, Canada, and Bulgaria. 87 subjects rolled over from study UX001-CL301 (NCT02377921), 49 subjects rolled over from study UX001-CL202 (NCT01830972), and 7 subjects rolled over from UX001-CL203 (NCT02731690).

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 143
    Number of subjects completed
    		 142

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Withdrew consent prior to receiving first dose: 1
    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
    		 Ace-ER 6 g/Day
    Arm description
    		 4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aceneuramic Acid Extended-Release Tablets
    Investigational medicinal product code
    UX001
    Other name
    Sialic Acid Extended Release, Ace-ER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose was taken with food (i.e. within 30 minutes after a meal or snack).

    Number of subjects in period 1 [1]
    		Ace-ER 6 g/Day
    Started
    142
    Completed
    0
    Not completed
    142
         Adverse Event
    1
         Not Specified
    6
         Discontinuation of Study by Sponsor
    134
         Withdrawal by Subject
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 subject withdrew consent prior to receiving the first dose and is accounted for in preassignment details.

    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
    		 142 142
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74 ( 68 ) -
    Gender categorical
    Units: Subjects
        Female
    		 74 74
        Male
    		 68 68
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 14 14
        Not Hispanic or Latino
    		 125 125
        Unknown or Not Reported
    		 3 3
    Race
    Units: Subjects
        White
    		 111 111
        Asian
    		 19 19
        Other, Not Specified
    		 12 12
    Hand Held Dynamometry (HHD) Upper Extremity Composite Score (UEC)
    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)
    		 ( ) -
    GNEM Functional Activities Scale (GNEM-FAS) Mobility Score
    GNEM-FAS Expanded Version Mobility subscale score has 13 items and ranges from 0 to 52 with higher scores representing greater mobility.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 ( ) -
    GNEM-FAS Expanded Version Upper Extremity Score
    GNEM-FAS Expanded Version Upper Extremity subscale score has 9 items and ranges from 0 to 36 with higher scores representing more skilled, independent use of the arms during functional activity performance.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 ( ) -
    HHD Lower Extremity Composite (LEC) Score
    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. n=86 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: kgf
        arithmetic mean (standard deviation)
    		 ( ) -
    Sit-to-Stand Test
    Lower extremity function was assessed using a sit-to-stand test. The number of times the subject can rise from a seated to a standing position in a 30-second period was recorded.
    Units: stands
        arithmetic mean (standard deviation)
    		 ( ) -
    30-second Weighted Arm Lift Test
    Upper extremity function was assessed using a weighted arm lift test performed bilaterally. The number of times the subject can raise a 1 kg weight above the head in a 30-second period was recorded. n=72 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: lifts
        arithmetic mean (standard deviation)
    		 ( ) -
    Six-Minute Walk Test (6MWT)
    The total distance walked (meters) in a 6-minute period was measured. n=83 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: meters
        arithmetic mean (standard deviation)
    		 ( ) -
    Percent Predicted Meters Walked in 6MWT
    The total distance walked (meters) in a 6-minute period was measured, and the percent predicted distance based on normative data for age and gender was estimated. Predicted 6MWT distance (meters) = 868.8 - (2.99 x Age) – (74.7 x Sex), where age is baseline age in years, and sex = 0 for males, and 1 for females. n=83 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: percentage of predicted meters
        arithmetic mean (standard deviation)
    		 ( ) -
    Total Force in Knee Extensors
    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. n=84 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: kgf
        arithmetic mean (standard deviation)
    		 ( ) -
    Percent of Predicted Total Force in Knee Extensors
    The percent predicted total force value of lower extremity muscle strength in the knee extensors was determined based on reference equations adjusting for age, gender, height, and weight. n=81 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: percent of predicted total force
        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 in parent study UX001-CL301 with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of study drug in UX001-CL302.

    Subject analysis set title
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in subjects who took Ace-ER in study UX001-CL301

    Subject analysis set title
    Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in subjects who took placebo in study UX001-CL301

    Subject analysis sets values
    		 Full Analysis Set Safety Analysis Set Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects
    87
    142
    44
    43
    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
    Hand Held Dynamometry (HHD) Upper Extremity Composite Score (UEC)
    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)
    52.98 ( 28.814 )
    ( )
    ( )
    ( )
    GNEM Functional Activities Scale (GNEM-FAS) Mobility Score
    GNEM-FAS Expanded Version Mobility subscale score has 13 items and ranges from 0 to 52 with higher scores representing greater mobility.
    Units: score on a scale
        arithmetic mean (standard deviation)
    24.17 ( 7.772 )
    ( )
    ( )
    ( )
    GNEM-FAS Expanded Version Upper Extremity Score
    GNEM-FAS Expanded Version Upper Extremity subscale score has 9 items and ranges from 0 to 36 with higher scores representing more skilled, independent use of the arms during functional activity performance.
    Units: score on a scale
        arithmetic mean (standard deviation)
    27.53 ( 4.938 )
    ( )
    ( )
    ( )
    HHD Lower Extremity Composite (LEC) Score
    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. n=86 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: kgf
        arithmetic mean (standard deviation)
    51.91 ( 37.474 )
    ( )
    ( )
    ( )
    Sit-to-Stand Test
    Lower extremity function was assessed using a sit-to-stand test. The number of times the subject can rise from a seated to a standing position in a 30-second period was recorded.
    Units: stands
        arithmetic mean (standard deviation)
    12.75 ( 4.977 )
    ( )
    ( )
    ( )
    30-second Weighted Arm Lift Test
    Upper extremity function was assessed using a weighted arm lift test performed bilaterally. The number of times the subject can raise a 1 kg weight above the head in a 30-second period was recorded. n=72 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: lifts
        arithmetic mean (standard deviation)
    30.93 ( 13.171 )
    ( )
    ( )
    ( )
    Six-Minute Walk Test (6MWT)
    The total distance walked (meters) in a 6-minute period was measured. n=83 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: meters
        arithmetic mean (standard deviation)
    359.4 ( 123.94 )
    ( )
    ( )
    ( )
    Percent Predicted Meters Walked in 6MWT
    The total distance walked (meters) in a 6-minute period was measured, and the percent predicted distance based on normative data for age and gender was estimated. Predicted 6MWT distance (meters) = 868.8 - (2.99 x Age) – (74.7 x Sex), where age is baseline age in years, and sex = 0 for males, and 1 for females. n=83 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: percentage of predicted meters
        arithmetic mean (standard deviation)
    49.52 ( 16.962 )
    ( )
    ( )
    ( )
    Total Force in Knee Extensors
    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. n=84 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: kgf
        arithmetic mean (standard deviation)
    26.60 ( 9.746 )
    ( )
    ( )
    ( )
    Percent of Predicted Total Force in Knee Extensors
    The percent predicted total force value of lower extremity muscle strength in the knee extensors was determined based on reference equations adjusting for age, gender, height, and weight. n=81 subjects in the Full Analysis Set with a baseline assessment for this measure
    Units: percent of predicted total force
        arithmetic mean (standard deviation)
    13.69 ( 15.323 )
    ( )
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Ace-ER 6 g/Day
    Reporting group description
    		 4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in parent study UX001-CL301 with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of study drug in UX001-CL302.

    Subject analysis set title
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in subjects who took Ace-ER in study UX001-CL301

    Subject analysis set title
    Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in subjects who took placebo in study UX001-CL301

    Primary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs [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. The severity of all AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03: grade1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5=death.
    End point type
    Primary
    End point timeframe
    From first dose of study drug through the end of treatment plus 30 days (+5 days). Mean (SD) duration of treatment was ---?
    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
    142
    Units: subjects
        TEAEs
    104
        Serious TEAEs (SAEs)
    7
        Deaths
    0
        Grade 3 or 4 TEAEs
    11
        TEAEs Leading to Study Drug Discontinuation
    2
        TEAEs Leading to Study Discontinuation
    1
    No statistical analyses for this end point

    Primary: Change From Baseline in HHD UEC Score Over Time

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    End point title
    		 Change From Baseline in HHD UEC Score Over Time
    End point description
    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. The UEC is derived from the sum of the average of the right and left total force (measured in kgf). Analyzed using a repeated measure generalized estimation equation (GEE) model, which includes the baseline value as a covariate.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 8, 16, 24, 48
    End point values
    		 Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects analysed
    44
    43
    Units: kgf
    least squares mean (confidence interval 95%)
        Week 8
    0.88 (-0.75 to 2.51)
    0.09 (-1.05 to 1.23)
        Week 16
    0.10 (-1.47 to 1.67)
    -0.26 (-1.26 to 0.74)
        Week 24
    -1.40 (-2.92 to 0.12)
    -0.49 (-2.13 to 1.15)
        Week 48
    -2.24 (-4.95 to 0.47)
    -2.18 (-4.30 to -0.07)
    Statistical analysis title
    		 Week 8
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4287 [2]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.17
         upper limit
    		 2.77
    Notes
    [2] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 16
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7031 [3]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.49
         upper limit
    		 2.21
    Notes
    [3] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4253 [4]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.14
         upper limit
    		 1.32
    Notes
    [4] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 48
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9747 [5]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.49
         upper limit
    		 3.38
    Notes
    [5] - Baseline is fit into the model as a covariate.

    Secondary: Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time

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    End point title
    		 Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time
    End point description
    GNEM-FAS Expanded Version Mobility subscale score has 13 items and ranges from 0 to 52 with higher scores representing greater mobility. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 24, 48
    End point values
    		 Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects analysed
    44
    43
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Week 8
    -0.12 (-0.66 to 0.42)
    0.15 (-0.35 to 0.65)
        Week 16
    -0.30 (-0.87 to 0.27)
    -0.12 (-0.72 to 0.49)
        Week 24
    -0.78 (-1.31 to -0.25)
    -0.34 (-0.92 to 0.23)
        Week 48
    -0.73 (-1.43 to -0.03)
    -0.45 (-1.67 to 0.77)
    Statistical analysis title
    		 Week 8
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Placebo) v Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4721 [6]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 0.47
    Notes
    [6] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 16
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6611 [7]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 0.47
    Notes
    [7] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.276 [8]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.22
         upper limit
    		 0.35
    Notes
    [8] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 48
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6977 [9]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.69
         upper limit
    		 1.13
    Notes
    [9] - Baseline is fit into the model as a covariate.

    Secondary: Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time

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    End point title
    		 Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time
    End point description
    GNEM-FAS Expanded Version Upper Extremity subscale score has 9 items and ranges 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 baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 24, 48
    End point values
    		 Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects analysed
    44
    43
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Week 8
    0.68 (0.15 to 1.22)
    -0.02 (-0.55 to 0.51)
        Week 16
    0.34 (-0.21 to 0.89)
    -0.40 (-0.99 to 0.19)
        Week 24
    0.26 (-0.41 to 0.93)
    -0.17 (-1.01 to 0.67)
        Week 48
    -0.82 (-2.16 to 0.51)
    -0.48 (-1.03 to 0.07)
    Statistical analysis title
    		 Week 8
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Placebo) v Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0648 [10]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 1.45
    Notes
    [10] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 16
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0692 [11]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 1.55
    Notes
    [11] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4317 [12]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 1.52
    Notes
    [12] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 48
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6416 [13]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.78
         upper limit
    		 1.1
    Notes
    [13] - Baseline is fit into the model as a covariate.

    Secondary: Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time

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    End point title
    		 Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time
    End point description
    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. The LEC is derived from the sum of the average of the right and left total force (measured in kgf). Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 24, and 48
    End point values
    		 Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects analysed
    44
    43
    Units: kgf
    arithmetic mean (confidence interval 95%)
        Week 8
    0.01 (-2.01 to 2.04)
    -0.77 (-3.65 to 2.11)
        Week 16
    -1.63 (-3.95 to 0.34)
    -0.98 (-3.77 to 1.81)
        Week 24
    -0.60 (-3.90 to 2.71)
    -0.10 (-3.82 to 3.62)
        Week 48
    -0.32 (-4.02 to 3.39)
    -4.47 (-7.45 to -1.49)
    Statistical analysis title
    		 Week 8
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6546 [14]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.65
         upper limit
    		 4.22
    Notes
    [14] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 16
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7054 [15]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.97
         upper limit
    		 2.69
    Notes
    [15] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8441 [16]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.45
         upper limit
    		 4.45
    Notes
    [16] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 48
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0864 [17]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 8.9
    Notes
    [17] - Baseline is fit into the model as a covariate.

    Secondary: Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time

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    End point title
    		 Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time
    End point description
    Lower extremity function was assessed using a sit-to-stand test. The number of times the subject can rise from a seated to a standing position in a 30-second period was recorded. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 24, and 48
    End point values
    		 Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects analysed
    44
    43
    Units: stands
    least squares mean (confidence interval 95%)
        Week 8
    0.02 (-0.43 to 0.46)
    -0.05 (-0.61 to 0.51)
        Week 16
    -0.04 (-0.49 to 0.40)
    0.14 (-0.39 to 0.66)
        Week 24
    0.06 (-0.43 to 0.56)
    -0.41 (-0.94 to 0.12)
        Week 48
    -0.39 (-1.36 to 0.57)
    -0.36 (-1.11 to 0.39)
    Statistical analysis title
    		 Week 8
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Placebo) v Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8603 [18]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 0.78
    Notes
    [18] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 16
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6154 [19]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.86
         upper limit
    		 0.51
    Notes
    [19] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1999 [20]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 1.2
    Notes
    [20] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 48
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9568 [21]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 1.18
    Notes
    [21] - Baseline is fit into the model as a covariate.

    Secondary: Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time

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    End point title
    		 Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time
    End point description
    Upper extremity function was assessed using a weighted arm lift test performed bilaterally. The number of times the subject can raise a 1 kg weight above the head in a 30-second period was recorded. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 24, and 48
    End point values
    		 Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects analysed
    44
    43
    Units: lifts
    least squares mean (confidence interval 95%)
        Week 8
    0.26 (-1.00 to 1.52)
    -0.19 (-0.90 to 0.53)
        Week 16
    0.03 (-1.22 to 1.27)
    0.59 (-0.50 to 1.68)
        Week 24
    0.13 (-0.98 to 1.24)
    -0.14 (-1.33 to 1.06)
        Week 48
    -1.58 (-3.60 to 0.45)
    -1.17 (-2.55 to 0.22)
    Statistical analysis title
    		 Week 8
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5447 [22]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1.9
    Notes
    [22] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 16
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5051 [23]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.22
         upper limit
    		 1.09
    Notes
    [23] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7478 [24]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.36
         upper limit
    		 1.9
    Notes
    [24] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 48
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7429 [25]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.86
         upper limit
    		 2.04
    Notes
    [25] - Baseline is fit into the model as a covariate.

    Secondary: Change From Baseline in Meters Walked in 6MWT Over Time

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    End point title
    		 Change From Baseline in Meters Walked in 6MWT Over Time
    End point description
    The total distance walked (meters) in a 6-minute period was measured. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 24, and 48
    End point values
    		 Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects analysed
    44
    43
    Units: meters
    least squares mean (confidence interval 95%)
        Week 8
    -1.40 (-8.34 to 5.53)
    -3.41 (-7.92 to 1.10)
        Week 16
    -3.91 (-12.03 to 4.20)
    -1.93 (-8.32 to 4.47)
        Week 24
    -2.73 (-10.81 to 5.35)
    -6.88 (-13.43 to -0.33)
        Week 48
    -13.91 (-25.58 to -2.25)
    -21.89 (-38.51 to -5.28)
    Statistical analysis title
    		 Week 8
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6434 [26]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.48
         upper limit
    		 10.49
    Notes
    [26] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 16
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7118 [27]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.53
         upper limit
    		 8.55
    Notes
    [27] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4399 [28]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.39
         upper limit
    		 14.69
    Notes
    [28] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 48
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.443 [29]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    7.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.41
         upper limit
    		 28.37
    Notes
    [29] - Baseline is fit into the model as a covariate.

    Secondary: Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time

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    End point title
    		 Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time
    End point description
    The total distance walked (meters) in a 6-minute period was measured, and the percent predicted distance based on normative data for age and gender was estimated. Predicted 6MWT distance (meters) = 868.8 - (2.99 x Age) –(74.7 x Sex), where age is baseline age in years, and sex = 0 for males, and 1 for females. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 24, and 48
    End point values
    		 Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects analysed
    44
    43
    Units: percent of predicted distance
    least squares mean (confidence interval 95%)
        Week 8
    -0.17 (-1.12 to 0.79)
    -0.45 (-1.09 to 0.20)
        Week 16
    -0.49 (-1.60 to 0.61)
    -0.24 (-1.15 to 0.67)
        Week 24
    -0.38 (-1.49 to 0.73)
    -0.96 (-1.88 to -0.03)
        Week 48
    -1.94 (-3.56 to -0.31)
    -2.93 (-5.04 to -0.81)
    Statistical analysis title
    		 Week 8
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6428 [30]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 1.46
    Notes
    [30] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 16
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7334 [31]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.72
         upper limit
    		 1.21
    Notes
    [31] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4409 [32]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.89
         upper limit
    		 2.04
    Notes
    [32] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 48
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4687 [33]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.69
         upper limit
    		 3.68
    Notes
    [33] - Baseline is fit into the model as a covariate.

    Secondary: Change From Baseline in Total Force in Knee Extensors Over Time

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    End point title
    		 Change From Baseline in Total Force in Knee Extensors Over Time
    End point description
    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. Bilateral total force was defined as the average of the right and left force (measured in kgf). Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 24, and 48
    End point values
    		 Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects analysed
    44
    43
    Units: kgf
    least squares mean (confidence interval 95%)
        Week 8
    0.50 (-0.77 to 1.78)
    -0.64 (-1.53 to 0.25)
        Week 16
    -0.95 (-2.03 to 0.14)
    -0.75 (-2.05 to 0.55)
        Week 24
    0.33 (-1.33 to 2.00)
    -0.46 (-2.15 to 1.23)
        Week 48
    0.63 (-2.30 to 3.56)
    -0.08 (-2.28 to 2.13)
    Statistical analysis title
    		 Week 8
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15 [34]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 2.69
    Notes
    [34] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 16
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8188 [35]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.89
         upper limit
    		 1.49
    Notes
    [35] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5122 [36]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.58
         upper limit
    		 3.17
    Notes
    [36] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 48
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7022 [37]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.96
         upper limit
    		 4.4
    Notes
    [37] - Baseline is fit into the model as a covariate.

    Secondary: Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time

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    End point title
    		 Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time
    End point description
    The percent predicted total force value of lower extremity muscle strength in the knee extensors was determined based on reference equations adjusting for age, gender, height, and weight. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 16, 24, and 48
    End point values
    		 Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects analysed
    44
    43
    Units: percent of predicted total force (kgf)
    least squares mean (confidence interval 95%)
        Week 8
    -0.98 (-1.78 to -0.19)
    -1.17 (-2.44 to 0.09)
        Week 16
    -0.59 (-1.48 to 0.31)
    -1.25 (-2.43 to -0.07)
        Week 24
    -0.70 (-1.92 to 0.53)
    -0.85 (-2.53 to 0.83)
        Week 48
    -1.02 (-2.17 to 0.13)
    -3.10 (-4.40 to -1.80)
    Statistical analysis title
    		 Week 8
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7906 [38]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.22
         upper limit
    		 1.6
    Notes
    [38] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 16
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3531 [39]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.74
         upper limit
    		 2.07
    Notes
    [39] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8846 [40]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.92
         upper limit
    		 2.23
    Notes
    [40] - Baseline is fit into the model as a covariate.
    Statistical analysis title
    		 Week 48
    Comparison groups
    Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day) v Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0168 [41]
    Method
    		 GEE model
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 3.79
    Notes
    [41] - Baseline is fit into the model as a covariate.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug through the end of treatment plus 30 days (+5 days). Mean (SD) duration of treatment was ---?
    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
    		 4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day

    Serious adverse events
    		 Ace-ER 6 g/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 142 (4.93%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Biopsy kidney
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal pain
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 142 (0.70%)
         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
    83 / 142 (58.45%)
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    30 / 142 (21.13%)
         occurrences all number
    67
    Laceration
         subjects affected / exposed
    5 / 142 (3.52%)
         occurrences all number
    8
    Procedural pain
         subjects affected / exposed
    4 / 142 (2.82%)
         occurrences all number
    7
    Skin abrasion
         subjects affected / exposed
    7 / 142 (4.93%)
         occurrences all number
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 142 (3.52%)
         occurrences all number
    6
    Extensor plantar response
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    8 / 142 (5.63%)
         occurrences all number
    11
    Hypotonia
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 142 (5.63%)
         occurrences all number
    24
    Influenza like illness
         subjects affected / exposed
    7 / 142 (4.93%)
         occurrences all number
    10
    Peripheral swelling
         subjects affected / exposed
    4 / 142 (2.82%)
         occurrences all number
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 142 (2.82%)
         occurrences all number
    5
    Diarrhoea
         subjects affected / exposed
    10 / 142 (7.04%)
         occurrences all number
    12
    Flatulence
         subjects affected / exposed
    9 / 142 (6.34%)
         occurrences all number
    9
    Nausea
         subjects affected / exposed
    7 / 142 (4.93%)
         occurrences all number
    7
    Reproductive system and breast disorders
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 142 (4.93%)
         occurrences all number
    8
    Oropharyngeal pain
         subjects affected / exposed
    7 / 142 (4.93%)
         occurrences all number
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 142 (11.97%)
         occurrences all number
    22
    Back pain
         subjects affected / exposed
    13 / 142 (9.15%)
         occurrences all number
    16
    Muscular weakness
         subjects affected / exposed
    6 / 142 (4.23%)
         occurrences all number
    8
    Musculoskeletal pain
         subjects affected / exposed
    11 / 142 (7.75%)
         occurrences all number
    16
    Neck pain
         subjects affected / exposed
    5 / 142 (3.52%)
         occurrences all number
    7
    Pain in extremity
         subjects affected / exposed
    10 / 142 (7.04%)
         occurrences all number
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 142 (5.63%)
         occurrences all number
    12
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 142 (2.11%)
         occurrences all number
    5
    Urinary tract infection
         subjects affected / exposed
    5 / 142 (3.52%)
         occurrences all number
    7
    Viral upper respiratory tract infection
         subjects affected / exposed
    6 / 142 (4.23%)
         occurrences all number
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2016
    1. The protocol was amended to allow for the inclusion of subjects who complete the UX001-CL202 study. This change affected multiple sections of the protocol, including the synopsis, Table 2.1, and Inclusion Criterion 1 (Section 7.3.1). Subjects enrolling from the UX001-CL202 study will follow the same schedule of events as subjects who roll over from the UX001-CL301 study. 2. With regard to Change #1 above, the amendment clarifies that subjects who rollover from UX001-CL202 will receive 6 g/day of Ace-ER. No subjects will receive 12 g/day in this study. 3. Treatment duration language changed to remove “until commercial availability of study drug in subject’s region.” This change affected multiple sections of the protocol, including Synopsis, Figure 2.1 and Section 7. The treatment duration on the study will be 24 Months. 4. Table 7.5.5.5.1 was updated to include blood/RBC and leukocyte esterase to the urinalysis panel and to add a footnote indicating that microscopic evaluation will be conducted for abnormal urine test results. 5. Language was added to the synopsis and multiple sections of the protocol instructing that for UX001-CL202 subjects, assessments that cannot be safely performed due to disease progression should not be administered. 6. The number of samples drawn from each subject (Table 7.5.5.5.1.1) was increased for the serum sialic acid assessments from 2 samples to 5 samples. The total volume of blood sample to be obtained increased from 87 mL to 108 mL for subjects rolling over from UX001-CL203 and from 108 to 129.5 for subjects rolling over from UX001-CL301. 7. Record Retention: Section 8.4.3 has been updated to state that all study records must be retained for at least 25 years after the end of the clinical trial or in accordance with national law.

    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.
    No efficacy result summaries or analyses were performed for subjects rolling over from UX001-CL202 or UX001-CL203 because of the limited data from those subjects due to the early study closure.
    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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