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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Adaptive Study to Assess the Safety and Efficacy of UX007 in Subjects with Glucose Transporter Type 1 Deficiency Syndrome

    Summary
    EudraCT number
    2013-003771-35
    Trial protocol
    IT   GB   FR   HU   ES   DK  
    Global end of trial date
    20 Sep 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    04 Jul 2020
    First version publication date
    27 Feb 2019
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Added new p-value for primary endpoint

    Trial information

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    Trial identification
    Sponsor protocol code
    UX007G-CL201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01993186
    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
    20 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are to evaluate the efficacy of UX007 compared to placebo as measured by the reduction from randomization to week 8 in frequency of seizures and to evaluate the safety of UX007 via adverse event (AE) rates, laboratory values, and electrocardiogram (ECG).
    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
    28 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    36
    EEA total number of subjects
    11
    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)
    15
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    8
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Beginning with the Screening visit, subjects recorded seizure frequency during a 6-week Baseline Period. If the subject did not meet the seizure count criteria, the subject was considered a screen failure and was not randomized.

    Period 1
    Period 1 title
    Double-Blind Placebo-Controlled Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    The investigator and site personnel remained blinded to the randomization code during the study. Treatment assignment for an individual subject would be unblinded by the Investigator only in an emergency, and only if knowledge of the treatment assignment were urgently needed for the clinical management or welfare of the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    UX007
    Arm description
    Subjects randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    triheptanoin
    Investigational medicinal product code
    UX007
    Other name
    C7 oil, glycerol triheptanoate, glycerol trienanthate, 1, 2, 3-trienanthoylglycerol, trienanthin, 2,3-di(heptanoyloxy)propyl heptanoate
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment was mixed with food (or formula, if appropriate) and administered orally (PO) or by gastronomy tube at least four times per day (breakfast, lunch, dinner, and before bed).

    Arm title
    Placebo
    Arm description
    Subjects randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    safflower oil
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment was mixed with food (or formula, if appropriate) and administered PO or by gastronomy tube at least four times per day (breakfast, lunch, dinner, and before bed).

    Number of subjects in period 1
    UX007 Placebo
    Started
    25
    11
    Completed
    23
    11
    Not completed
    2
    0
         Consent withdrawn by subject
    1
    -
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    Open-Label Extension Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    UX007
    Arm description
    Following completion of the Week 8 study visit, subjects continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
    Arm type
    Experimental

    Investigational medicinal product name
    triheptanoin
    Investigational medicinal product code
    UX007
    Other name
    C7 oil, glycerol triheptanoate, glycerol trienanthate, 1, 2, 3-trienanthoylglycerol, trienanthin, 2,3-di(heptanoyloxy)propyl heptanoate
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment was mixed with food (or formula, if appropriate) and administered PO or by gastronomy tube at least four times per day (breakfast, lunch, dinner, and before bed).

    Arm title
    Placebo
    Arm description
    Following completion of the Week 8 study visit, placebo subjects continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
    Arm type
    Experimental

    Investigational medicinal product name
    triheptanoin
    Investigational medicinal product code
    UX007
    Other name
    C7 oil, glycerol triheptanoate, glycerol trienanthate, 1, 2, 3-trienanthoylglycerol, trienanthin, 2,3-di(heptanoyloxy)propyl heptanoate
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment was mixed with food (or formula, if appropriate) and administered PO or by gastronomy tube at least four times per day (breakfast, lunch, dinner, and before bed).

    Number of subjects in period 2
    UX007 Placebo
    Started
    23
    11
    Completed
    16
    5
    Not completed
    7
    6
         Consent withdrawn by subject
    4
    5
         Subject non-compliance
    1
    -
         Other, not specified
    -
    1
         Adverse event
    1
    -
         Principal investigator decision
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    UX007
    Reporting group description
    Subjects randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.

    Reporting group values
    UX007 Placebo Total
    Number of subjects
    25 11 36
    Age categorical
    Units: Subjects
        2 years to < 12 years
    8 7 15
        12 years to < 18 years
    12 1 13
        18 years to < 65 years
    5 3 8
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    13.86 ± 5.107 15.24 ± 13.795 -
    Gender categorical
    Units: Subjects
        Female
    15 7 22
        Male
    10 4 14
    Primary Race
    Units: Subjects
        American Indian or Alaska Native
    0 1 1
        Asian
    1 0 1
        Black or African American
    0 1 1
        Native Hawaiian or other Pacific Islander
    0 0 0
        White
    23 9 32
        Other (not specified)
    1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    2 1 3
        Not Hispanic or Latino
    21 9 30
        Unknown
    2 1 3
    Total Seizure Frequency Per 4 Weeks
    Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. Absence seizures from electroencephalography (EEG). Includes absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec).
    Units: seizures per 4 weeks
        median (full range (min-max))
    96.6 (0 to 10250) 2.1 (0 to 1176) -

    End points

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    End points reporting groups
    Reporting group title
    UX007
    Reporting group description
    Subjects randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.
    Reporting group title
    UX007
    Reporting group description
    Following completion of the Week 8 study visit, subjects continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).

    Reporting group title
    Placebo
    Reporting group description
    Following completion of the Week 8 study visit, placebo subjects continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).

    Subject analysis set title
    Efficacy Analysis Set – 6MWT: UX007
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subset of subjects taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) 6MWT assessment performed.

    Subject analysis set title
    Efficacy Analysis Set - 6MWT: Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subset of subjects taking placebo during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) 6MWT assessment performed.

    Subject analysis set title
    Efficacy Analysis Set - GMFM-88: UX007
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subset of subjects taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) GMFM-88 assessment performed.

    Subject analysis set title
    Efficacy Analysis Set - GMFM-88: Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subset of subjects taking placebo during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) GMFM-88 assessment performed.

    Subject analysis set title
    Efficacy Analysis Set: UX007
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomized subjects who received at least one dose of investigational product.

    Subject analysis set title
    Efficacy Analysis Set: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomized subjects who received at least one dose of investigational product.

    Subject analysis set title
    Safety Analysis Set: UX007
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of investigational product.

    Subject analysis set title
    Safety Analysis Set: Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of investigational product.

    Subject analysis set title
    Efficacy Analysis Set - CANTAB: UX007
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subset of subjects taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) CANTAB assessment performed.

    Subject analysis set title
    Efficacy Analysis Set - CANTAB: Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subset of subjects taking placebo during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) CANTAB assessment performed.

    Primary: Percent Reduction from Baseline to Week 8 in Frequency of Total Seizures (Normalized to a 4-Week Rate)

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    End point title
    Percent Reduction from Baseline to Week 8 in Frequency of Total Seizures (Normalized to a 4-Week Rate)
    End point description
    Reduction from baseline to Week 8 in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary and absence seizures measured overnight by electroencephalography (EEG). Seizure types include: generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor and absence seizures. A negative value indicates an increase in frequency.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set: UX007 Efficacy Analysis Set: Placebo
    Number of subjects analysed
    25
    11
    Units: percent reduction of seizures per 4 wks
        median (full range (min-max))
    12.6 (-651 to 100)
    0.0 (-1021 to 100)
    Statistical analysis title
    Between Group Comparison
    Statistical analysis description
    Non-parametric post-hoc analysis: Hodges-Lehmann estimate of the location shift with 90% CI and Wilcoxon Rank Sum test p-value, based on Wilcoxon rank-sum test
    Comparison groups
    Efficacy Analysis Set: Placebo v Efficacy Analysis Set: UX007
    Number of subjects included in analysis
    36
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.5812
    Method
    Wilcoxon rank-sum test
    Parameter type
    Hodges-Lehmann estimate
    Point estimate
    13.45
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -38.63
         upper limit
    80.95

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Discontinuations Due to TEAEs During the Placebo-Controlled Period

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Discontinuations Due to TEAEs During the Placebo-Controlled Period [1]
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence, whether or not considered drug related. An SAE was defined as an AE or suspected adverse reaction that at any dose resulted in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, or an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definition. An AE was considered a TEAE if it occurred or worsened in severity on or after the date of the first dose of study drug. An AE was considered a UX007 emergent adverse event if it occurred or worsened in severity on or after the first date of first dose of UX007 during the study.
    End point type
    Primary
    End point timeframe
    Weeks 0 to 8
    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: UX007 Safety Analysis Set: Placebo
    Number of subjects analysed
    25
    11
    Units: subjects
        TEAE
    22
    9
        Serious TEAE
    1
    0
        Grade 3 or 4 TEAE
    2
    0
        TEAE Leading to Study Discontinuation
    0
    0
        TEAE Leading to Death
    0
    0
        Gastrointestinal TEAE
    18
    5
        Related TEAE
    18
    5
        Related Serious TEAE
    0
    0
        Related Gastrointestinal TEAE
    17
    4
        UX007 Emergent AE
    22
    0
        Serious UX007 Emergent AE
    1
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With TEAEs, Serious TEAEs and Discontinuations Due to TEAEs During the Extension Period

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    End point title
    Number of Subjects With TEAEs, Serious TEAEs and Discontinuations Due to TEAEs During the Extension Period [2]
    End point description
    An AE was defined as any untoward medical occurrence, whether or not considered drug related. An SAE was defined as an AE or suspected adverse reaction that at any dose resulted in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, or an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definition. An AE was considered a TEAE if it occurred or worsened in severity on or after the date of the first dose of study drug. An AE was considered a UX007 emergent adverse event if it occurred or worsened in severity on or after the first date of first dose of UX007 during the study.
    End point type
    Primary
    End point timeframe
    Weeks 9 to 52 plus 30 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented per protocol.
    End point values
    Safety Analysis Set: UX007 Safety Analysis Set: Placebo
    Number of subjects analysed
    23
    11
    Units: subjects
        TEAE
    21
    11
        Serious TEAE
    2
    0
        Grade 3 or 4 TEAE
    1
    0
        TEAE Leading to Study Discontinuation
    1
    0
        TEAE Leading to Death
    0
    0
        Gastrointestinal TEAE
    15
    10
        Related TEAE
    19
    8
        Related Serious TEAE
    0
    0
        Related Gastrointestinal TEAE
    13
    8
        UX007 Emergent AE
    21
    11
        Serious UX007 Emergent AE
    2
    0
    No statistical analyses for this end point

    Secondary: Percent Reduction From Baseline to Week 8 in Frequency of Observable Seizures (Normalized to a 4-Week Rate)

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    End point title
    Percent Reduction From Baseline to Week 8 in Frequency of Observable Seizures (Normalized to a 4-Week Rate)
    End point description
    Observable generalized and partial-onset seizures measured for 6 weeks by diary. Seizure types include: generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory and simple partial/focal psychological. A negative value indicates an increase in frequency.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set: UX007 Efficacy Analysis Set: Placebo
    Number of subjects analysed
    17 [3]
    10 [4]
    Units: percent reduction in seizures
        median (full range (min-max))
    0.0 (-651 to 84)
    0.0 (-1021 to 75)
    Notes
    [3] - observable seizures subjects
    [4] - observable seizures subjects
    Statistical analysis title
    Between Group Comparison
    Statistical analysis description
    Non-parametric post-hoc analysis: Hodges-Lehmann estimate of the location shift with 90% CI and Wilcoxon Rank Sum test p-value, based on Wilcoxon rank-sum test
    Comparison groups
    Efficacy Analysis Set: UX007 v Efficacy Analysis Set: Placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.8197
    Method
    Wilcoxon rank-sum test
    Parameter type
    Hodges-Lehmann estimate
    Point estimate
    0
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -51.23
         upper limit
    84.25

    Secondary: Percent Reduction From Baseline to Week 8 in Frequency of Absence Seizures (Normalized to a 4-Week Rate)

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    End point title
    Percent Reduction From Baseline to Week 8 in Frequency of Absence Seizures (Normalized to a 4-Week Rate)
    End point description
    Reduction from baseline to Week 8 in frequency of absence seizures measured overnight by EEG. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set: UX007 Efficacy Analysis Set: Placebo
    Number of subjects analysed
    17 [5]
    6 [6]
    Units: percent reduction in seizures
        median (full range (min-max))
    0.0 (-2400 to 100)
    0.0 (0 to 100)
    Notes
    [5] - absence seizure subjects
    [6] - absence seizure subjects
    Statistical analysis title
    Between Group Comparison
    Statistical analysis description
    Non-parametric post-hoc analysis: Hodges-Lehmann estimate of the location shift with 90% CI and Wilcoxon Rank Sum test p-value, based on Wilcoxon rank-sum test
    Comparison groups
    Efficacy Analysis Set: UX007 v Efficacy Analysis Set: Placebo
    Number of subjects included in analysis
    23
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.7276
    Method
    Wilcoxon rank-sum test
    Parameter type
    Hodges-Lehmann estimate
    Point estimate
    0
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0
         upper limit
    37.5

    Secondary: Percentage of Subjects With at Least a 50% Reduction From Baseline to Week 8 in Frequency of Total Seizures

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    End point title
    Percentage of Subjects With at Least a 50% Reduction From Baseline to Week 8 in Frequency of Total Seizures
    End point description
    Seizure response, defined as the percentage of participants with at least 50% reduction from randomization to Week 8 in frequency of total seizures. Includes observable generalized and partial-onset seizures measured for 6 weeks by diary and absence seizures measured overnight by EEG. Observable seizures from the diary include generalized tonic clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set: UX007 Efficacy Analysis Set: Placebo
    Number of subjects analysed
    25
    11
    Units: percentage of subjects
        number (not applicable)
    20.0
    36.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With at Least 50% Reduction From Baseline to Week 8 in Frequency of Observable Seizures

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    End point title
    Percentage of Subjects With at Least 50% Reduction From Baseline to Week 8 in Frequency of Observable Seizures
    End point description
    Observable seizure response, defined as the percentage of participants with at least 50% reduction from randomization to Week 8 in frequency of observable seizures. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set: UX007 Efficacy Analysis Set: Placebo
    Number of subjects analysed
    17 [7]
    10 [8]
    Units: percentage of subjects
        number (not applicable)
    5.9
    30.0
    Notes
    [7] - Subjects with observable seizures.
    [8] - Subjects with observable seizures.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With at Least 50% Reduction From Baseline to Week 8 in Frequency of Absence Seizures

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    End point title
    Percentage of Subjects With at Least 50% Reduction From Baseline to Week 8 in Frequency of Absence Seizures
    End point description
    Absence seizure response, at least 50% reduction from baseline in frequency of absence seizures measured overnight by EEG, is defined as percent reduction in absence seizure frequency greater than or equal to 50%. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set: UX007 Efficacy Analysis Set: Placebo
    Number of subjects analysed
    17 [9]
    6 [10]
    Units: percentage of subjects
        number (not applicable)
    23.5
    16.7
    Notes
    [9] - Subjects with absence seizures.
    [10] - Subjects with absence seizures.
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 8 in Cambridge Neuropsychological Test Automated Battery (CANTAB), Reaction Time (RTI) Scores, Generalized Estimating Equation (GEE)

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    End point title
    Change From Baseline to Week 8 in Cambridge Neuropsychological Test Automated Battery (CANTAB), Reaction Time (RTI) Scores, Generalized Estimating Equation (GEE)
    End point description
    CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. RTI Simple choice reaction time standard deviation (RTISRTSD) assesses the cognitive domain of attention, with scores on a continuous range from 0 to 5000; lower scores indicate better function. RTI median simple choice reaction time (RTIMDSRT) assesses the cognitive domain of reaction time, with scores on a continuous range from 100 to 5100; lower scores indicate better function. RTI median 5-choice reaction time (RTIMDFRT) assesses the cognitive domain of reaction time, with scores on a continuous range from 100 to 5100; lower scores indicate better function. GEE statistical model.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set - CANTAB: UX007 Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects analysed
    25
    11
    Units: score on a scale
    least squares mean (standard error)
        RTISRTSD
    41.698 ± 42.3539
    44.082 ± 53.3552
        RTIMDSRT
    15.512 ± 15.9204
    -48.157 ± 48.8781
        RTIMDFRT
    -14.723 ± 14.1862
    49.112 ± 58.4722
    Statistical analysis title
    RTISRTSD
    Comparison groups
    Efficacy Analysis Set - CANTAB: UX007 v Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.486 [11]
    Method
    GEE model
    Parameter type
    Least squares mean difference
    Point estimate
    -2.384
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -114.44
         upper limit
    109.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    68.1231
    Notes
    [11] - One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
    Statistical analysis title
    RTIMDSRT
    Comparison groups
    Efficacy Analysis Set - CANTAB: UX007 v Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8849 [12]
    Method
    GEE model
    Parameter type
    Least squares mean difference
    Point estimate
    63.669
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -23.6
         upper limit
    150.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    53.0537
    Notes
    [12] - One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
    Statistical analysis title
    RTIMDFRT
    Comparison groups
    Efficacy Analysis Set - CANTAB: UX007 v Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1463 [13]
    Method
    GEE model
    Parameter type
    Least squares mean difference
    Point estimate
    -63.835
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -163.59
         upper limit
    35.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    60.6496
    Notes
    [13] - One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.

    Secondary: Change From Baseline to Week 8 in CANTAB, Paired Associates Learning (PAL) Scores, GEE

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    End point title
    Change From Baseline to Week 8 in CANTAB, Paired Associates Learning (PAL) Scores, GEE
    End point description
    CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. PAL total errors adjusted (PALTEA) assesses the cognitive domain of episodic memory/new learning, with scores on a discrete, ordinal scale from 0 to 137; lower scores indicate better function. PAL first trial memory score (PALFTMS) assesses the cognitive domain of episodic memory, with scores on a discrete, ordinal scale from 0 to 27; higher scores indicate better function. GEE statistical model.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set - CANTAB: UX007 Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects analysed
    25
    11
    Units: score on a scale
    least squares mean (standard error)
        PALTEA
    -10.082 ± 2.4784
    -27.849 ± 11.3061
        PALFTMS
    2.574 ± 0.6833
    3.105 ± 2.0766
    Statistical analysis title
    PALTEA
    Comparison groups
    Efficacy Analysis Set - CANTAB: UX007 v Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9378 [14]
    Method
    GEE model
    Parameter type
    Least squares mean difference
    Point estimate
    17.768
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.26
         upper limit
    36.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.5659
    Notes
    [14] - One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
    Statistical analysis title
    PALFTMS
    Comparison groups
    Efficacy Analysis Set - CANTAB: UX007 v Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5959 [15]
    Method
    GEE model
    Parameter type
    Least squares mean difference
    Point estimate
    -0.531
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -4.13
         upper limit
    3.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1853
    Notes
    [15] - One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.

    Secondary: Change From Baseline to Week 8 in CANTAB, Spatial Span (SSP) Span Length Scores, GEE

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    End point title
    Change From Baseline to Week 8 in CANTAB, Spatial Span (SSP) Span Length Scores, GEE
    End point description
    CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. SSP Span Length (SSPSLF) assesses the cognitive domain of sequential memory, with scores on a discrete, ordinal scale from 2 to 9; higher scores indicate better function. GEE statistical model.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set - CANTAB: UX007 Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects analysed
    25
    11
    Units: score on a scale
        least squares mean (standard error)
    0.019 ± 0.2387
    -0.041 ± 0.4246
    Statistical analysis title
    SSPSLF
    Comparison groups
    Efficacy Analysis Set - CANTAB: Placebo v Efficacy Analysis Set - CANTAB: UX007
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4522 [16]
    Method
    GEE model
    Parameter type
    LS Mean Difference
    Point estimate
    0.06
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.76
         upper limit
    0.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4988
    Notes
    [16] - One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.

    Secondary: Change From Baseline to Week 8 in CANTAB, Spatial Working Memory (SWM) Scores, GEE

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    End point title
    Change From Baseline to Week 8 in CANTAB, Spatial Working Memory (SWM) Scores, GEE
    End point description
    CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. SWM between errors (SWMBE48) assesses the cognitive domain of working memory, with scores on a discrete, ordinal scale from 0 to 360; lower scores indicate better function. SWM strategy (SWMS68) assesses the cognitive domain of executive function/strategy, with scores on a discrete, ordinal scale from 4 to 28; lower scores indicate better function. GEE statistical model.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set - CANTAB: UX007 Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects analysed
    25
    11
    Units: score on a scale
    least squares mean (standard error)
        SWMBE48
    1.003 ± 1.4582
    2.240 ± 1.8036
        SWMS68
    0.060 ± 0.4794
    0.022 ± 0.4279
    Statistical analysis title
    SWMBE48
    Comparison groups
    Efficacy Analysis Set - CANTAB: UX007 v Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3017 [17]
    Method
    GEE model
    Parameter type
    LS Mean Difference
    Point estimate
    -1.237
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -5.15
         upper limit
    2.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.381
    Notes
    [17] - One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
    Statistical analysis title
    SWMS68
    Comparison groups
    Efficacy Analysis Set - CANTAB: UX007 v Efficacy Analysis Set - CANTAB: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5235 [18]
    Method
    GEE model
    Parameter type
    LS Mean Difference
    Point estimate
    0.038
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.03
         upper limit
    1.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6495
    Notes
    [18] - One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.

    Secondary: Change From Baseline to Week 8 in Distance Traveled (in Meters) as Measured by 6-Minute Walk Test (6MWT)

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    End point title
    Change From Baseline to Week 8 in Distance Traveled (in Meters) as Measured by 6-Minute Walk Test (6MWT)
    End point description
    Subjects were instructed to walk the length of a pre-measured 20-30 meter course in a hallway for 6 consecutive minutes. The total distance walked (meters) in a 6 minute period was recorded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set – 6MWT: UX007 Efficacy Analysis Set - 6MWT: Placebo
    Number of subjects analysed
    23
    11
    Units: meters
        least squares mean (standard error)
    -10.336 ± 14.8614
    -3.439 ± 16.1506
    Statistical analysis title
    6MWT distance traveled
    Comparison groups
    Efficacy Analysis Set – 6MWT: UX007 v Efficacy Analysis Set - 6MWT: Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6205 [19]
    Method
    GEE model
    Parameter type
    LS Mean Difference
    Point estimate
    -6.897
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -43.874
         upper limit
    30.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    22.4806
    Notes
    [19] - One-sided p-value. Additional model covariates include the corresponding baseline value, visit and the interaction between visit and treatment.

    Secondary: Change From Baseline to Week 8 in Distance Traveled (in Percent Predicted) as Measured by 6MWT

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    End point title
    Change From Baseline to Week 8 in Distance Traveled (in Percent Predicted) as Measured by 6MWT
    End point description
    Subjects were instructed to walk the length of a pre-measured 20-30 meter course in a hallway for 6 consecutive minutes. The total distance walked (meters) in a 6 minute period was recorded. The percent of predicted normal distance walked was determined based on published normative data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set – 6MWT: UX007 Efficacy Analysis Set - 6MWT: Placebo
    Number of subjects analysed
    23
    11
    Units: percent of predicted distance
        least squares mean (standard error)
    -1.338 ± 2.4752
    0.016 ± 2.6398
    Statistical analysis title
    6MWT distance traveled (percent predicted)
    Comparison groups
    Efficacy Analysis Set – 6MWT: UX007 v Efficacy Analysis Set - 6MWT: Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6476 [20]
    Method
    GEE model
    Parameter type
    LS Mean Difference
    Point estimate
    -1.354
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -7.236
         upper limit
    4.527
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.5759
    Notes
    [20] - One-sided p-value. Additional model covariates include the corresponding baseline value, visit and the interaction between visit and treatment.

    Secondary: Time (in Minutes) to Onset of Paroxysmal Exertional Dyskinesia (PED) as Measured During 6MWT Over Time Through Week 8

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    End point title
    Time (in Minutes) to Onset of Paroxysmal Exertional Dyskinesia (PED) as Measured During 6MWT Over Time Through Week 8
    End point description
    For the 6MWT, subjects were instructed to walk the length of a pre-measured 20-30 meter course in a hallway for 6 consecutive minutes. The total distance walked (meters) in a 6 minute period was recorded. PED occurring during the 6MWT was assessed. (PED is characterized by transient abnormal, involuntary movements primarily affecting the legs and feet, and typically precipitated by prolonged exertion.)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8
    End point values
    Efficacy Analysis Set – 6MWT: UX007 Efficacy Analysis Set - 6MWT: Placebo
    Number of subjects analysed
    3 [21]
    0 [22]
    Units: minutes
    arithmetic mean (standard deviation)
        Week 4
    4.7 ± 4.73
    ±
        Week 8
    1.8 ± 1.30
    ±
    Notes
    [21] - subjects with at least 1 PED
    [22] - subjects with at least 1 PED
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 8 in Gross Motor Function Measure-88 (GMFM-88) Total Score

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    End point title
    Change From Baseline to Week 8 in Gross Motor Function Measure-88 (GMFM-88) Total Score
    End point description
    The GMFM-88 is a standardized observational measure of abilities that includes the following 5 domains: lying/rolling, sitting, crawling/kneeling, standing, and walking/running/jumping. The GMFM-88 scores include the following: • Lying & Rolling Score, Range 0–100%, higher is better • Sitting Score, Range 0–100%, higher is better • Crawling & Kneeling Score, Range 0–100%, higher is better • Standing Score, Range 0–100%, higher is better • Walking, Running & Jumping Score, Range 0–100%, higher is better • Total Score = (Sum of 5 Above Scores) / 5, Range 0–100%, higher is better.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    Efficacy Analysis Set - GMFM-88: UX007 Efficacy Analysis Set - GMFM-88: Placebo
    Number of subjects analysed
    21
    11
    Units: score on a scale
        least squares mean (standard error)
    3.209 ± 2.3669
    1.642 ± 2.6690
    Statistical analysis title
    GMFM-88 UX007-Placebo
    Comparison groups
    Efficacy Analysis Set - GMFM-88: UX007 v Efficacy Analysis Set - GMFM-88: Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3435 [23]
    Method
    GEE model
    Parameter type
    LS Mean Difference
    Point estimate
    1.568
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -4.83
         upper limit
    7.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.8899
    Notes
    [23] - One-sided p-value. Additional model covariates include baseline GMFM-88 total score, visit and the interaction between visit and treatment.

    Secondary: Percent Reduction from Baseline Over Time in Frequency of Total Seizures (Normalized to a 4-Week Rate)

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    End point title
    Percent Reduction from Baseline Over Time in Frequency of Total Seizures (Normalized to a 4-Week Rate)
    End point description
    Reduction from baseline over time in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary and absence seizures measured overnight by EEG. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, Week 31
    End point values
    UX007 Placebo
    Number of subjects analysed
    22 [24]
    11 [25]
    Units: percent reduction of seizures per 4 wks
    median (full range (min-max))
        Week 26; n= 22, 11
    7.8 (-409 to 100)
    0.0 (-207 to 94)
        Week 31; n=19, 8
    42.7 (-267 to 100)
    5.3 (-681 to 75)
    Notes
    [24] - n=subjects with an assessment at given time point.
    [25] - n=subjects with an assessment at given time point.
    No statistical analyses for this end point

    Secondary: Percent Reduction From Baseline Over Time in Frequency of Observable Seizures (Normalized to a 4-Week Rate)

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    End point title
    Percent Reduction From Baseline Over Time in Frequency of Observable Seizures (Normalized to a 4-Week Rate)
    End point description
    Reduction from baseline over time in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. A negative value indicates an increase in frequency.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, Week 31, Week 36, and Week 52
    End point values
    UX007 Placebo
    Number of subjects analysed
    15 [26]
    10 [27]
    Units: percent reduction in seizures per 4 wks
    median (full range (min-max))
        Week 26; n=15, 10
    0.0 (-260 to 88)
    -27.7 (-207 to 74)
        Week 31; n=12, 7
    23.6 (-267 to 100)
    0.0 (-681 to 67)
        Week 36; n=12, 7
    42.5 (-438 to 100)
    -49.8 (-400 to 77)
        Week 52; n=12, 6
    31.0 (-222 to 100)
    -10.3 (-358 to 85)
    Notes
    [26] - n=subjects with observable seizures and an assessment at given time point.
    [27] - n=subjects with observable seizures and an assessment at given time point.
    No statistical analyses for this end point

    Secondary: Percent Reduction From Baseline Over Time in Frequency of Absence Seizures (Normalized to a 4-week Rate)

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    End point title
    Percent Reduction From Baseline Over Time in Frequency of Absence Seizures (Normalized to a 4-week Rate)
    End point description
    Absence seizures measured overnight by EEG. The absence seizure frequency from EEG (normalized to a 24-hour rate) is defined as Absence Seizure Frequency=Total number of absence seizures/Number of hours observed×24. Seizure types include: absence awake (≥10 sec), absence sleep (≥10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, Week 31
    End point values
    UX007 Placebo
    Number of subjects analysed
    14 [28]
    4 [29]
    Units: percent reduction in seizures per 4 wks
    median (full range (min-max))
        Week 26; n=14, 4
    0.0 (-3135 to 100)
    0.0 (0 to 94)
        Week 31; n=12, 3
    0.0 (-3905 to 100)
    0.0 (0 to 75)
    Notes
    [28] - n=subjects with absence seizures and an assessment at given time point.
    [29] - n=subjects with absence seizures and an assessment at given time point.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Placebo-controlled period from first dose of study drug through Week 8. Extension period: Week 9 up to Week 52 plus 30 days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo Controlled Period / Placebo
    Reporting group description
    Subjects randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.

    Reporting group title
    Placebo Controlled Period / UX007
    Reporting group description
    Subjects randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.

    Reporting group title
    Extension Period / UX007
    Reporting group description
    Following completion of the Week 8 study visit, placebo and UX007 subjects continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).

    Serious adverse events
    Placebo Controlled Period / Placebo Placebo Controlled Period / UX007 Extension Period / UX007
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
    2 / 34 (5.88%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Subcutaneous Haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 25 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Status Epilepticus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 25 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Controlled Period / Placebo Placebo Controlled Period / UX007 Extension Period / UX007
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 11 (81.82%)
    21 / 25 (84.00%)
    31 / 34 (91.18%)
    Investigations
    Weight Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 25 (12.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    3
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 25 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    2
    0
    2
    Fall
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 25 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    3
    Head Injury
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 25 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    2
    Ligament Sprain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 25 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Lip Injury
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 25 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Clonic Convulsion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 25 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 25 (8.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    5
    2
    Headache
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 25 (12.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    4
    34
    Seizure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 25 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 25 (8.00%)
    6 / 34 (17.65%)
         occurrences all number
    0
    2
    6
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 25 (8.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    7 / 25 (28.00%)
    3 / 34 (8.82%)
         occurrences all number
    1
    13
    27
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 11 (0.00%)
    7 / 25 (28.00%)
    5 / 34 (14.71%)
         occurrences all number
    0
    10
    7
    Breath Odour
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 25 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Constipation
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 25 (8.00%)
    5 / 34 (14.71%)
         occurrences all number
    0
    2
    8
    Diarrhoea
         subjects affected / exposed
    3 / 11 (27.27%)
    9 / 25 (36.00%)
    18 / 34 (52.94%)
         occurrences all number
    10
    14
    76
    Flatulence
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 25 (4.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    1
    2
    Nausea
         subjects affected / exposed
    0 / 11 (0.00%)
    5 / 25 (20.00%)
    5 / 34 (14.71%)
         occurrences all number
    0
    5
    24
    Vomiting
         subjects affected / exposed
    2 / 11 (18.18%)
    11 / 25 (44.00%)
    15 / 34 (44.12%)
         occurrences all number
    4
    21
    30
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 25 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 25 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    3
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 25 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    3
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 25 (8.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Psychiatric disorders
    Abnormal Behaviour
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 25 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    3
    Agitation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    3
    Insomnia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 25 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 25 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Infections and infestations
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    Otitis Media Acute
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 25 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 25 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    2
    0
    4
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 25 (12.00%)
    6 / 34 (17.65%)
         occurrences all number
    1
    3
    8
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 25 (4.00%)
    5 / 34 (14.71%)
         occurrences all number
    1
    1
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2013
    1. Study Sites. The number of study sites was increased. 2. Number of Subjects Planned was increased. 3. Study Procedures and Assessments were modified. 4. Primary Efficacy Hypothesis was modified. 5. The primary objective language was modified. 6. Inclusion Criteria was modified. 7. Treatment Administration: A recommended dose titration schedule was inserted. In addition, dose administration guidelines were modified. 8. Drug Concentration Measurements for population PK assessments were modified. 9. Suicidal Ideation and Behavior Assessments were modified. 10. Statistical Methods plans were modified.
    20 May 2014
    1. Number of Subjects Planned was revised. 2. Primary Efficacy Hypothesis was modified. 3. Study Objectives were modified or added to Section 6 in order to align study objectives with modifications to study design and endpoints. 4. Overall Study Design and Plan was modified. 5. Inclusion Criteria was modified. 6. Study Procedures and Assessments were modified 7. Efficacy Measures were changed. 8. Drug Concentration Measurements were modified. 9. Statistical Analysis & Determination of Sample Size was updated.
    09 Dec 2014
    1. The adaptive study design component of the protocol was eliminated. 2. Inclusion criteria were updated, changed, and/or removed. 3. The primary and secondary objectives of the study were updated and the primary and secondary endpoints were updated to reflect the changes to the objectives to include a more robust evaluation of triheptanoin in patients with absence seizures. 4. The randomization was changed from 1:1 to 3:1 (UX007: placebo). 5. An EEG assessment was added at the Screening Visit. 6. Removal of Subjects from Therapy or Assessment was updated to clarify the conditions under which subjects either will be removed or may be removed from study participation.
    30 Nov 2015
    1. Edited Inclusion Criteria. 2. Updated the list of excluded medications. 3. Primary objective changed to ‘Evaluate the efficacy of UX007 compared to placebo as measured by the reduction from randomization to week 8 in frequency of seizures’. 4. The EEG at Screening for patients with absence seizures only was required for ~3 hours, not overnight. 5. The Erythrocyte Glucose Uptake Assay was removed from the protocol. 6. Plasma level sample collection range for the population PK study at Week 26 was changed from 30 – 180 minutes to 60 and 180 minutes.

    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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