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    Clinical Trial Results:
    An Open-label Extension Study to Assess the Long-term Safety and Efficacy of UX007 in Subjects with Glucose Transporter Type 1 Deficiency Syndrome

    Summary
    EudraCT number
    2015-000389-69
    Trial protocol
    GB   ES   DK  
    Global end of trial date
    22 Oct 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    03 May 2020
    First version publication date
    03 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UX007G-CL202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02599961
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    EMA/190573: Unique Product Identifier (UPI)
    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 8887568657, medinfo@ultragenyx.com
    Scientific contact
    Medical Information, Ultragenyx Pharmaceutical Inc., +1 8887568657, 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
    22 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the long-term safety of UX007 in glucose transporter type 1 deficiency syndrome (Glut1 DS) subjects.
    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
    10 Sep 2015
    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: 9
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Denmark: 1
    Worldwide total number of subjects
    15
    EEA total number of subjects
    4
    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)
    5
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study enrolled pediatric, adolescent, and adult Glut1 DS subjects who completed the UX007G-CL201 study (2013-003771-35; rollover subjects). No non-rollover subjects (subjects from other clinical studies, investigator sponsored trials, or expanded access/compassionate use treatment) enrolled.

    Pre-assignment
    Screening details
    For continuing UX007G-CL201 subjects, the Week 52 visit of that study may have been conducted in conjunction with the Baseline visit for this study to avoid duplication of assessments.

    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
    UX007 (Triheptanoin)
    Arm description
    UX007 dosing was targeted and/or maintained at 35% of total daily caloric intake.
    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 gastrostomy tube at least four times per day (breakfast, lunch, dinner, and before bed).

    Number of subjects in period 1
    UX007 (Triheptanoin)
    Started
    15
    Completed
    0
    Not completed
    15
         Other, Not Specified
    3
         Subject Non-Compliance
    2
         Discontinuation of Study by Sponsor
    9
         Consent withdrawn by subject
    1

    Baseline characteristics

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

    Reporting group values
    Overall Study Total
    Number of subjects
    15 15
    Age categorical
    Units: Subjects
        2 to < 12 years
    5 5
        12 to < 18 years
    5 5
        18 to < 65 years
    5 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    15.24 ± 6.106 -
    Gender categorical
    Units: Subjects
        Female
    11 11
        Male
    4 4
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1 1
        Not Hispanic or Latino
    13 13
        Unknown or Not Reported
    1 1
    Race
    Units: Subjects
        American Indian or Alaska Native
    1 1
        Asian
    1 1
        Black or African American
    1 1
        White
    11 11
        Other, Not Specified
    1 1
    Overall Seizure Frequency Per 4 Weeks
    The number of observable seizures were recorded by the subject or caregiver via diary. Observable seizures were defined as: 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; absence.
    Units: seizures per 4 weeks
        arithmetic mean (standard deviation)
    312.17 ± 528.057 -
    Baseline (2013-003771-35) Columbia Neurological Score (CNS) Total Score
    The CNS evaluates measures of neurological function and development delay, and is the sum of scores for the following domains: Weight, Height, Head Circumference, General Medical Exam, Funduscopic Exam, Cranial Nerves, Stance & Gait, Involuntary Movements, Sensation, Cerebellar Function, Muscle Bulk, Tone & Strength, Myotatic Reflexes, Toe Sign, Other Findings. The CNS is only scored when all domains are measured and ranges from 0 (abnormal exam) to 76 (normal exam). Higher scores are associated with higher neurological function. n=12 (subjects with a baseline assessment).
    Units: score on a scale
        arithmetic mean (standard deviation)
    38.63 ± 25.428 -
    Baseline (2013-003771-35) Short Form 10 (SF-10) Health Survey for Children Physical Summary Score
    The SF-10 Health Survey for Children was administered to caregivers of subjects aged 5-17 years. Responses are used to generate 2 component summary scores: Physical Summary Score and the Psychosocial Summary Score. The T-score based scale scores were centered so that a score of 50 corresponds to the average score in a comprehensive 2006 sample (a combination of general population and supplemental disability and chronic condition samples). Higher scores are associated with better quality of life. n=10 (subjects with a baseline assessment).
    Units: T-score
        arithmetic mean (standard deviation)
    32.63 ± 17.027 -
    Baseline (2013-003771-35) SF-10 Health Survey for Children Psychosocial Summary Score
    The SF-10 Health Survey for Children was administered to caregivers of subjects aged 5-17 years. Responses are used to generate 2 component summary scores: Physical Summary Score and the Psychosocial Summary Score. The T-score based scale scores were centered so that a score of 50 corresponds to the average score in a comprehensive 2006 sample (a combination of general population and supplemental disability and chronic condition samples). Higher scores are associated with better quality of life. n-=10 (subjects with a baseline assessment).
    Units: T-score
        arithmetic mean (standard deviation)
    48.29 ± 10.196 -
    Baseline (2013-003771-35) SF 12 V.2 (SF-12v2) Health Survey Physical Component Summary (PCS) Score
    SF-12v2 was assessed for adults >= 18 years. 8 domain scores were used to generate 2 component summary scores: physical health (PCS) and mental health (MCS). Scores have mean of 50 and SD of 10. T-score based scoring method scores the data in relation to U.S. general population T-scores. Therefore, all scores obtained that are below 50 can be interpreted as below the US general population T-score. Scores above 50 can be interpreted as above the U.S. general population T-score. Higher global scores are associated with better quality of life. n=2 (subjects with a baseline assessment).
    Units: T-score
        arithmetic mean (standard deviation)
    39.37 ± 0.523 -
    Baseline (2013-003771-35) SF-12v2 Health Survey MCS Score
    SF-12v2 was assessed for adults >= 18 years. 8 domain scores were used to generate 2 component summary scores: physical health (PCS) and mental health (MCS). Scores have mean of 50 and SD of 10. T-score based scoring method scores the data in relation to U.S. general population T-scores. Therefore, all scores obtained that are below 50 can be interpreted as below the US general population T-score. Scores above 50 can be interpreted as above the U.S. general population T-score. Higher global scores are associated with better quality of life. n=2 (subjects with a baseline assessment).
    Units: T-score
        arithmetic mean (standard deviation)
    43.49 ± 4.356 -

    End points

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    End points reporting groups
    Reporting group title
    UX007 (Triheptanoin)
    Reporting group description
    UX007 dosing was targeted and/or maintained at 35% of total daily caloric intake.

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

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Discontinuations Due to TEAEs, and Deaths [1]
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence, whether or not considered drug related. Serious adverse events (SAEs) are AEs that at any dose, in the view of either the investigator or sponsor, 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; a congenital anomaly/birth defect; other important medical event. An AE was considered a TEAE if it occurred on or after the first dose in this study, and was not present prior to the first dose in this study, or it was present at the first dose in this study but increased in severity during the study. Severity was based on Common Terminology Criteria for Adverse Events (CTCAE): 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, and 5 = death related to AE.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 36 months. The mean (SD) treatment duration was 667.9 (357) days.
    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
    UX007 (Triheptanoin)
    Number of subjects analysed
    15
    Units: subjects
        TEAEs
    13
        Serious TEAEs
    2
        Related TEAEs
    10
        Serious and Related TEAEs
    0
        Grade 3 or 4 TEAEs
    1
        Gastrointestinal TEAEs
    9
        TEAEs Leading to Treatment Discontinuation
    0
        TEAEs Leading to Study Discontinuation
    0
        TEAEs Leading to Death
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in Overall Seizure Frequency Per 4 Weeks

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    End point title
    Change From Baseline Over Time in Overall Seizure Frequency Per 4 Weeks
    End point description
    The number of observable seizures were recorded by the subject or caregiver via diary throughout the study. Observable seizures were defined as: 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; absence.
    End point type
    Secondary
    End point timeframe
    Baseline (2013-003771-35), Month 0-3, Month 4-6, Month 7-9, Month 10-12, Month 13-18, Month 19-24, Month 25-30, Month 31-36
    End point values
    UX007 (Triheptanoin)
    Number of subjects analysed
    15 [2]
    Units: seizures per 4 weeks
    arithmetic mean (standard deviation)
        Change at Month 0-3; n=10
    -64.22 ± 185.564
        Change at Month 4-6; n=7
    -64.19 ± 142.460
        Change at Month 7-9; n=7
    -61.81 ± 164.770
        Change at Month 10-12; n=7
    -91.93 ± 216.834
        Change at Month 13-18; n=8
    -75.56 ± 206.406
        Change at Month 19-24; n=6
    -110.12 ± 233.492
        Change at Month 25-30; n=5
    -135.60 ± 249.871
        Change at Month 31-36; n=2
    -51.88 ± 101.378
    Attachments
    Untitled (Filename: Statistical Analysis for Change From Baseline Over Time in Overall Seizure Frequency Per 4 Weeks.docx)
    Notes
    [2] - n=subjects with a baseline (BL) and postbaseline (PBL) assessment at given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in CNS Total Score

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    End point title
    Change From Baseline Over Time in CNS Total Score
    End point description
    The CNS evaluates measures of neurological function and development delay, and is the sum of scores for the following domains: Weight, Height, Head Circumference, General Medical Exam, Funduscopic Exam, Cranial Nerves, Stance & Gait, Involuntary Movements, Sensation, Cerebellar Function, Muscle Bulk, Tone & Strength, Myotatic Reflexes, Toe Sign, Other Findings. The CNS is only scored when all domains are measured and ranges from 0 (abnormal exam) to 76 (normal exam). Higher scores are associated with higher neurological function.
    End point type
    Secondary
    End point timeframe
    Baseline (2013-003771-35), Month 0, Month 6, Month 12, Month 24, Month 36
    End point values
    UX007 (Triheptanoin)
    Number of subjects analysed
    12 [3]
    Units: T-score
    arithmetic mean (standard deviation)
        Change at Month 0; n=10
    11.85 ± 20.331
        Change at Month 6; n=7
    9.36 ± 18.495
        Change at Month 12; n=7
    13.64 ± 21.371
        Change at Month 24; n=4
    3.38 ± 3.092
        Change at Month 36; n=1
    0.00 ± 99999
    Notes
    [3] - n=subjects with a BL and PBL assessment at given time point. 99999=not applicable (1 subject).
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in SF-10 Health Survey for Children Physical Summary Score

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    End point title
    Change From Baseline Over Time in SF-10 Health Survey for Children Physical Summary Score
    End point description
    The SF-10 Health Survey for Children was administered to caregivers of participants aged 5-17 years. Responses are used to generate 2 component summary scores: Physical Summary Score and the Psychosocial Summary Score. The T-score based scale scores were centered so that a score of 50 corresponds to the average score in a comprehensive 2006 sample (a combination of general population and supplemental disability and chronic condition samples). Higher scores are associated with better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline (2013-003771-35), Month 0, Month 6, Month 12, Month 18, Month 24, Month 30
    End point values
    UX007 (Triheptanoin)
    Number of subjects analysed
    10 [4]
    Units: T-score
    arithmetic mean (standard deviation)
        Change at Month 0; n=9
    0.25 ± 16.917
        Change at Month 6; n=7
    9.56 ± 21.522
        Change at Month 12; n=6
    -2.67 ± 9.475
        Change at Month 18; n=5
    -9.35 ± 12.702
        Change at Month 24; n=4
    -8.96 ± 20.075
        Change at Month 30; n=2
    7.74 ± 2.273
    Notes
    [4] - n=pediatric subjects with a BL and PBL assessment at given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in SF-10 Health Survey for Children Psychosocial Summary Score

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    End point title
    Change From Baseline Over Time in SF-10 Health Survey for Children Psychosocial Summary Score
    End point description
    The SF-10 Health Survey for Children was administered to caregivers of participants aged 5-17 years. Responses are used to generate 2 component summary scores: Physical Summary Score and the Psychosocial Summary Score. The T-score based scale scores were centered so that a score of 50 corresponds to the average score in a comprehensive 2006 sample (a combination of general population and supplemental disability and chronic condition samples). Higher scores are associated with better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline (2013-003771-35), Month 0, Month 6, Month 12, Month 18, Month 24, Month 30
    End point values
    UX007 (Triheptanoin)
    Number of subjects analysed
    10 [5]
    Units: T-score
    arithmetic mean (standard deviation)
        Change at Month 0; n=9
    0.59 ± 11.049
        Change at Month 6; n=7
    -2.29 ± 12.366
        Change at Month 12; n=6
    -7.43 ± 15.514
        Change at Month 18; n=5
    -6.60 ± 14.987
        Change at Month 24; n=4
    -8.25 ± 15.316
        Change at Month 30; n=2
    8.91 ± 12.599
    Notes
    [5] - n=pediatric subjects with a BL and PBL assessment at given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in SF-12v2 Health Survey PCS Score

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    End point title
    Change From Baseline Over Time in SF-12v2 Health Survey PCS Score
    End point description
    SF-12v2 was assessed for adults 18 years of age and older. Eight domain scores were used to generate 2 component summary scores: physical health (PCS) and mental health (MCS). The PCS and MCS scores have mean of 50 and SD of 10. The T-score based scoring method scores the data in relation to U.S. general population T-scores. Therefore, all scores obtained that are below 50 can be interpreted as below the U.S. general population T-score and scores above 50 can be interpreted as above the U.S. general population T-score. Higher global scores are associated with better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline (2013-003771-35), Month 0, Month 6, Month 12, Month 18
    End point values
    UX007 (Triheptanoin)
    Number of subjects analysed
    2 [6]
    Units: T-score
    arithmetic mean (standard deviation)
        Change at Month 0; n=2
    10.25 ± 5.077
        Change at Month 6; n=2
    12.37 ± 5.367
        Change at Month 12; n=2
    5.09 ± 1.619
        Change at Month 18; n=1
    -0.35 ± 99999
    Notes
    [6] - n=adult subjects with a BL and PBL assessment at given time point. 99999=not applicable (1 subject).
    No statistical analyses for this end point

    Secondary: Change From Baseline Over Time in SF-12v2 Health Survey MCS Score

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    End point title
    Change From Baseline Over Time in SF-12v2 Health Survey MCS Score
    End point description
    SF-12v2 was assessed for adults 18 years of age and older. Eight domain scores were used to generate 2 component summary scores: physical health (PCS) and mental health (MCS). The PCS and MCS scores have mean of 50 and SD of 10. The T-score based scoring method scores the data in relation to U.S. general population T-scores. Therefore, all scores obtained that are below 50 can be interpreted as below the U.S. general population T-score and scores above 50 can be interpreted as above the U.S. general population T-score. Higher global scores are associated with better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline (2013-003771-35), Month 0, Month 6, Month 12, Month 18
    End point values
    UX007 (Triheptanoin)
    Number of subjects analysed
    2 [7]
    Units: T-score
    arithmetic mean (standard deviation)
        Change at Month 0; n=2
    8.63 ± 2.249
        Change at Month 6; n=2
    5.84 ± 3.316
        Change at Month 12; n=2
    6.90 ± 5.706
        Change at Month 18; n=1
    16.96 ± 99999
    Notes
    [7] - n=adult subjects with a BL and PBL assessment at given time point. 99999=not applicable (1 subject).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 36 months. The mean (SD) treatment duration was 667.9 (357) days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    UX007 (Triheptanoin)
    Reporting group description
    UX007 dosing was targeted and/or maintained at 35% of total daily caloric intake.

    Serious adverse events
    UX007 (Triheptanoin)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 15 (13.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Intestinal Obstruction
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Croup Infectious
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear Infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis Media
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis Media Acute
         subjects affected / exposed
    1 / 15 (6.67%)
         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
    UX007 (Triheptanoin)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 15 (86.67%)
    Vascular disorders
    Hot Flush
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Immune system disorders
    Seasonal Allergy
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Thirst
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Vulvovaginal Pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Head Injury
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    3
    Ligament Sprain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Procedural Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood Glucose Increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Weight Increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nasal Congestion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nervous system disorders
    Disturbance In Attention
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dysarthria
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Head Titubation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    79
    Lethargy
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Petit Mal Epilepsy
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Seizure
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    5
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    26
    Breath Odour
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    7 / 15 (46.67%)
         occurrences all number
    13
    Dysphagia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Haematochezia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    12
    Vomiting
         subjects affected / exposed
    5 / 15 (33.33%)
         occurrences all number
    16
    Skin and subcutaneous tissue disorders
    Hair Growth Abnormal
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Muscle Spasms
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Muscular Weakness
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pain In Extremity
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    5
    Hyponatraemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infections and infestations
    Ear Infection
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    3
    Influenza
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Otitis Media
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Otitis Media Acute
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Pharyngitis Streptococcal
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    9
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jun 2016
    • The number of study sites was changed from ‘approximately 12’ to ‘up to 16.’ The number of subjects planned was approximated at 40 subjects from the UX007 CL201 study and additional subjects who participated in qualified ISTs. • Updated inclusion criteria to state that all subjects at least 1 year of age at time of informed consent are eligible for participation in this study. • Modified inclusion criteria to remove the 3 month window following completion of the feeder study, to allow more flexibility. • The inclusion criterion regarding pregnancy testing and contraception was split into 2 separate inclusion criteria for clarity. • The exclusion criterion regarding serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels was removed, as it was not considered a likely safety concern. • Removed specific requirements regarding percent of daily fat intake from the exclusion criteria, to allow investigators to manage subject diet. • Removed diabetes mellitus as an exclusionary condition. • The first secondary objective was changed to ‘Evaluate the long-term effect of UX007 efficacy on seizures associated with Glut1 DS’. This change affects multiple sections of the protocol related to statistical evaluations and analyses. • Stopping rules were modified to correct notification procedures should unexpected and study drug-related SAEs occur, or if the study was restarted. • The Investigational Product section was modified to specify UX007 should be mixed with food; the requirement to never administer directly as the oil was removed. In addition, the language around dose level was modified to recognize and allow the subject to remain on current dose, which may be different (ie, lower or higher) than 35% of total daily caloric intake.
    02 Jun 2016
    (continued) • Study Duration section was modified to state “The planned duration of treatment in this study is 3 years, or until one of the following occurs: the subject withdraws consent or is discontinued from the study at the discretion of the Investigator or Ultragenyx; the study is terminated, or until commercial availability of study drug in a subject’s region, whichever occurs first.”. Due to this change, specific references to a “3-year Treatment Extension” were changed to “Treatment Extension Period” throughout the protocol. • Updated Prohibited Medications section to remove valproate, MCT oil, KetoCal, or other KD supplements, or other prescribed diet plan as prohibited medications; pancreatic lipase inhibitors was added to the list of prohibited medications. • The frequency of overnight EEG assessments was increased. Interictal epileptiform discharges will not be examined as an efficacy variable. • Efficacy assessments including Cambridge Neuropsychological Test Automated Battery Six Minute Walk Test and associated paroxysmal exertional dyskinesia (6MWT/PED), the Clinical Global Impression Scales (CGI), and the Pediatric Evaluation of Disability Inventory – Computer Adaptive Test (PEDI-CAT) were removed from the study. Study objectives and endpoints were updated to reflect this change. The Short Form Health Surveys (SF-10 and SF-12v2) will not be performed if no pre-treatment baseline data was available from feeder study. • Beta-ketopentanoic acid (BKP) will no longer be assayed. • Physical examination of the genitourinary system was no longer specified. • Dietitian Consultation and Diet Assessment Section was modified to remove the requirement for a 3-day diet diary prior to the Baseline Visit. Daily caloric intake and UX007 dose determined by interview with the dietitian at the Baseline Visit.
    02 Jun 2016
    (continued) • Separate safety analysis and intent-to-treat populations were replaced with 1 analysis set to include all subjects who receive at least 1 dose of UX007 during the study. • Reduction in frequency of seizures was removed as an efficacy analysis and replaced with a list of efficacy measures to be assessed. • A coordinating investigator will be named for this multicenter study. • The Record Retention section was 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. • The Adverse Event Reporting section was updated to match Sponsor’s current safety reporting procedures.
    28 Jul 2016
    The main purpose of Amendment 2 was to update the list of examples of highly effective contraception methods, to add a Safety Follow-up Phone Call to standardize how AE information was collected 30 days following the last dose of UX007, and to clarify that the end of study was the last subject’s Safety Follow-up Phone Call, per Regulatory Authorities’ request for end of study clarification.
    20 Sep 2017
    • Phone calls were added 3 months between study site visits during Years 2 and 3. • Optional study site visits were added 3 months between study site visits during Years 2 and 3. • Additional language was added throughout the protocol and within the Study Schema to specify that, at the discretion of the Sponsor, additional subjects who participated in other clinical studies, ISTs, or expanded access/compassionate use treatment programs may be eligible for inclusion in UX007G-CL202. • The window of time to draw blood for UX007 metabolites was expanded from 90 min (± 5 min) to 90 min (± 10 min) following consumption of food and study drug, as specified within Footnote 6 in the Schedule of Events.

    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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